What attracts cells to: pathogens, professional antigen-presenting cells, and cells with an antigen on its MHC-1 protein?

What attracts cells to: pathogens, professional antigen-presenting cells, and cells with an antigen on its MHC-1 protein?

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I have a few questions in regards to attraction/stimulation in the immune system.

  1. What attracts leukocytes and antibodies to pathogens in the first place?
  2. What attracts CD4+ cells to professional antigen-presenting cells (APC)?
  3. What attracts CD8+ cells to cells with an antigen on a MHC-1 protein?
  4. What attracts macrophages to pathogens that have been tagged with antibodies?

Is it just a case of everything bumping into each other and if cells (and antibodies??) bump into chemokines and/or cytokines they will be stimulated (and not attracted) to stay around that area moving to an area of a greater concentration of chemokines and/or cytokines?

That said point 1 can occur without chemokines and/or cytokines (in the case of antibodies, they could be taken/administered by the person). While in case of point 3, (I may be wrong here) but chemokines and/or cytokines may not be present in the case of MHC-1?

What attracts leukocytes and antibodies to pathogens in the first place?

They just bump into them. If secreted antibody is already present in the blood then complement system can be activated.

What attracts CD4+ cells to professional antigen-presenting cells (APC)?

APC release chemokines. All that is known is that this is a CC-type chemokine and signals via CCR4/CCR8 receptors. See this list of articles (from Google Scholar). This study reports a peptide called Chemrin that promotes chemotaxis via ChemR23 receptor.

What attracts CD8+ cells to cells with an antigen on a MHC-1 protein?

CD8+/NK cells are activated by CD4+ cells before they kill their target. The MHC-1+antigenic peptide is just a mark for the cells that are to be attacked, as far as I understand.

What attracts macrophages to pathogens that have been tagged with antibodies?

Complement factors.

NOTE: Many of these concepts are old but still relevant. You should check out recent articles in this area for novel/atypical mechanisms.

MHC Molecules, Antigen Processing and Presentation

  • The Major Histocompatibility complex is a genetic locus that encodes the glycoprotein molecules (transplantation antigens) which are responsible for tissue rejection of grafts between genetically unidentical individuals.
  • It is also the molecule that binds the peptide antigens processed by Antigen-presenting Cells and presents them to T-cells, hence they are responsible for antigen recognition by the T-cell receptors.
  • Unlike the B-cell receptors that directly interact with the antigens, the T-cell receptors have an intertwined relationship with the MHC molecule, in that T-cell receptors can only receive and bind processed antigens in form of peptides that are bound to the MHC molecule, and therefore, T-cell receptors are specific for MHC molecules.
  • In humans, the Major Histocompatibility complex is known as Human Leukocyte Antigen (HLA). There are three common MHC molecules i.e class I, class II, and class III MHC proteins.
  • The genes of the MHC exhibit genetic variability and the MHC has several genes for each class hence it is polygenic.
  • The MHC is also polymorphic, meaning a large number of alleles exist in the population for each of the genes.
  • Therefore, a large number of alleles exist in the population for each of the genes. Each individual inherits a restricted set of alleles from his or her parent. Sets of MHC genes tend to be inherited as a block or haplotype. There are relatively infrequent cross-over events at this locus.
  • The structure of the MHC class I have two domains that are distant from each other, made up of two parallel α helices on top of a platform that is created by a β-pleated sheet. The general structure looks like a cleft whose sides are formed by the α helices and the floor is β-sheet.
  • Generally, the MHC molecules have a broad specificity for peptide antigens and many different peptides can be presented by any given MHC allele binding a single peptide at a time.
  • The α helices forming the binding clefts are the site of the amino acid residues that are polymorphic (varying allelic forms) in MHC proteins, meaning that different alleles can bind and present different peptide antigens. For all these reasons, MHC polymorphism has a major effect on antigen recognition.
  • The function of T-cells on interaction with the MHC molecules reveals that the peptide antigens associated with class I MHC molecules are recognized by CD8+ cytotoxic T-lymphocytes (Tc cells) and MHC class-II associated with peptide antigens that are recognized by CD4+ Helper T-cells (Th cells).

What is MHC Class 1

MHC class 1 refers to one class of major histocompatibility complex molecules found on the surface of all nucleated cells in mammals. MHC class 1 molecule is composed of three alpha domains (alpha 1, alpha 2, and alpha 3) and a single beta domain. Alpha domains are encoded by the chromosome 6 while the beta domain is encoded by chromosome 11. The alpha 3 domain serves as the membrane-spanning domain. The alpha 1 and alpha 2 domains consist of most variable amino acid sequences and antigens are bound to these two domains. The structure of the MHC class 1 molecule is shown in figure 1.

Figure 1: MHC Class 1

MHC class 1 molecules are expressed on almost every nucleated cell in the body. Hence, they present endogenous antigens that originate from the cytoplasm. However, these endogenous antigens can be either self-proteins or foreign protein such as viral proteins produced within the cell. Generally, viral proteins are produced inside animal cells with the help of cellular machinery of the host. Upon presentation on the cell membrane, antigens are recognized by cytotoxic T cells. MHC class 1 molecules are involved in the presentation of antigens that belong to every type of protein produced inside the cell. These antigens are monitored by killer T cells. This identification serves as a part of the surveillance system that destroys over-abundant or unfamiliar antigen presenting cells. Thus, malignant cells, as well as virus-harboring cells, can be destroyed.

What attracts cells to: pathogens, professional antigen-presenting cells, and cells with an antigen on its MHC-1 protein? - Biology

Human leukocyte antigens (HLAs) are an inherent system of alloantigens, which are the products of genes of the major histocompatibility complex (MHC). These genes span a region of approximately 4 centimorgans on the short arm of human chromosome 6 at band p 21.3 and encode the HLA class I and class II antigens, which play a central role in cell-to-cell interaction in the immune system. These antigens interact with the antigen-specific cell surface receptors of T lymphocytes (TCR) thus causing activation of the lymphocytes and the resulting immune response. Class I antigens restrict cytotoxic T-cell (CD8+) function thus killing viral infected targets, while class II antigens are involved in presentation of exogenous antigens to T-helper cells (CD4+) by antigen presenting cells (APC). The APC processes the antigens, and the immunogenic peptide is then presented at the cell surface along with the MHC molecule for recognition by the TCR. Since the MHC molecules play a central role in regulating the immune response, they may have an important role in controlling resistance and susceptibility to diseases. In this review we have highlighted studies conducted to look for an association between HLA and infectious diseases such studies have had a variable degree of success because the pathogenesis of different diseases varies widely, and most diseases have a polygenic etiology.

Major Histocompatibility Complex (MHC) and Immune Response

Because of its remarkable power to deal with infection, the immune system is central to the prevention and control of infectious disease. Immune responsiveness is affected, even controlled, by gene products of the major histocompatibility system (1). Many diseases are associated with human leukocyte antigens (HLAs) (2,3). Moreover, in some infectious diseases (4-6), the host immune reactivity, which is responsible for the pathologic manifestation of disease, has been correlated with HLA specificities.

The discovery of the human MHC dates from the mid 1950s when leukoagglutinating antibodies were found in the sera of patients who received multiple transfusions and in the sera of 20% to 30% of multiparous women. In humans, the entire histocompatibility complex is termed the HLA complex. Genes coding for HLAs occupy a segment of approximately 4 centimorgans on the short arm of chromosome 6. The HLA-A, -B, and -C genetic loci determine class I antigens HLA-DR, -DP, -DQ genetic loci determine class II antigens. Class I antigens are found on virtually every human cell class II antigens are found chiefly on the surfaces of immunocompetent cells, including macrophages/monocytes, resting T lymphocytes, activated T lymphocytes, and particularly B lymphocytes.

The MHC molecule provides a context for the recognition of antigens by T lymphocytes. The polymorphic binding site of MHC class I and class II molecules is composed of a ß-pleated sheet flanked by two alpha helixes. They form a groove that accommodates one single microbial peptide ligand.

MHC class I molecules bind to peptides produced by the intracellular degradation of viral proteins and display them on the cell surface for recognition by CD8+ T lymphocytes. A class of white blood cells, the CD8 T lymphocytes, bear receptors specific for the HLA class I antigens and route pathogens such as viruses. Surface expression of class I MHC molecules depends on the availability of peptides that bind MHC molecules in the endoplasmic reticulum. A peptide transporter, associated with antigen processing (TAP), plays an important role in maintaining adequate levels of peptide (7). The transporter is a heterodimer encoded by two genes, TAP1 and TAP2, located in the MHC class II region. TAP genes belong to the adenosine triphosphate (ATP) binding cassette super family of transport proteins, which have two ATP-binding cassette domains and two transmembrane domains. TAP genes are polymorphic (8), and allelic MHC differences may be associated with disease by altering the peptides that bind class I MHC molecules. Since human TAP genes are located between HLA-DP and HLA-DQ, TAP alleles could result in an apparent disease association with class II HLA alleles. Class I, i.e., HLA-A, -B, and -C molecules, play an important role in viral infections in the lysis of target cells by cytotoxic killer T lymphocytes.

MHC class II molecules are highly polymorphic membrane glycoproteins that bind peptide fragments of proteins and display them for recognition by CD4+ T lymphocytes. The white blood cells known as CD4 T lymphocytes are of central importance in defeating the bacteria and other parasites that live within cells. The CD4 T lymphocytes are called helper T cells because they secrete substances that amplify and control virtually all aspects of immunity. These T cells have receptor molecules that can recognize one particular peptide-HLA class II antigen combination. The binding capability of any given peptide to MHC class II molecules depends on the primary sequence of the peptide and allelic variation of the amino acid residues in the binding site of the MHC receptor. Anchor residues defining allele-specific peptide motifs have been identified in the class II binding peptides. The proposed anchor residues combining with MHC pockets through their side chains seem to be a primary requirement for peptide-MHC interaction. The invariant chain (Ii) plays a critical role in the assembly, intracellular transport, and function of MHC class II molecules (9). In intracellular parasites (e.g., Leishmania infections of macrophages), it is the class II MHC molecules that specifically bind to receptors on these microbes.

HLA Association with Infectious Diseases

Infectious diseases are associated with impaired immunity. Some persons mount very effective immune responses when given vaccines, while others respond to vaccines poorly or not at all. The level of response is determined by several factors: intensity of infection, factors related to the intensity of the host immune response, T-cell state, T-cell function, and perhaps most important, the genetic factor that interacts with the other factors to determine the outcome of the disease. Infectious disease research is now focusing on genetic markers such as allelic forms of HLA molecules.

HLA Association with Mycobacterial Infections

Genetic factors may control host responses to Mycobacterium tuberculosis (10-12). Several investigators have conducted population studies to determine an association between pulmonary tuberculosis (TB) and HLA specificities. HLA-DR2 is associated with the development of multibacillary forms of both TB and leprosy (13,14) molecular subtyping of DR2 showed that the majority of the allele in patients and controls was DRB1*1501 and DRB1*1502. The frequency of these molecular subtypes of DR2 in patients was not skewed, suggesting that the entire DR2 molecule or its closely linked gene(s) may govern patient susceptibility to pulmonary TB and, particularly, to drug-resistant TB. When the three-dimensional structure of the HLA-DR molecule is elucidated (15), sequencing of class II alleles in patients with pulmonary TB and drug-resistant TB could identify an amino acid residue(s) critical for the binding of a M. tuberculosis-derived pathogenic peptide(s) responsible for the detrimental or protective immune response.

HLA alleles also modulate the immune response that determines the form of leprosy (a heterogeneous disease caused by Mycobacterium leprae) that develops in each patient (16,17). At one pole of the spectrum of leprosy are the multibacillary lepromatous leprosy (LL) patients, who are anergic to the antigens of M. leprae, and at the other extreme are the paucibacillary tuberculoid leprosy (TT) patients, who exhibit a good cell-mediated immune response. Humoral immunity is present throughout the spectrum but does not seem to provide protection. Between the two poles are patients with intermediate features as seen in the borderline lepromatous, borderline leprosy (BB), and borderline tuberculoid forms (18). An increased frequency of HLA-DR2 and -DQ1 in LL patients (19) and of HLA-DR3 in TT patients has been reported (20). These antigens can be further subdivided into alleles defined by their amino acid sequence. A single amino acid substitution may give rise to alleles with different immunologic properties. The allele DRB1*1501 showed a stronger association with LL patients than with TT patients (p < 0.00001). In addition, DQB1*0601 was found significantly more often in LL patients than in controls (p < 0.00001) DQA1*0103 was more frequent in the LL group than in the tuberculoid leprosy group and DQA1*0102 was selectively increased in patients with borderline lepromatous leprosy (Table 1). However, DRB1*0701, DQB1*0201, and DQA1*0201 were decreased in LL patients compared with TT patients and controls, and DQB1*0503 was selectively decreased in TT patients, suggesting that these alleles might modulate the immune response that determines the form of leprosy that develops in each patient (21).

HLA Association with Parasitic Infections

Because there are significant differences between malaria-exposed and -unexposed populations in the frequencies of HLA genes at the A and B loci, the HLA complex may protect populations in endemic-disease areas who are exposed to malaria parasites. The adaptative mechanisms may be expressed by HLA-associated genes that control immune responsiveness to malaria antigens. The association between the HLA class I antigen HLA-B53 and protection from severe malaria has been well established (5). This link might be mediated by HLA class I restricted cytotoxic T lymphocytes (CTL) during the liver stage of the parasite's life cycle (22). The protective association between HLA-B53 and severe malaria was investigated by sequencing peptides eluted from this molecule before testing candidate epitopes from preerythrocytic-stage antigens of Plasmodium falciparum in biochemical and cellular assays. Among malaria-immune Africans, HLA-B53 restricted CTL recognized a conserved nonamerpeptide from liver stage-specific antigen, but no HLA-B53 restricted epitopes were identified in antigens from other stages (5). These findings indicate a possible molecular basis for this HLA disease association and support the candidacy of liver stage-specific antigen as a malaria vaccine component.

The association between HLA-DR/-DQ phenotypes and immune response to circumsporozoite protein of the human malaria parasite were investigated in Thai adults (23). Evidence suggests that human T- and B-cell responses to a major P. falciparum antigen (Pf RESA) in persons primed by repeated infections are genetically regulated (24). To associate T-cell and antibody responses with the donors' MHC class II genotypes, genomic HLA class II typing of DQ antigens of leukocytes from 145 donors living in endemic-disease regions of Africa were performed by restriction fragment length polymorphism (24). These data imply that the impact of MHC class II gene products on specific immune responses to Pf 155/ RESA epitopes is weak and hard to demonstrate in outbred human populations naturally primed by infection. The relationship between class II HLA and immune recognition of three candidate antigens for a vaccine against P. falciparum was investigated in persons extremely heterozygous for HLA class II alleles living in an endemic-disease area of West Africa (25). One class II DQA-DQB combination (serologic specificity DQw2) was particularly common among these persons. This haplotype was significantly associated with higher than average levels of antibody to a peptide epitope (EENV)6 of Pf RESA. There was little evidence of association between HLA class II genotype and cellular proliferation responses to the antigen tested.

The frequency of HLAs was studied in 62 patients with scabies and 27 patients with cutaneous leishmaniasis to evaluate the role of HLA antigens as genetic markers in the pathogenesis of these parasitic skin diseases. A significant statistical association was found between HLA-A11 antigen and scabies and between HLA-A11, -B5, and -B7 antigens and diffuse cutaneous leishmaniasis (26). In another study, 24 families with one or more cases of localized cutaneous leishmaniasis from an endemic-disease region with the highest incidence of localized cutaneous leishmaniasis in Venezuela were typed for HLA-A, -B, -C, -DR, and -DQ antigens and complement factors. The parental HLA haplotypes segregated at random among healthy and affected siblings, but in backcross families significantly higher frequencies of HLA-A28, -Bw22 or -DQw8 were present in infected compared with healthy siblings (27). In addition, HLA-B15 showed a higher frequency among healthy siblings. Haplotypes Bw22, DR11, DQw7 were also significantly more frequent in infected than in healthy siblings. No HLA linkage with a putative localized cutaneous leishmaniasis susceptibility gene(s) could be demonstrated in this study (27). A case/control comparison of 26 unrelated localized cutaneous leishmaniasis patients and healthy persons of the same ethnic origin confirmed the association of HLA-Bw22 and DQw3 with this disease. The relative risk reached 12.5 for Bw22 and 4.55 for DQw3. HLA-DQw3 apparently makes the major contribution as a genetic risk factor for localized cutaneous leishmaniasis at the population level. In another study, a statistically significant association was found between HLA-B5 and -DR3 and schistosomiasis (28).

A study of the association of HLA class I antigen frequencies in 52 patients with kala-azar and 222 unrelated healthy controls in Iran found HLA-A26 to be statistically significant (p = 0.004) (29). This indicates a high risk of contracting the disease for HLA-A26 positive persons and a remarkable influence of this antigen on the prevalence rate of kala-azar.

The significance of susceptibility/protection correlations between HLA and parasitic diseases has been established by serologic typing methods. To improve the accuracy of MHC-disease associations, we have used a DNA-based HLA typing method, namely polymerase chain reaction with sequence specific oligonucleotide probes, for the molecular typing of kala-azar patients in India (30). To study the possible association at the molecular level of HLA class I (A and B) as well as class II (DR) antigens in kala-azar patients, we typed patients with kala-azar by polymerase chain reaction with sequence specific oligonucleotide probes and compared the antigen frequencies with healthy family-based controls. On the basis of the distribution of alleles in each sample, percentage phenotype and genotype frequencies were calculated for both control and kala-azar patients. Statistical analysis using the Transmission Disequilibrium Test was carried out to assess the association of different HLA allelic specificities with kala-azar patients. No significant association between any of the HLA class I or class II antigens was found. We will conduct a linkage analysis study based on the data from typing the above-mentioned case/controls. The findings might lead to a new dimension in the study of HLA association with parasitic infections: genetic markers, such as HLA, that are sufficiently polymorphic (as measured by their heterozygosities) can be used in linkage and association analysis to detect Mendelian segregation underlying disease phenotypes (31).

Comprehensive analysis of HLA associations with infectious diseases has allowed precise definition of susceptibility and protective alleles in large populations of different ethnic origins. Of great interest in the fine dissection of molecular mechanisms leading to parasitic diseases, these studies also provide the genetic basis for identification of the subset of persons at risk for subsequent infection. Infectious diseases may have exerted significant pressure on the development and maintenance of HLA polymorphism (32). Widespread and frequently fatal parasitic diseases such as malaria have selectively maintained certain gene frequencies in endemic-disease areas (33).

Although HLA associations with parasitic diseases have provided clues to pathogenesis, the molecular basis of these associations has not yet been defined. The determinant selection hypothesis, which states that associations result from the ability of a particular HLA type to present a critical antigenic peptide, has been difficult to investigate because, for most disease associations, the relevant antigen is unknown. Recently, the identification of characteristic sequence features in peptides eluted from HLA class I molecules (34,35) suggested that the relevant antigen might be identifiable by assessing cellular immune responses to peptides containing such motifs among antigens that are candidates for mediating HLA disease associations. With the development of modern techniques of the HLA assembly assay (36), relevant peptides can be synthesized it can then be determined whether they have any function as CTL epitopes during immune responses. Such studies will elucidate the HLA associations with parasitic infections and the molecular basis of these associations and facilitate the development of vaccines for these infectious diseases.

HLA Association with Viral Infections

The associations of viral diseases with HLA alleles have not been studied extensively. However, mechanisms by which HLA molecules determine the immune response to viral peptides have been well studied as part of efforts to develop safe and efficient virus vaccines. Successful development of vaccines against viral infections depends on the ability of inactivated and live virus vaccines to induce a humoral immune response and produce antiviral neutralization antibodies. Additionally, virus vaccines that induce a cellular immune response leading to the destruction of virus-infected cells by CD8+ CTLs may be needed to provide protection against some viral infections. Antiviral CD8+ CTLs are induced by viral peptides presented within the peptide binding grooves of HLA class I molecules on the surface of infected cells. Studies in the last decade have provided an insight into the presentation of viral peptides by HLA class I molecules to CD8+ T cells.

Herpesvirus saimiri, an oncogenic, lymphotropic, gamma-herpesvirus, transforms human and simian T cells in vitro and causes lymphomas and leukemias in various species of New World primates. An open reading frame of the H. saimiri genome encodes a heavily glycosylated protein that is secreted and binds to heterodimeric MHC class II HLA-DR molecules (37). These results indicate that the open reading frame can function as an immunomodulator that may contribute to the immunopathology of H. saimiri infection.

Cytotoxic T cells that recognize dengue virus peptides have been reported (38). Analysis of HLA class I haplotype-restricted peptides showed that HLA-A2 and -A68 motifs were abundant compared with nonpeptides with HLA-A24, -B8, and -B53 motifs. Studies by Zeng et al. (39) suggest that the T-cell response to dengue virus is restricted by the HLA-DR15 allele. Becker (40) developed an approach to priming antiviral CD8+ CTLs that may provide cellular immune protection from flavivirus infection without inducing the humoral immune response associated with dengue fever shock syndrome. He proposed using synthetic flavivirus peptides with an amino acid motif to fit with the HLA class I peptide binding group of HLA haplotypes prevalent in a given population in an endemic-disease area as an immunogen. These synthetic viral peptides may be introduced into the human skin by using a lotion containing the peptides (Peplotion) and substances capable of enhancing the penetration of these peptides into the skin to reach Langerhans cells. The peptide-treated Langerhans cells, professional antigen presenting cells, may bind the synthetic viral peptides by their HLA class I peptide binding grooves. Antigens carrying Langerhans cells can migrate and induce the cellular immune response in the lymph nodes.

Transmission of human immunodeficiency virus 1 (HIV-1) from an infected woman to her offspring during gestation and delivery is influenced by the infant's MHC class II DRB1 alleles. Forty-six HIV-infected infants and 63 seroreverting infants, born with passively acquired anti-HIV antibodies but not becoming detectably infected, were typed by an automated nucleotide-sequence-based technique (41). One or more DR-13 alleles, including DRB1*1301, 1302, and 1303 were found in 15.2% of those becoming HIV-infected and 31.7% of seroreverting infants (p = 0.048) this association was influenced by ethnicity. Upon examining for other allelic associations, only the DR2 allele DRB1*1501 was associated with seroreversion in Caucasian infants. Among these infants, the DRB1*03011 allele was positively associated with HIV infection.

Molecular mimicry, where structural properties borne by a pathogen "imitate" or "simulate" molecules of the host, also appears to be an important mechanism in the association of HLA molecules with viral disease. Molecular mimicry takes different forms in the molecular biology of HIV-1 (42). Molecular mimicry between HIV envelope proteins and HLA class II molecules may lead to autoimmunity against CD4+ T cell expressing class II molecules (43). Bisset (44) states that both the HIV-1 gp 120 envelope and Mycoplasma genitalium adhesion proteins share an area of significant similarity with the CD4-binding site of the class II MHC proteins. Interaction with this triad could contribute to T-cell dysfunction, T-cell depletion, Th1-cell-Th2-cell shift, B-cell proliferation, hyperglobulinemia, and antigen-presenting cell dysfunction.

HLA-DR has been evaluated as a marker for immune response related to human cytomegalovirus infection (45) this virus plays a role in chronic inflammatory reaction in inflammatory abdominal aortic aneurysm. In the fibrously thickened adventitia of this aneurysm, human cytomegalovirus-infected cells and HLA-DR positive cells were more frequently encountered than in that of atherosclerotic aneurysms and control cases (p < 0.01).

An estimated 250 million people throughout the world are chronically infected with hepatitis B virus, the primary cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma in endemic-disease areas (46,47). Because HLA class I antigens contain viral peptides, they may be important targets for immune mediated hepatocytolysis by CD8+ CTLs in hepatitis B virus infection (48). Davenport et al. (49) have shown that HLA-DR13 is associated with resistance to hepatitis B virus infection. Prognosis may be quite different among patients infected with hepatitis C virus: a chronic liver disease occurs in half the patients, while the other half exhibits no signs of histologic progression of liver damage. The host immune responses may play an important role in such different outcomes. To identify human CTL epitopes in the NS3 region of hepatitis C virus, Kurokohchi et al. (50) modified an approach using recombinant protein and the ability of short peptides to bind to class I MHC molecules. They identified a cytotoxic T-cell epitope presented by HLA-A2 in the hepatitis C virus NS3 region. A study conducted by Peano et al. (51) establishes that HLA-DR5 antigen appears as a protective factor against a severe outcome of hepatitis C virus infection.

Epstein-Barr virus, a member of the herpesvirus family, has been associated with virus replication (infectious mononucleosis, oral hairy leukoplakia) as well as neoplastic conditions such as nasopharyngeal carcinoma, B-cell lymphoma, and Hodgkin disease associated with viral latency. An influence of CTL response on Epstein-Barr virus evolution was first suggested by the finding that virus isolates from highly HLA-A11-positive Asian populations were specifically mutated in two immunodominant A11 restricted CTL epitopes (52). Additionally, B35.01-restricted CTL responses in white donors reproducibly map to a single peptide epitope (53). However, most Epstein-Barr virus isolates from a population where B35.01 was prevalent (in the Gambia) either retained the CTL epitope sequence or carried a mutation that conserved antigenicity changes leading to reduced antigenicity were found in only a minority of cases. Two epitopes for Epstein-Barr virus specific CTLs restricted by the common allele HLA-B7 were identified by Hill et al. (54).

The level of serum HLA class I antigens markedly increases during the course of viral infections such as those caused by cytomegalovirus, hepatitis B virus, hepatitis C virus, HIV-1, and varicella-zoster virus (55-57). During HIV-1 infection, the level of serum HLA class I antigens correlates with disease stage and represents a good prognostic marker of disease progression (55).

HLA Association with Bacterial Infections

Vaccines based on recombinant attenuated bacteria represent a potentially safe and effective immunization strategy. A carrier system was developed by Verjans et al. (58) to analyze in vitro whether foreign T-cell epitopes, inserted in the outer membrane protein PhoE of Escherichia coli and expressed by recombinant bacteria, are efficiently processed and presented through HLA class I and II molecules by infected human macrophages.

A well-defined HLA-B27 restricted cytotoxic T-cell epitope and an HLA-DR53 restricted T-helper epitope of the fusion protein of measles virus were genetically inserted in a surface-exposed region of PhoE, and the chimeric proteins were expressed in E. coli and Salmonella typhimurium. Macrophages infected with recombinant bacteria presented the T-helper epitope to a specific CD4+ T-cell clone but failed to present the CTL epitope to the specific CD8+ T-cell clone. Phagocytic processing of intact bacteria within infected macrophages was essential for antigen presentation by HLA class II. Nascent HLA class II molecules were also required for the presentation of the T-helper epitope to the CD4+ T-cell clone by infected macrophages.

HLA associations may also link various diseases for example the HLA-B27 association for ankylosing spondylitis, Reiter disease, reactive arthropathy, and acute anterior uveitis indicate that these disorders may share a pathogenic pathway. According to the molecular mimicry hypothesis, antigens carried by a particular pathogen may resemble a certain HLA allomorph. As the person carrying this allomorph is unresponsive to it, it is susceptible to the disease caused by the pathogen. For example, some investigators believe that one of the antigens of Klebsiella resembles HLA-B27 and that pathogen is responsible for ankylosing spondylitis (59). In most patients who have an acute attack of anterior uveitis, a common ocular disease characterized by inflammation of the iris and ciliary body, the only clues to the pathogenesis of this disease are its close association with the genetic marker HLA-B27 and the likely triggering role of a variety of gram-negative bacteria (60). HLA-B27 acute anterior uveitis appears to be a distinct clinical entity frequently associated with the seronegative arthropathies, such as ankylosing spondylitis and Reiter syndrome.

Sasazuki (61) showed that low responsiveness to streptococcal cell wall antigen was inherited as an HLA-linked dominant trait. The immune suppression gene for streptococcal cell wall was in strong linkage disequilibrium with particular alleles of the HLA-DQ locus. This shows that the HLA-linked immune suppression genes exist in humans to control low response to natural antigens.

Table 2 lists the associations that have been established between various HLA factors and certain infectious diseases. Only the antigens showing statistically significant associations are indicated. Because some persons are unresponsive to certain critical epitopes of the pathogens presumably responsible for certain infectious diseases, particular HLA alleles occur more frequently in patients with certain infectious diseases than in healthy persons therefore, researchers associate these diseases with certain HLA alleles. This article has summarized the findings from population genetic analysis and from studies of the association of immune response mechanisms of infectious diseases and HLA.

Dr. Singh is a scientist in the Department of Biochemistry, Central Drug Research Institute, Lucknow. Her research interest is visceral leishmaniasis, or kala-azar, as it is known in eastern India, where the disease is now epidemic. She is developing PCR-based diagnostics for the disease focusing on kinetoplast DNA, studying the molecular mechanisms of drug resistance, and striving to answer the most important question: are host genetic factors, like HLA, involved in susceptibility to kala-azar in India.

Endocytic Receptors Involved in Uptake of Viruses by DC

Being intracellular parasites, viruses use the host machinery for internalization, proliferation, and transmission. DC are attractive target cells for viral entry because they express numerous receptors at their cell surface and they migrate through the body, which facilitates viral dissemination. Viruses can enter DC via docking with their viral envelop to endocytic receptors expressed at the cell membrane (43, 44, 46). A commonly described receptor used by viruses to enter DC is DC-specific C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN/CD209). DC-SIGN is involved in the infection of moDC by DV (32, 65), HCMV (28), HSV (66), MV (67), and IAV (68) and also in DC-mediated transmission of HIV-1 (69) and HTLV-1 (70) to CD4 + T cells. DC-SIGN is part of the large family of C-type lectin receptors (CLR), comprising Ca 2+ -dependent receptors that each have unique functions but share the recognition of carbohydrate structures present on micro-organisms (71). Other CLR family members involved in interaction with viruses include Langerin (CD207), involved in the interaction with MV and HIV-1 (25, 41), DC immunoreceptor (DCIR) (72), proposed as an alternative receptor for HIV-1 promoting infection in cis and trans and macrophage mannose receptor (MMR/CD206), possibly involved in uptake of HBsAg by liver BDCA1 + DC (73). Also non-CLR can be involved in the interaction with viruses or VLP. DC-specific heparin sulfate proteoglycan Syndecan-3 cooperates together with DC-SIGN to facilitate infection of DC and transmission to CD4 + T cells (74) and is involved in the interaction with HPV VLP (75). Since expression of endocytic receptors varies widely between DC subsets (Table ​ (Table1), 1 ), the different subsets will likely have specialized roles in the interaction with different viruses, determined by the combination of receptors expressed on each DC subset.

Table 1

Summary of receptors that are involved in DC–virus interaction on different DC subsets.

FamilyNameBDCA1 + mDCBDCA3 + mDCpDCEpidermal LCDermal intDCmoDCReference
C-type lectin receptorsDEC-205 (CD205)+++++MacDonald et al. (76), Ebner et al. (77)
DCIR (CLEC4A)+++++Bates et al. (78), Lambotin et al. (79), Eklöw et al. (80), Klechevsky et al. (81)
MMR (CD206)±+++Chatterjee et al. (82), MacDonald et al. (76), Lambotin et al. (79)
DC-SIGN (CD209)++Turville et al. (83), MacDonald et al. (76)
CLEC9A (DNGR1)+Huysamen et al. (84)
Langerin (CD207)+Turville et al. (83), MacDonald et al. (76)
Toll-like receptors1++++++Kadowaki et al. (5), Jongbloed et al. (9), Lambotin et al. (79)
Fcγ receptorsFcγRI (CD64)+nfnfnf±Flinsenberg et al. (85)
FcγRIIA (CD32)+++nfnf+Flinsenberg et al. (85), Tel et al. (86)
FcγRIII (CD16)nfnfFlinsenberg et al. (85)
Complement receptorsCR4 (CD11c)+++++MacDonald et al. (76), Lambotin et al. (79)
CR3 (CD11b)±±++Donaghy et al. (87), Lui et al. (88), Poulin et al. (21)
Heparan sulfate proteoglycanSyndecan-3nfnfnfnfnf+de Witte et al. (74)
Chemokine receptorXCR1+Crozat et al. (89), Bachem et al. (90)

pDC, plasmacytoid DC LC, Langerhans cell intDC, interstitial DC moDC, monocyte-derived DC nf, information not found.

Are these CLRs only involved in supporting viruses to enter the host or did they evolve to support activation of the host’s immune system through antigen presentation? Langerin is an important receptor for interaction with pathogens in the skin and has been shown to support antigen presentation in MHC class II, but its role in MHC class I-mediated antigen presentation is under debate (25). Moris et al. showed that blocking of DC-SIGN partly reduced MHC class I presentation of internalized HIV-1 by DC, arguing in favor of a role of DC-SIGN in cross-presentation of HIV-1 (91). In contrast, Sabado et al. showed that blocking of DC-SIGN, DEC-205 (CD205), or MR did not reduce MHC class I presentation of HIV-1 antigens (46) whereas Tjomsland and colleagues showed that blockade of MR even promoted cross-presentation of HIV-1 by DC (92). Thus, the physiological role of DC-SIGN in cross-presentation of HIV-1 is thus far inconclusive, which may be explained by differences in experimental set-up such as the HIV-1 strain used. Antibody-mediated delivery of antigen to the CLRs MR, DEC-205 (82), DCIR (81), DC-SIGN (93), and CLEC9A (94) (Table ​ (Table1) 1 ) on human DCs facilitates efficient cross-presentation. These examples show that CLR can facilitate cross-presentation, however, the physiological role of these receptors in cross-presentation of viral antigens is still under debate.

Whereas CLR can directly recognize viral envelop antigens, complement receptors and Fc receptors (FcR) selectively recognize viral antigens that are opsonized with complement and immunoglobulins, respectively. Antigen immune complexes naturally exist and are formed when pre-existing antibodies bind to blood-borne antigens in the circulation, for example, during HCMV re-infection (85). Binding of immune complexes to Fcγ receptor (FcγR) on DC leads to efficient cross-presentation in MHC class I (85). Strikingly, the observation that FcR-dependent uptake of HBsAg can enhance activation of HBV-specific CTL was made years before the concept of cross-presentation by DC was recognized (95), indicating that opsonization of viral antigens may be important for generating virus-specific CTL. Similarly, opsonization of antigen by complement can efficiently enhance cross-presentation, as was recently demonstrated for HIV-1 by targeting HIV-1 particles to CR3 (92). In addition, although not classically referred to as opsonization, binding of high-density lipoprotein (HDL) to HCV VLP supported efficient Scavenger receptor B-mediated uptake and cross-presentation (96). A similar role for extracellular heat-shock proteins (HSP) has been proposed [reviewed by Ref. (97)], mainly based on mouse studies in the field of cancer immunotherapy. However, the role of HSP in cross-presentation of viral antigens by human DC remains to be investigated.

Although these results indicate that several endocytic receptors may be involved in facilitating cross-presentation, their exact role needs to be determined. Especially recognition of viral antigens by opsonins seems to be an effective way of natural antigen targeting to DC for cross-presentation. Increased knowledge on the receptors used by viruses for infection on the one hand and the receptors that facilitate cross-presentation on the other hand may be of great value for therapeutic interventions.

What is the role of MHC in the immune response?

Lot more interesting detail can be read here. Similarly, it is asked, what is the function of MHC I?

The epitope peptide is bound on extracellular parts of the class I MHC molecule. Thus, the function of the class I MHC is to display intracellular proteins to cytotoxic T cells (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in a process known as cross-presentation.

Additionally, what does MHC stand for? major histocompatibility complex

Accordingly, what are the functions of MHC I and MHC II?

MHC Genes and Functions:

MHC Class I MHC Class II
End Result Presentation of foreign-intracellular antigens or altered self-antigens targets cell for destruction Presentation of foreign extracellular antigens induces antibody production, and attracts immune cells to area of infection

The major histocompatibility complex (MHC) genes code for proteins which the immune system uses to identify cells and tissues in the body as &ldquoself&rdquo or &ldquoother&rdquo. It presents snippets of information (peptides) on the state of the cell- allowing the immune system to check for infection, cancer, and other maladies.


Presentation of lipid antigens by primary lung epithelial cells

We have previously shown that the LA-4 cells (a mouse lung alveolar epithelial cell line) could present αGC lipid moiety through the CD1d pathway in vitro [26]. We demonstrated this by using previously described αGC-CD1d model system of Yu et al. [31]. The model is based on specific recognition of αGC bound to CD1d molecule by the L363 antibody. The capacity of primary lung epithelial cells to present lipid antigens was however not demonstrated. In the present study, we used the αGC-CD1d model to assess the ability of PLE cells to present αGC lipid moiety through the CD1d pathway. Freshly isolated PLE cells from mouse lungs comprise a mixture of type I (podoplanin + CD74 - ) and type II (podoplanin - CD74 + ) epithelial cells. In cell culture, however, type II cells are lost and the surviving cells are essentially of type I by day 3 to 4 of culture [32,33]. PLE cells cultured for 3 days were used to assess αGC presentation. Fresh BAL cells, that essentially comprise alveolar macrophages, were also used in this study. Results in Fig 1 show that about 21.6% of the PLE cells pre-incubated with αGC were stained with L363 antibody, whereas only background staining was observed if αGC pre-incubation step was omitted. In BAL cells 68.2% cells were stained with L363 antibody. These results indicate that PLE cells, as well as BAL cells, had the ability to present αGC lipid through CD1d pathway but BAL cells were relatively more efficient presenters of the lipid antigen.

CD1d mediated antigen presentation of αGC by PLE and BAL cells were assayed by flow cytometry. 8x10 5 cells were cultured overnight (for BAL cells) or for 3 days (for PLE cells) in 24 well plate and then incubated with 25 nM αGC lipid for 24 h at 37°C. Cells were washed, blocked by Fc block antibody followed by staining with isotype control or L363 antibody. Representative dot plots from 3 separate experiments with mean percent positive values ± SEM are shown. *p < 0.05 for significant difference.

Internalization of BCG by PLE cells in culture

Owing to its anatomical location, lung epithelial cells lining alveoli as well as BAL cells present in the alveoli are exposed to air-borne pathogens entering the lungs [34,35]. Therefore, next, we examined the interaction of Mycobacterium bovis BCG with PLE and BAL cells. For this purpose, live BCG tagged with the fluorescent dye CFSE were incubated with PLE and BAL cells to study the uptake of BCG by these cells. Labeling of BCG by CFSE was found to be more than 98.8% (Fig 2A). Our uptake studies showed that 68% of the PLE cells incubated with fluoresceinated BCG were positive for BCG intake (Fig 2B, left panel) whereas 92.5% of the BAL cells were positive for BCG uptake (Fig 2B, right panel). Confocal microscopic examination and Z-sectioning further indicated that BCG was internalized by both PLE cells as well as BAL cells (Fig 2C & 2D respectively).

Panel A shows the labelling of BCG with CFSE where more than 98% of BCG cells were labelled with the fluorescent dye (filled histogram—unlabeled BCG, open histogram CFSE labelled BCG). PLE and BAL cells were cultured with CFSE labelled BCG for 24 h (MOI 100:1) to study BCG uptake. Flow histograms in Panel B show the uptake of labelled BCG by PLE and BAL cells (filled histogram–control cells, open histograms–cells incubated with CFSE labelled BCG). Values for mean + SEM (3 experiments) of BCG positive cells are given within the histograms. Confocal microscopy and Z-sectioning to demonstrate intracellular BCG in PLE and BAL cells are shown in panels C and D respectively.

Up-regulation of molecules involved in CD1d lipid antigen presentation in BCG infected PLE and BAL cells

The ability of PLE and BAL cells to present αGC lipid (Fig 1) was an indirect proof of the expression of CD1d molecule on these cells. We also examined directly the expression of CD1d and its modulation by BCG infection on PLE and BAL cells. PLE cells were found to express significant levels of CD1d molecule that was boosted 2 folds in BCG infected PLE cells (Fig 3). Similarly, significant up-regulation of CD1d (28% as compared to the basal expression) was also observed on BAL cells (Fig 3). Expression of some select crucial molecules like CD1d, MTTP, Saposin and SR-B1 involved in the uptake of lipid antigen and their processing was also examined on PLE and BAL cells by using quantitative real-time PCR. The relative quantitation values showed significant up-regulation for these molecules in PLE as well as BAL cells exposed to BCG (Fig 4).

PLE and BAL cells were incubated with or without BCG (MOI 100:1 for 24 h) and CD1d expression were examined as described in Materials and Methods. Values in each panel indicate mean percent CD1d positive cells + SEM. *p < 0.05 for significant up-regulation of CD1d expression upon BCG infection.

Quantitative RT-PCR was performed as described in Materials and methods in presence or absence of BCG infection (MOI 100:1 for 24 h). Closed bars represent the relative expression values for the 4 selected markers, for control, PLE (Panel A) or BAL (Panel B) cells, and open bars represent the corresponding relative expression values for BCG infected cells. Each bar graph is a representative of at least 3 independent experiments and the values shown represent the mean relative expression + SEM normalized to GAPDH control. *p < 0.05 for significant up-regulation of mRNA expression upon BCG infection.

In situ expression of CD1d on lung epithelial cells

While we were able to confirm the expression of CD1d molecule on PLE cells in culture, it was necessary to confirm whether CD1d is expressed in situ on lung epithelial cells. In lung sections stained with HE, the structure of the alveolus along with the epithelial cells lining the alveoli could be identified (Fig 5A–5D). To visualize the in situ expression of CD1d molecules on lung epithelial cells, IHC of the lung sections was carried out using a monoclonal anti-mouse CD1d antibody. An isotype control and a ‘no CD1d primary antibody’ was used as the experimental controls (Fig 5E & 5F). CD1d expression on the cells lining the alveolus could be clearly seen (Fig 5G–5J). In order to see if BCG infection modulates the CD1d expression, mice were administered BCG through intra-tracheal route. Results of HE staining of BCG infected lungs showed inflammatory changes and formation of granulomas (Fig 5B & 5D). Results in Fig 5J shows that the expression of CD1d on lung epithelial cells was up-regulated in lungs from BCG infected mice through random blind scoring method.

In situ expression of CD1d on the cells of the lung was studied by IHC as described in Materials and Methods. Panels A-D shows the HE staining of control and infected lungs. Left panels show control lungs at 10 and 40X magnifications. Right panels similarly show BCG infected lungs. Panels G-J shows the immunohistochemical (IHC) staining for CD1d staining in similar order. Panel E & F are the experimental controls for IHC using isotype control or “no CD1d primary antibody’. Within figure letters denote—Alveolar Space (AS), Terminal bronchiole (BL), lymphocyte-rich granuloma (Lyo’s), Arrows in panels I and J (←) indicate CD1d expression. Each image shown is a representative of at least 3 independent experiments.

What is MHC I?

MHC Class I molecules are present on cell surfaces of all nucleated cells and are one of the main two classes of MHC molecules. These molecules don’t occur in red blood cells but are present in platelets. MHC Class I molecules detect protein fragments from nonself proteins within the cell. These protein fragments are known as antigens. Nonself antigens detected by MHC I molecules are situated on Tc cells. Tc cells possess coreceptor molecules, CD8. MHC I molecules which present antigens on CD8 receptors that will initiate an immunological response.

Figure 01: MHC I

Since the peptides present on MHC Class I molecules are derived from cytosolic proteins, the antigen presentation pathway of these molecules is referred as endogenous (cytosolic) pathway. MHC Class I molecules are composed of two nonidentical chains, long alpha chain, and one short beta chain. They are encoded by human leukocyte antigen genes (HLA) HLA-A, HLA-B, and HLA-C. Alpha chain is coded on the locus of MHC in chromosome 6 and beta chain is encoded on chromosome 15.

MHC I molecules function as a messenger in displaying intracellular proteins to Tc cells to prevent immunological responses directed upon host’s own cells. When intracellular proteins degrade by the proteasome, peptide particles bind to MHC I molecules. These peptide particles are known as epitopes. The MHC Class I protein complex is presented into the external plasma membrane of the cell via the endoplasmic reticulum. Afterwards, the epitopes get bound on extracellular surfaces of MHC I molecules. Due to this process, Tc cells will not be activated in response to self-antigens. This is known as T cell tolerance (Central and peripheral tolerance). MHC Class I proteins are capable of presenting exogenous antigens derived from various pathogens. This is known as cross-presentation. During such conditions, when a foreign antigen is presented on Tc cells by MHC I molecules, immunological responses will be initiated.

Antigen presentation steps

. There is also an interaction between the CD8+ molecule on the surface of the T cell and non-peptide binding regions on the MHC class I molecule Antigen presentation is essential for development of a robust immune response. Binding of an MHC-peptide complex by a T cell receptor is the initial and critical step for starting a new adaptive immune response or for regulating an ongoing one

These proteins target MHC class I antigen presentation at all steps of the pathway, ensuring that viral peptides are no longer displayed for CD8 + T-cell recognition. As such, the major effectors of adaptive immunity can no longer detect infected cells. Specific examples of how viruses subvert MHCI antigen presentation will be discussed Antigen presentation consists of the internalization of antigen by pinocytosis, followed by degradation and re-expression of the peptides in close association with class II MHC molecules. Such peptides are recognized by class II restricted lymphocytes bearing T cell receptors, i.e. the response of these lymphocytes is restricted to when they are stimulated by antigen borne by cells bearing class II (HLA DR) markers . Antigen presentation is the process by which certain cell in the body especially antigen presenting cells (APCs) express. If antigen.

Antigen processing consists of ingestion and partial digestion of the antigen by the APC, followed by presentation of fragments on the cell surface. (From Rosen et al., Dictionary of Immunology, 1989 . T-celler har ingen aning om vad som sker i deras omgivning, de måste ha en annan cell som presenterar ett antigen åt dem. Det är den dendritiska cellen som gör det. En dendritisk cell känner igen ett Pothegen Associated Molecular Patterns (PAMP) genom sin Toll Like Receptor (TLR) Antigen presentation is one aspect of the immune response. In it, cells of the body digest foreign proteins or antigens into small peptides and express them on their surface. These peptides are embedded in the cell membrane and are presented to other cells that can generate an immune response Antigen Processing & Presentation Foreign protein antigen are degraded into small antigenic peptides that form complexes with class I or class II MHC molecules. This conversion of proteins into MHC-associated peptide fragments is called antigen processing and presentation. Whether a particular antigen will be processed and presented together with class I MHC or class II MHC molecules appears to be determined by the route that the antigen takes to enter a cell

Presentation of antigen on Class I molecules. Requires intracellular protein synthesis of the endogenous antigen They are degraded in the proteasome the active part is the 20S component some are regulated with 19S regulator lid (26S proteasome is the whole thing) The 19S lid recognizes ubiquitin which is the degradation signal in the cell Antigen Presentation First Group: Exogenous antigens. Exogenous antigens (inhaled, ingested, or injected) are taken up by antigen-presenting. Second Group: Endogenous antigens. Here they may be recognized by CD8+ T cells . Most CD8 + T cells are cytotoxic. They. The Class I Pathway. Class I. Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes.It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens (e.g. viruses), or. Antigen Presentation T cells recognize foreign antigens in the form of short peptides that have been processed and dis-played on the cell surface bound to MHC-I or MHC-II molecules (Figure 5). Antigens are often categorized according to whether they are derived from (1) viruses, intracellular bacteria, or protozoan parasites (endogenous pathogens) or (2) exogenous pathogens that replicate.

The cell begins the process by the exogenous pathway but ends up diverting the antigens to the endogenous pathway this allows the cell to skip some of the steps along the exogenous pathway. As the exogenous pathway can involve infection before presenting the antigens, the cross-presentation allows dendritic cells to process and present antigens without being infected 1. Binding and uptake of the antigen 2. Antigen processing onto MHC 3. Antigen presentation to T cel T cells can only recognise antigens when they are displayed on cell surfaces. This is carried out by Antigen-presenting cells (APCs), the most important of which are dendritic cells, B cells and macrophages. APCs can digest proteins they encounter and display peptide fragments from them on their surfaces for another immune cell to recognise

Antigen Processing and Presentation British Society for

  1. Antigen Processing Pathways: Feature: MHC Class I: MHC Class II: Function: Allow for sampling of intracellular antigens Signal that a cell is infected or abnormal Allow for sampling of extracellular antigens Signal that pathogens are within the host Target cell: CD8+ killer T-cells Rule of 8: (MHC) 1 x (CD) 8 = 8 CD4+ helper T-cells Rule of 8: (MHC) 2 x (CD) 4 =
  2. Antigen processing or cytosolic' pathway is an immunological process that prepares antigens for presentation to special cells of the immune system called T l..
  3. g Cellular and Molecular Immunology 8th Ed
  4. This Review discusses how antigenpresentation, which is crucial for the success of this therapy, Tumours exploit multiple escape mechanisms to evade immune recognition at both of these steps
  5. g 2) peptide transport 3) assembly of the MHC class I loading complex and 4) antigen presentation ( 11-15 ) ( Figure 2 )

Antigen Presentation - A critical step for development of

  1. Please check out other IMMUNOLOGY videos on this channel:
  2. Antigen Presentation in TLOs. We have recently extensively studied antigen presentation in ATLOs , by using the Eα-GFP/Y-Ae system to visualize antigen uptake through a GFP tag and tracking of Eα peptide/MHC-II presentation using a commercially available (Y-Ae) Ab (73-75)
  3. Cross-Presentation: Transferring Exogenous Antigens to the Class I Pathway. Cross-presentation is the transferring of extracellular antigens like bacteria, some tumor antigens, and antigens in cells infected by viruses into the class I pathway for stimulation of CD8 + cytotoxic T cells (CTL). Only certain professional antigen-presenting cells (APCs) like dendritic cells can do this - use the.
  4. While antigen presentation is the process that accessory cells present MHC class II molecule/antigen complexes to helper T cells and make them bind with T cell receptors, which is a necessary step.
  5. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome (b) the synthesis of MHC class II (i.e. HLA-D associated) alpha, beta, and invariant (Ii) chains in the endoplasmic reticulum (c) the initial association of alpha-Ii and beta-Ii chains.

Antigen Presentation - an overview ScienceDirect Topic

  1. The first step of peptide selection in antigen presentation by MHC class I molecules Malgorzata A. Garstkaa, Alexander Fishb, Patrick H. N. Celieb, Robbie P. Joostenb, George M. C. Janssenc, Ilana Berlina, Rieuwert Hoppes a, Magda Stadnik b, Lennert Janssen , Huib Ovaaa, Peter A. van Veelenc, Anastassis Perrakis , and Jacques Neefjesa,1 Departments of aCell Biology and bBiochemistry.
  2. Antigen presentation broadly consists of pathogen recognition, phagocytosis of the pathogen or its molecular components, processing of the antigen, and then the presentation of the antigen to naive (mature but not yet activated) T cells
  3. Presentation of Superantigens. Superantigens are antigens that can polyclonally activate T cells (see antigens) to produce large quantities of cytokines that can have pathological effects. These antigens must be presented to T cells in association with class II MHC molecules but the antigen does not need to be processed
  4. antigen presentation through mhc molecules can be summarised into four steps adhesion, antigen-specific activation, co- stimulaion ad cytokine signalling. all these signals results in te successful activation, proliferation and differentiation of t-cells. related papers
  5. Antigen Presentation: T and B Cell Differentiation By Carol Parent-Paulson. This learning object demonstrates the process by which antigens are identified, processed, and presented to mediators of the cellular immune system
  6. The basic cell biology of antigen presentation is now broadly understood, and the focus of interest is shifting to modulations of the basic process that may answer broader biological questions about how the T-cell repertoire is selected in the thymus and modified by specialized antigen-presenting cells in the lymph nodes

Antigen Presentation - A Critical Step for Development of Immune Therapies, Upcoming Webinar Hosted by Xtalks Share Article In this free webinar, you will learn how a robust and industrialized mass spectrometry platform is used to directly observe and investigate MHC-presented and physiologically relevant peptides Antigen Processing and Presentation. Antigen processing and presentation is the process of digestion of antigens into smaller peptide fragments by an antigen-presenting cell (APCs) that are then displayed on the surface of the cells via antigen-presenting molecules like MHC class I and II for recognition by lymphocytes.. Antigen processing and presentation can occur via three different pathways Antigen presentation is a subject most often considered at the molecular level, but its results are, of course, also relevant to the whole organism. This compilation of chapters from experts is aimed at reviewing the broad spectrum from molecular, biochemical and pharmacological considerations through to the effects on host immunity and the diseases which result from defects in these pathways meanwhile, antigen presentation takes place with the activation of specific T helper cells CD4 helper T cells then co-ordinate a targeted antigen-specific immune response involving two adaptive cell systems: humoral immunity from B cells and antibodies, and cell-mediated immunity from cytotoxic CD8 T cells Let's start at the very beginning

Restoring antigen presentation: the first step on the road to complete immune restoration. Konlee M. AIDS: Successful restoration of the immune system and eradication of any chronic infection, possibly including cancer, requires the ability of healthy cells to process and present foreign antigens on the cell's surface We earlier developed a method to evaluate antigen presentation based on presentation of the cognate CMV pp65 antigen for which detectable memory T-cell responses are common in healthy CMV-seropositive blood donors. 37-39 We used this method to assess whether neutrophils are capable of presenting antigens to T cells in a side-by-side comparison with monocyte and DC subsets Non-peptide antigen presentation to T-cell receptors on NKT cells, marks T-cells at the short cortical thymic stage of differentiation. CD1b-Cortical thymocytes, Langerhans cells and dendritic cells. Non peptide antigen presentation to T-cell receptors on NKT cells. CD1c-Cortical thymocytes, Langerhans cells, dendritic cells and B-cell subsets In contrary, whole cell antigen presentation provides an easier alternative to keep membrane protein antigens in their native membrane environment with correct, stable, and functional foldings. No need for tedious purification, reconstitution steps

Antigen processing and presentation: Cytosolic and

  • The data concerning CD1 antigen presentation point out the existence of a third pathway for the processing of antigens, a pathway with distinct intracellular steps that do not involve the molecules found to facilitate class I antigen processing. For example, CD1 molecules are able to process antigen in TAP-deficient cells
  • Antigen Presentation by B Cells in Multiple Sclerosis N Engl J Med. 2021 Jan 28384(4):378-381. doi: 10.1056/NEJMcibr2032177. Authors Scott S Zamvil 1 , Stephen L Hauser 1 Affiliation 1 From the UCSF Weill Institute for.
  • The PCR tests takes at least 24 hours to get results and the antigen test has a slightly higher degree of providing false negative tests. But there are positives for using the antigen test
  • g in the proteasome 2) peptide transport 3) assembly of the MHC class loading complex in the endoplasmic reticulum (ER) and 4) antigen presentation on cell surface (Leone et al., 2013)
  • Antigen presentation consists of pathogen recognition, phagocytosis of the pathogen or its molecular components, processing of the antigen, and then presentation of the antigen to naive T cells. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the major histocompatibility complex (MHC), also known in humans as human leukocyte.

Dendritic cells (DCs) have the unique ability to pick up dead cells carrying antigens in tissue and migrate to the lymph nodes where they can cross-present cell-associated antigens by MHC class I to CD8+ T cells. There is strong in vivo evidence that the mouse XCR1+ DCs subset acts as a key player in this process. The intracellular processes underlying cross-presentation remain controversial. Antigen Presentation - A critical step for development of immune therapies. Accueil > Ressources > Webinaire (anglais): Antigen Presentation - A critical step for development of immune therapies. Retourner à la liste Prochain article Article précédent. June 10, 2020. In this webinar you will learn Are you studying antigen processing and presentation? STEMCELL has partnered with Nature Reviews Immunology to bring you this valuable reference. Provides an updated overview of intracellular pathways and mechanisms by which antigens are captured, processed and loaded onto MHC class I, class II and CD1d molecules for presentation to T cells Antigenpresenterande cell (APC), cell som presenterar ett antigen för en annan cell. Detta leder till en aktivering av den andra cellen. Exempel på antigenpresenterande celler är B-lymfocyter, makrofager och dendritiska celler.. Presentationen av antigen sker på MHC-molekyler i cellens yttermembran, molekyler som hos människan kallas för HLA-antigen The pathway is denoted cross‐presentation and plays a key role in cancer immunosurveillance, as well as in immune responses against infections and transplants. 2, 6, 40-42 Two main pathways for antigen‐processing and presentation on MHC class I molecules have been suggested for cross‐presentation, that is the phagosomal‐to‐cytosol pathway and the vacuolar pathway. 6, 7, 43 In the.

Antigen Presentation - Svensk MeS

  • Dose-dependent induction of murine Th1/Th2 responses to sheep red blood cells occurs in two steps: antigen presentation during second encounter is decisive. Claudia Stamm Center for Structural and Cell Biology in Medicine, Institute of Anatomy, University of Lübeck, Lübeck, Germany
  • MHC class I molecules select and present a limited set of peptides from a broad repertoire provided by TAP. How MHC class I makes this selection is unclear. We show that MHC class I H-2Kb molecules initially bind many peptides because of highly flexible binding pockets. Peptide binding is followed by a selection step wherein a large fraction of these peptides is released, leaving the canonical.
  • Unlike T cells that recognize digested peptides, B cells recognize their cognate antigen in its native form. The B cell receptor used in recognition can also be secreted to bind to antigens and initiate multiple effector functions such as phagocytosis, complement activation, or neutralization of receptors. While B cells can interact with soluble antigens, it is now clear that the presentation.
  • Note: Antigen tests can be used in a variety of testing strategies to respond to the coronavirus disease 2019 (COVID-19) pandemic. This interim guidance is intended for clinicians who order antigen tests, receive antigen test results, and perform point-of-care testing, as well as for laboratory professionals who perform antigen testing in a laboratory setting or at the point of care and report.
  • Professional antigen presenting cells (APCs) are immune cells that specialize in presenting an antigen to a T-cell. The main types of professional APCs are dendritic cells (DC), macrophages, and B cells. A professional APC takes up an antigen, processes it, and returns part of it to its surface, along with a class II major histocompatibility complex (MHC)

Antigenpresentation - Biomedicinsk Analytike

Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen. Question: Question 7 2 Pts Choose The False Statement: • After Antigen Presentation And Recognition, The Next Step To Both Humoral And Cellular Immunity Is The Many Divisions Or Clonal Expansion Of A Lymphocyte. Select) • B Lymphocytes Take Up Antigen Using Their Antibody And Present That Antigen On MHC Upon Recognition, These B Cells Will Cause Clonal Expansion. Antigen Presentation and Processing. The T cells can recognize the foreign antigen when the antigen is attached to the MHC molecules as an MHC peptide complex. The formation of the MHC-peptide complex requires the degradation of protein antigen by several steps. The degradation process is known as antigen processing Download this Premium Vector about Covid testing infographic template. rapid antigen, antibody testing presentation design elements. data visualization with three steps. process timeline chart. workflow layout with linear icons, and discover more than 12 Million Professional Graphic Resources on Freepi antigen processing and presentation by antigen presenting cells that . display antigens as peptides bound to MHC migrate to draining lymph nodes specific binding of the T-cell receptor to the antigen concurrently with. binding of CD4 coreceptors to MHC class II in helper T-cells binding of CD8 coreceptors to MHC class I in killer T-cell

What is Antigen Presentation? (with picture

Antigen Presentation and Autoimmune Disease Nelfinavir) can inhibit this initial Ii cleavage step with varying efficiency. Impairment of this step is intuitively detrimental to normal immune function. Currently, we are developing an immunoprecipitation assay aimed at detecting Ii in healthy white blood cells First, the larger pore size induced stronger cross-presentation of the antigen, the last step in the DUMP cascade, as shown studies of DC2.4 cells in vitro . Second, our results showed that MSNs with larger pores degraded faster in the lymph nodes, which may result in faster release of OVA inside the lymph nodes, providing stronger exposure of antigen to DCs (fig. S7) Dose-Dependent Induction of Murine Th1/Th2 Responses to Sheep Red Blood Cells Occurs in Two Steps: Antigen Presentation during Second Encounter Is Decisive. Claudia Stamm, Julia Barthelmann, Natalia Kunz, Kai-Michael Toellner, Jürgen Westermann, Kathrin Kalie This latter data type incorporates information not only related to the peptide-MHC binding event, but also information about prior steps in the biological antigen presentation pathway processes. However, except for genetically engineered cells, cellular MHC expression profile is very diverse due to the multiple MHC allelic variants The three of us were fortunate to have lived through this era as young immunologists, awestruck by each new paper that modified our view of antigen presentation. In this special issue of Immunogenetics, we take you from Jan Klein's 1986 history chapter entitled The Story to the modern-day perspectives of antigen processing and presentation

Antigen processing and presentation - SlideShar

Abstract Class I and class II MHC molecules bind peptides during their biosynthetic maturation and provide a continuously updated display of intracellular and environmental protein composition, respectively, for scrutiny by T cells. Receptor-mediated endocytosis, phagocytosis, and macropinocytosis all contribute to antigen uptake by class II MHC-positive antigen-presenting cells. Capture of. Describe the six steps in antigen processing and presentation via the class I MHC restricted pathway. Answer. Topics. No Related Subtopics. Molecular Cell Biology 7th. Chapter 23. Immunology Discussion. You must be signed in to discuss. Top Educators. Recommended Videos. 00:32

History. The principles of IHC have been known since the 1930s, but it was not until 1942 that the first IHC study was reported. Coons et al. (1942) used FITC-labeled antibodies to identify Pneumococcal antigens in infected tissue.Since then, major improvements have been made in tissue fixation and sectioning methods, antigen/epitope retrieval, antibody conjugation, immunostaining methods and. Background Knowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches. Methods Original articles covering antigen processing and presentation, epitope.

We show on the molecular level that activated rat hepatic stellate cells express the class II transactivator, the invariant chain (CD74), the MHC class II molecules, as well as cathepsin S, all of which are known to be responsible for the initial steps of successful antigen presentation The key difference between endogenous and exogenous antigens is that the endogenous antigen is generated within the cells while the exogenous antigen enters the body from the outside.. Antigen is a molecule or a substance that reacts to a product of a specific immune response and stimulates antibody generation. Antigenicity of that particular molecule is the ability of an antigen to induce. In this context, several cytoplasmic chaperones form cascaded machinery that accompanies and transmits self-antigens step by step for MHC class II presentation. As a chaperone, heat shock cognate protein 70 (HSC70) is required for vesicle formation and clathrin uncoating during clathrin-mediated endocytosis (8, 9) Endogenous Antigens. Let's pretend your community has been invaded by zombies. You and everyone else in the village bands together to fight them

Presentation of a prototype lipid antigen α-Galactosylceramide (αGC) was examined on primary epithelial cells derived from mouse lungs and on bronchoalveolar lavage (BAL) cells that essentially comprise alveolar macrophages. Presence of CD1d molecules coupled to αGC was demonstrated on both types of cells pre-treated with αGC, suggesting that both cell types are equipped to present lipid. Many immunotherapies for cancer have emerged in recent years, but none are universally effective. One potential problem is the loss of interferon signaling in tumors, which impairs the effectiveness of both immune checkpoint blockade and cell-based therapies. Kalbasi et al. determined that both JAK1 and JAK2 signaling were essential for the success of immune checkpoint blockade, whereas cell. Antigens of choice include mutant sequences, selected cancer testis antigens, and viral antigens. Drugs or physical treatments can mitigate the immunosuppressive cancer microenvironment and include chemotherapeutics, radiation, indoleamine 2,3-dioxygenase (IDO) inhibitors, inhibitors of T cell checkpoints, agonists of selected TNF receptor family members, and inhibitors of undesirable cytokines

Van Kaer L, Wu L, Joyce S. Mechanisms and Consequences of Antigen Presentation by CD1. Trends Immunol 2016 37:738. Schiefner A, Wilson IA. Presentation of lipid antigens by CD1 glycoproteins. Curr Pharm Des 2009 15:3311. Jayawardena-Wolf J, Bendelac A. CD1 and lipid antigens: intracellular pathways for antigen presentation Antigen presentation is a critical step in the initiation of immune response. Many types of cells can serve this function but the macrophages are the principal cells. The antigen-presenting cells (APC) must express Ia antigens and most of them produce interleukin-1. Macrophages bind, endocytose, catabolize and then express the antigen on the surface in the context if Ia and present it to T and. Antigen Presentation. Some immune cells don't recognize specific antigens like lymphocytes do. Instead, they survey the body, randomly eating up anything that could potentially be harmful Lanzavecchia A. (1986) Antigen Presentation by B Lymphocytes: A Critical Step in T-B Collaboration. In: Koprowski H., Melchers F. (eds) Peptides as Immunogens. Current Topics in Microbiology and Immunology, vol 130

Antigen Presentation - A Critical Step for Development of

Thus, to improve presentation of tumor antigens and expose neoantigens we engineered a single-step nanoparticle antigen presentation system (SNAPS) that enables both membrane and cytosolic cancer proteins to be covalently coupled to an injectable nanoparticle emulsion. Methods Antigen presentation by MHC class II, in contrast, can only be performed by specialized cell types, so-called professional antigen presenting cells (APCs), including dendritic cells and macrophages. MHC class II presentation is usually restricted to extracellular antigens and is recognized by CD4 + T-helper-cells that are important for immune regulation and activation of B-cell responses In Class I antigen presentation, position 2 and position 9 are thought to be the essential anchor residues. The peptide can lay flat in the MHC Class I binding pocket or can bulge out. For Class II, instead of having a peptide that is constrained within this cleft, especially at the carboxyl terminus, class II peptides can be much larger in size (10 to >30 amino acids) POSTER PRESENTATION Open Access Single-step nanoparticle antigen presentation system for tumor immunotherapy Frederick Kohlhapp1, Erica Huelsmann2, Jai Rudra3, Arman Nabatiyan2, Andrew Zloza1. Peptides originate from different sources endogenous or intracellular, for MHC class I and exogenous or extracellular for MHC class II. Also, cross-presentation takes place in which exogenous antigens can be presented by MHC class I molecules. Endogenous antigens can also be presented by MHC class II when they are degraded through autophagy

Antigen Presentation & Processing Flashcards Quizle

  • g experience if you allow it to be one. The strategies and steps below are provided to help you break down what you might view as a large job into smaller, more manageable tasks
  • Step 1: When a naïve B cell interacts with an antigen specific for its surface antibody, it gets activated and starts dividing rapidly. The process is called clonal selection.The phenomenon of selective proliferation of B cells in response to their interaction with the antigen is called clonal selection
  • nt06229 MHC presentation . N00363 Antigen processing and presentation by MHC class I molecules nt06129 MHC presentation (viruses) . N00590 Antigen processing and presentation by MHC class II molecules Antigen processing and presentation by MHC class II molecule
  • Thus, to improve presentation of tumor antigens and expose neoantigens we engineered a single-step nanoparticle antigen presentation system (SNAPS) that enables both membrane and cytosolic cancer proteins to be covalently coupled to an injectable nanoparticle emulsion
  • ate The Antigen
  • es the sensitivity of an ELISA.

Antigen Presentation - Biology Page

Antigen presentation by B cells to T helper cells on MHC Class II Step 1: B cell activation=Antigen binding to Naïve B cell receptor followed by Antigen degradation inside B cell. Step 2: B cell acts as antigen presenting cells (APCs). Degrades antigenic peptides are displayed on MHC Class II recetor Dose-Dependent Induction of Murine Th1/Th2 Responses to Sheep Red Blood Cells Occurs in Two Steps: Antigen Presentation during Second Encounter Is Decisive.pdf. Available via license: CC BY 4.0

Antigen processing - Wikipedi

Why is antigen-presentation important in fighting infection? When fragments of the pathogen are presented, its signals are picked up by other cells of the adaptive immune system. A T cell is a type of white blood cell that has surface receptors that recognize antigens Endogenous Antigens. Let's pretend your community has been invaded by zombies. You and everyone else in the village bands together to fight them Multivalent antigen presentation, in which antigens are presented to the immune system in a repetitive array, has been demonstrated to increase the potency of humoral immune responses (Bennett et al., 2015 Snapper, 2018).This has been attributed to increased cross-linking of antigen-specific B cell receptors at the cell surface and modulation of immunogen trafficking to and within lymph nodes. Step 1. The antigen must encounter the B-lymphocytes, T-lymphocytes, and antigen-presenting cells (APCs) capable of carrying out an adaptive immune response. Step 2. Naive B-lymphocytes, T4-lymphocytes, and T8-lymphocytes must recognize epitopes of an antigen by means of antigen-specific receptor molecules on their surface and become activated

Antigen, substance that is capable of stimulating an immune response, specifically activating lymphocytes, which are the body's infection-fighting white blood cells. In general, two main divisions of antigens are recognized: foreign antigens (or heteroantigens) and autoantigens (or self-antigens) Antigen presentation is a multiple step processes by which antigen presenting cells (APCs), including macrophages and dendritic cells (DCs), ingest, process and present exogenous antigens, in a complex with MHC class II molecules, to T-cells Lines or antitumor response compared with the steps of proteins. Membrane and to their cell presentation would represent μmt mice was due to optimal vaccination protocols, with Archiving for cell antigen presentation of b cells in the endoplasmic reticulum of a matter of adaptive immune cells of vaccines have a browser only Antigen presentation. Performed by antigen-presenting cells Exogenous antigens are presented via MHC II to TCR/CD4. Endogenous antigens are presented via MHC I to TCR/CD8 (cross-presentation of antigens). Costimulatory signal: mediates survival and proliferation of T cells. B7 protein (CD80 or CD86) on the dendritic cell: interacts with CD28. However, antigen presentation of CD89-targeted cargo on moDCs did not lead to efficient antigen presentation , possibly due to the low expression of CD89 on moDC, as we previously demonstrated . Still this leaves the question why we did not see an enhanced presentation and T-cell activation when HLA monomers were targeted towards CD89

MHC & Antigen Presentation Immunopaedi

Antigen Presentation and Autoimmunity The precise steps involved in antigen processing by the antigen-presenting cell as well as the handling of antigen by target cells are still largely unknown and are the focus of a major research effort by many different laboratories Last Updated on February 25, 2020 by Sagar Aryal. Agglutination definition. Agglutination is an antigen-antibody reaction in which a particulate antigen combines with its antibody in the presence of electrolytes at a specified temperature and pH resulting in the formation of visible clumping of particles. It occurs optimally when antigens and antibodies react in equivalent proportions HSPs) c) by passing antigen processing as a method for generating stable antigen presentation in DCs (76), 3) enhancing DC and T cell interaction including a) prolonging DC survival to enhance T cell interaction b) induction of CD4+ T cell help as a strategy for augmenting CD8+ T cell responses (76) Dendritic cells (DCs) are probably the only APCs that can stimulate naive T cells in the secondary lymphoid organs. 4 DCs have a complex developmental history. The term maturation was originally introduced to refer to the changes undergone by skin Langerhans cells (LCs) (a DC type) during culture in vitro. 5 The so-called immature DCs are defined by 3 phenotypic and functional features. Step 1: Classroom exchange of simulated body fluids. Step 2: Follow protocol 2 or 3 below. Test applications: HIV, bird flu and West Nile viruses, common cold, cholera, smallpox, anthrax, influenza, and STDs. 2. ELISA for detecting antigens in a sample

Antigen Processing and Presentation Online Medical Librar

However, the physiological role of antigen presentation by EV is still unclear. We here demonstrate that the release of small EV by activated DC is strongly stimulated by phagocytic events. We show that, concomitant with the enhanced release of EV, a significant proportion of phagocytosed bacteria was expulsed back into the medium During antigen presentation, pre-existing lymphocytes that bear that antigen receptor are merely selected because they can bind with that antigen. It is also assumed that most lymphocytes never encounter the antigen for which they bear a receptor. Clonal selection may also be used during negative selection during T cell maturation Lillian Cohn, Bithi Chatterjee, Filipp Esselborn, Anna Smed-Sörensen, Norihiro Nakamura, Cécile Chalouni, Byoung-Chul Lee, Richard Vandlen, Tibor Keler, Peter Lauer, Dirk Brockstedt, Ira Mellman, Lélia Delamarre Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3 + dendritic cells at cross presentation. J Exp Med 6 May 2013 210 (5): 1049-1063. doi: https.

1. de Santa Barbara P, van den Brink GR, Roberts DJ. Molecular etiology of gut malformations and diseases. Am J Med Genet. (2002) 115:221�. doi: 10.1002/ajmg.10978

2. Metzger R, Wachowiak R, Kluth D. Embryology of the early foregut. Semin Pediatr Surg. (2011) 20:136�. doi: 10.1053/j.sempedsurg.2011.03.004

3. Gilbert S. Developmental Biology, 6th edn. Sunderland: Sinauer Associates (2000).

4. Mulholland M, Lillemoe KD, Doherty GM, Maier RV, Simeone DM, Upchurch Jr. GR. Greenfield's Surgery: Scientific Principles and Practice, 5th edn. Vol. 1. Philadelphia, PA: Wolters Kluwer Health (2011).

5. MacDonald TT, Monteleone G. Immunity, inflammation & allergy in the gut. Science (2005) 307:1920𠄵. doi: 10.1126/science.1106442

6. Hooper LV. Epithelial cell contributions to intestinal immunity. Adv Immunol. (2015) 126:129�. doi: 10.1016/

7. McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, Knoop KA, et al. Goblet cells deliver luminal antigen to CD103 + dendritic cells in the small intestine. Nature (2012) 483:345𠄹. doi: 10.1038/nature10863

8. Knoop KA, McDonald KG, McCrate S, McDole JR, Newberry RD. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol. (2015) 8:198�. doi: 10.1038/mi.2014.58

9. Schulz O, Pabst O. Antigen sampling in the small intestine. Trends Immunol. (2013) 34:155�. doi: 10.1016/

10. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science (2005) 307:254𠄸. doi: 10.1126/science.1102901

11. Kerneis S, Bogdanova A, Kraehenbuhl JP, Pringault E. Conversion by Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria. Science (1997) 277:949�.

12. Mayrhofer G, Pugh CW, Barclay AN. The distribution, ontogeny and origin in the rat of Ia-positive cells with dendritic morphology and of Ia antigen in epithelia, with special reference to the intestine. Eur J Immunol. (1983) 13:112�. doi: 10.1002/eji.1830130206

13. Spencer J, Finn T, Isaacson PG. Expression of HLA-DR antigens on epithelium associated with lymphoid tissue in the human gastrointestinal tract. Gut (1986) 27:153𠄷. doi: 10.1136/gut.27.2.153

14. Bjerke K, Brandtzaeg P. Lack of relation between expression of HLA-DR and secretory component (SC) in follicle-associated epithelium of human Peyer's patches. Clin Exp Immunol. (1988) 71:502𠄷.

15. MacDonald T, Weinel A, Spencer J. HLA-DR expression in human fetal intestinal epithelium. Gut (1988) 29:1342𠄸.

16. Nagura H, Ohtani H, Masuda T, Kimura M, Nakamura S. HLA-DR expression on M cells overlying Peyer's patches is a common feature of human small intestine. Acta Pathol Jpn. (1991) 41:818�.

17. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature (2016) 529:226�. doi: 10.1038/nature16527

18. Banerjee A, McKinley ET, von Moltke J, Coffey RJ, Lau KS. Interpreting heterogeneity in intestinal tuft cell structure and function. J Clin Invest. (2018) 128:1711𠄹. doi: 10.1172/JCI120330

19. Okumura R, Takeda K. Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Exp Mol Med. (2017) 49:e338. doi: 10.1038/emm.2017.20

20. Okumura R, Takeda K. Maintenance of intestinal homeostasis by mucosal barriers. Inflamm Regen. (2018) 38:5. doi: 10.1186/s41232-018-0063-z

21. Fukata M, Arditi M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol. (2013) 6:451�. doi: 10.1038/mi.2013.13

22. Otte JM, Cario E, Podolsky DK. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology (2004) 126:1054�. doi: 10.1053/j.gastro.2004.01.007

23. Melmed G, Thomas LS, Lee N, Tesfay SY, Lukasek K, Michelsen KS, et al. Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J Immunol. (2003) 170:1406�. doi: 10.4049/jimmunol.170.3.1406

24. Tam A, Wadsworth S, Dorscheid D, Man SF, Sin DD. The airway epithelium: more than just a structural barrier. Ther Adv Respir Dis. (2011) 5:255�. doi: 10.1177/1753465810396539

25. Reid L, Meyrick B, Antony VB, Chang LY, Crapo JD, Reynolds HY. The mysterious pulmonary brush cell: a cell in search of a function. Am J Respir Crit Care Med. (2005) 172:136𠄹. doi: 10.1164/rccm.200502-203WS

26. Leiva-Juarez MM, Kolls JK, Evans SE. Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense. Mucosal Immunol. (2018) 11:21�. doi: 10.1038/mi.2017.71

27. Adriaensen D, Brouns I, Pintelon I, De Proost I, Timmermans JP. Evidence for a role of neuroepithelial bodies as complex airway sensors: comparison with smooth muscle-associated airway receptors. J Appl Physiol. (1985) (2006) 101:960�. doi: 10.1152/japplphysiol.00267.2006

28. Hong KU, Reynolds SD, Watkins S, Fuchs E, Stripp BR. In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am J Physiol Lung Cell Mol Physiol. (2004) 286:L643𠄹. doi: 10.1152/ajplung.00155.2003

29. Knight DA, Holgate ST. The airway epithelium: structural and functional properties in health and disease. Respirology (2003) 8:432�. doi: 10.1046/j.1440-1843.2003.00493.x

30. Jeffery PK. Morphologic features of airway surface epithelial cells and glands. Am Rev Respir Dis. (1983) 128:S14�. doi: 10.1164/arrd.1983.128.2P2.S14

31. Spina D. Epithelium smooth muscle regulation and interactions. Am J Respir Crit Care Med. (1998) 158:S141𠄵. doi: 10.1164/ajrccm.158.supplement_2.13tac100a

32. De RW, Willems L, Van GM, Franken C, Fransen J, Dijkman J, et al. Ultrastructural localization of bronchial antileukoprotease in central and peripheral human airways by a gold-labeling technique using monoclonal antibodies. Am Rev Respir Dis. (1986) 133:882�.

33. Dobbs LG, Johnson MD. Alveolar epithelial transport in the adult lung. Respir Physiol Neurobiol. (2007) 159:283�. doi: 10.1016/j.resp.2007.06.011

34. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. (2005) 5:58�. doi: 10.1038/nri1528

35. Hiller AS, Tschernig T, Kleemann WJ, Pabst R. Bronchus-associated lymphoid tissue (BALT) and larynx-associated lymphoid tissue (LALT) are found at different frequencies in children, adolescents and adults. Scand J Immunol. (1998) 47:159�.

36. Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology (2000) 68:1𠄸. doi: 10.1159/000028109

37. Gay NJ, Symmons MF, Gangloff M, Bryant CE. Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol. (2014) 14:546�. doi: 10.1038/nri3713

38. Evans SE, Xu Y, Tuvim MJ, Dickey BF. Inducible innate resistance of lung epithelium to infection. Annu Rev Physiol. (2010) 72:413�. doi: 10.1146/annurev-physiol-021909-135909

39. Opitz B, van Laak V, Eitel J, Suttorp N. Innate immune recognition in infectious and noninfectious diseases of the lung. Am J Respir Crit Care Med. (2010) 181:1294�. doi: 10.1164/rccm.200909-1427SO

40. Heyl KA, Klassert TE, Heinrich A, Müller MM, Klaile E, Dienemann H, et al. Dectin-1 is expressed in human lung and mediates the proinflammatory immune response to nontypeable Haemophilus influenzae. MBio (2014) 5:e01492-01414. doi: 10.1128/mBio.01492-14.

41. Nayak A, Dodagatta-Marri E, Tsolaki AG, Kishore U. An insight into the diverse roles of surfactant proteins, SP-A and SP-D in innate and adaptive immunity. Front Immunol. (2012) 3:131. doi: 10.3389/fimmu.2012.00131

42. Jones PP, Murphy DB, Hewgill D, McDevitt HO. Detection of a common polypeptide chain in IA and IE sub-region immunoprecipitates. Mol Immunol. (1979) 16:51�.

43. Cloutier M, Gauthier C, Fortin JS, Geneve L, Kim K, Gruenheid S, et al. ER egress of invariant chain isoform p35 requires direct binding to MHCII molecules and is inhibited by the NleA virulence factor of enterohaemorrhagic Escherichia coli. Hum Immunol. (2015) 76:292𠄶. doi: 10.1016/j.humimm.2015.02.002

44. Neefjes J, Jongsma MLM, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. (2011) 11:823�. doi: 10.1038/nri3084

45. Mellins ED, Stern LJ. HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation. Curr Opin Immunol. (2014) 26:115�. doi: 10.1016/j.coi.2013.11.005

46. Guce AI, Mortimer SE, Yoon T, Painter CA, Jiang W, Mellins ED, et al. HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism. Nat Struct Mol Biol. (2013) 20:90𠄸. doi: 10.1038/nsmb.2460

47. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. (2005) 23:515�. doi: 10.1146/annurev.immunol.23.021704.115611

48. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A toll-like receptor recognizes bacterial DNA. Nature (2000) 408:740𠄵. doi: 10.1038/35047123

49. Alegre M-L, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. (2001) 1:220𠄸. doi: 10.1038/35105024

50. Ramig RF. Pathogenesis of intestinal and systemic rotavirus infection. J Virol. (2004) 78:10213�. doi: 10.1128/JVI.78.19.10213-10220.2004

51. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. (2014) 14:141�. doi: 10.1038/nri3608

52. Wiman K, Curman B, Forsum U, Klareskog L, MalmnäS-Tjernlund U, Rask L, et al. Occurrence of Ia antigens on tissues of non-lymphoid origin. Nature (1978) 276:711𠄳.

53. Scott H, Solheim BG, Brandtzaeg P, Thorsby E. HLA-DR-like antigens in the epithelium of the human small intestine. Scand J Immunol. (1980) 12:77�. doi: 10.1111/j.1365-3083.1980.tb00043.x

54. Parr EL, McKenzie IFC. Demonstration of Ia antigens on mouse intestinal epithelial cells by immunoferritin labeling. Immunogenetics (1979) 8:499�. doi: 10.1007/bf01561459

55. Chiba M, Iizuka M, Masamune O. Ubiquitous expression of HLA-DR antigens on human small intestinal epithelium. Gastroenterol Jpn. (1988) 23:109�. doi: 10.1007/bf02799021

56. Lin XP, Almqvist N, Telemo E. Human small intestinal epithelial cells constitutively express the key elements for antigen processing and the production of exosomes. Blood Cells Mol Dis. (2005) 35:122𠄸. doi: 10.1016/j.bcmd.2005.05.011

57. Byrne B, Madrigal-Estebas L, McEvoy A, Carton J, Doherty DG, Whelan A, et al. Human duodenal epithelial cells constitutively express molecular components of antigen presentation but not costimulatory molecules. Hum Immunol. (2002) 63:977�. doi: 10.1016/S0198-8859(02)00436-6

58. Oliver AM, Thomson AW, Sewell HF, Abramovch DR. Major histocompatibility complex (MHC) class II antigen (HLA-DR, DQ & DP) expression in human fetal endocrine organs and gut. Scand J Immunol. (1988) 27:731𠄷. doi: 10.1111/j.1365-3083.1988.tb02407.x

59. Natali PG, De Martino C, Pellegrino MA, Ferrone S. Analysis of the expression of I-Ak-like antigens in murine fetal and adult tissues with the monoclonal antibody 10𠄲.16. Scand J Immunol. (1981) 13:541𠄶. doi: 10.1111/j.1365-3083.1981.tb00167.x

60. Koretz K, Momburg F, Otto HF, Moller P. Sequential induction of MHC antigens on autochthonous cells of ileum affected by Crohn's disease. Am J Pathol. (1987) 129:493�.

61. Momburg F, Koretz K, Von Herbay A, Moller P. Nonimmune human cells can express MHC class II antigens in the absence of invariant chain𠄺n immunohistological study on normal and chronically inflamed small intestine. Clin Exp Immunol. (1988) 72:367�.

62. Fais S, Maiuri L, Pallone F, De Vincenzi M, De Ritis G, Troncone R, et al. Gliadin induced changes in the expression of MHC-class II antigens by human small intestinal epithelium. Organ culture studies with coeliac disease mucosa. Gut (1992) 33:472𠄵.

63. Kelly J, O⟺rrelly C, O'Mahony C, Weir D, Feighery C. Immunoperoxidase demonstration of the cellular composition of the normal and coeliac small bowel. Clin Exp Immunol. (1987) 68:177.

64. Mason DW, Dallman M, Barclay AN. Graft-versus-host disease induces expression of Ia antigen in rat epidermal cells and gut epithelium. Nature (1981) 293:150𠄱.

65. Dotan I, Allez M, Nakazawa A, Brimnes J, Schulder-Katz M, Mayer L. Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4 + T cells to proliferate and secrete interferon-γ. Am J Physiol. Gastrointest Liver Physiol. (2007) 292, G1630�. doi: 10.1152/ajpgi.00294.2006

66. Mayer L, Eisenhardt D, Salomon P, Bauer W, Plous R, Piccinini L. Expression of class II molecules on intestinal epithelial cells in humans. Differences between normal and inflammatory bowel disease. Gastroenterology (1991) 100:3�.

67. Zimmer KP, Poremba C, Weber P, Ciclitira PJ, Harms E. Translocation of gliadin into HLA-DR antigen containing lysosomes in coeliac disease enterocytes. Gut (1995) 36:703𠄹.

68. Arnaud-Battandier F, Cerf-Bensussan N, Amsellem R, Schmitz J. Increased HLA-DR expression by enterocytes in children with celiac disease. Gastroenterology (1986) 91:1206�. doi: 10.1016/S0016-5085(86)80018-X

69. Colgan SP, Resnick MB, Parkos CA, Delp-Archer C, McGuirk D, Bacarra AE, et al. IL-4 directly modulates function of a model human intestinal epithelium. J Immunol. (1994) 153:2122𠄹.

70. Niessner M, Volk BA. Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol. (1995) 101:428�. doi: 10.1111/j.1365-2249.1995.tb03130.x

71. Rojas R, Apodaca G. Immunoglobulin transport across polarized epithelial cells. Nat Rev Mol Cell Biol. (2002) 3:944�. doi: 10.1038/nrm972

72. Daar AS, Fuggle SV, Fabre JW, Ting A, Morris PJ. The detailed distribution of class II antigens in normal human organs. Transplantation (1984) 38:293𠄸.

73. Hirata I, Austin LL, Blackwell WH, Weber JR, Dobbins III WO. Immunoelectron microscopic localization of HLA-DR antigen in control small intestine and colon and in inflammatory bowel disease. Digest Dis Sci. (1986) 31:1317�.

74. Sarles J, Gorvel JP, Olive D, Maroux S, Mawas C, Giraud F. Subcellular localization of class I (A,B,C) and class II (DR and DQ) MHC antigens in jejunal epithelium of children with coeliac disease. J Pediatr Gastroenterol Nutr. (1987) 6:51𠄶.

75. Hundorfean G, Zimmer KP, Strobel S, Gebert A, Ludwig D, Büning J. Luminal antigens access late endosomes of intestinal epithelial cells enriched in MHC I and MHC II molecules: in vivo study in Crohn's ileitis. Am J Physiol Gastrointest Liver Physiol. (2007) 293:G798�. doi: 10.1152/ajpgi.00135.2007

76. Arnold MM, Srivastava S, Fredenburgh J, Stockard CR, Myers RB, Grizzle WE. Effects of fixation and tissue processing on immunohistochemical demonstration of specific antigens. Biotech Histochem. (1996) 71:224�.

77. Shi SR, Liu C, Pootrakul L, Tang L, Young A, Chen R, et al. Evaluation of the value of frozen tissue section used as “gold standard” for immunohistochemistry. Am J Clin Pathol. (2008) 129:358�. doi: 10.1309/7cxuyxt23e5al8kq

78. Hershberg RM, Cho DH, Youakim A, Bradley MB, Lee JS, Framson PE, et al. Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells. J Clin Invest. (1998) 102:792�.

79. Westendorf AM, Fleissner D, Groebe L, Jung S, Gruber AD, Hansen W, et al. CD4 + Foxp3 + regulatory T cell expansion induced by antigen-driven interaction with intestinal epithelial cells independent of local dendritic cells. Gut (2009) 58:211𠄹. doi: 10.1136/gut.2008.151720

80. Thelemann C, Eren RO, Coutaz M, Brasseit J, Bouzourene H, Rosa M, et al. Interferon-γ induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis. PLoS ONE (2014) 9:e86844. doi: 10.1371/journal.pone.0086844

81. Bar F, Sina C, Hundorfean G, Pagel R, Lehnert H, Fellermann K, et al. Inflammatory bowel diseases influence major histocompatibility complex class I (MHC I) and II compartments in intestinal epithelial cells. Clin Exp Immunol. (2013) 172:280𠄹. doi: 10.1111/cei.12047

82. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science (2015) 347:1260419. doi: 10.1126/science.1260419

83. Walseng E, Furuta K, Goldszmid RS, Weih KA, Sher A, Roche PA. Dendritic cell activation prevents MHC class II ubiquitination and promotes MHC class II survival regardless of the activation stimulus. J Biol Chem. (2010) 285:41749�. doi: 10.1074/jbc.M110.157586

84. Sanderson IR, Ouellette AJ, Carter EA, Walker WA, Harmatz PR. Differential regulation of B7 mRNA in enterocytes and lymphoid cells. Immunology (1993) 79:434𠄸.

85. Nakazawa A, Watanabe M, Kanai T, Yajima T, Yamazaki M, Ogata H, et al. Functional expression of costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa. Gastroenterology (1999) 117:536�.

86. Bloom S, Simmons D, Jewell DP. Adhesion molecules intercellular adhesion molecule-1 (ICAM-1), ICAM-3 and B7 are not expressed by epithelium in normal or inflamed colon. Clin Exp Immunol. (1995) 101:157�.

87. Borcherding F, Nitschke M, Hundorfean G, Rupp J, von Smolinski D, Bieber K, et al. The CD40-CD40L pathway contributes to the proinflammatory function of intestinal epithelial cells in inflammatory bowel disease. Am J Pathol. (2010) 176:1816�. doi: 10.2353/ajpath.2010.090461

88. Cayabyab M, Phillips JH, Lanier LL. CD40 preferentially costimulates activation of CD4 + T lymphocytes. J Immunol. (1994) 152:1523�.

89. Leitner J, Herndler-Brandstetter D, Zlabinger GJ, Grubeck-Loebenstein B, Steinberger P. CD58/CD2 is the primary costimulatory pathway in human CD28-CD8 + T cells. J Immunol. (2015) 195:477�. doi: 10.4049/jimmunol.1401917

90. Framson PE, Cho DH, Lee LY, Hershberg RM. Polarized expression and function of the costimulatory molecule CD58 on human intestinal epithelial cells. Gastroenterology (1999) 116:1054�.

91. Peters U, Papadopoulos T, Muller-Hermelink HK. MHC class II antigens on lung epithelial of human fetuses and neonates. Ontogeny and expression in lungs with histologic evidence of infection. Lab Invest. (1990) 63:38�.

92. Badve S, Deshpande C, Hua Z, Logdberg L. Expression of invariant chain (CD 74) and major histocompatibility complex (MHC) class II antigens in the human fetus. J Histochem Cytochem. (2002) 50:473�. doi: 10.1177/002215540205000404

93. Glanville AR, Tazelaar HD, Theodore J, Imoto E, Rouse RV, Baldwin JC, et al. The distribution of MHC class I and II antigens on bronchial epithelium. Am Rev Respir Dis. (1989) 139:330𠄴. doi: 10.1164/ajrccm/139.2.330

94. Rossi GA, Sacco O, Balbi B, Oddera S, Mattioni T, Corte G, et al. Human ciliated bronchial epithelial cells: expression of the HLA-DR antigens and of the HLA-DR alpha gene, modulation of the HLA-DR antigens by gamma-interferon and antigen-presenting function in the mixed leukocyte reaction. Am J Respir Cell Mol Biol. (1990) 3:431𠄹. doi: 10.1165/ajrcmb/3.5.431

95. Cunningham AC, Milne DS, Wilkes J, Dark JH, Tetley TD, Kirby JA. Constitutive expression of MHC and adhesion molecules by alveolar epithelial cells (type II pneumocytes) isolated from human lung and comparison with immunocytochemical findings. J Cell Sci. (1994) 107:443𠄹.

96. Kallenberg CG, Schilizzi BM, Beaumont F, Poppema S, De Leij L, The TH. Expression of class II MHC antigens on alveolar epithelium in fibrosing alveolitis. Clin Exp Immunol. (1987) 67:182�.

97. Kaneko Y, Kuwano K, Kunitake R, Kawasaki M, Hagimoto N, Hara N. B7-1, B7-2 and class II MHC molecules in idiopathic pulmonary fibrosis and bronchiolitis obliterans-organizing pneumonia. Eur Respir J. (2000) 15:49�. doi: 10.1034/j.1399-3003.2000.15a10.x

98. Papi A, Stanciu LA, Papadopoulos NG, Teran LM, Holgate ST, Johnston SL. Rhinovirus infection induces major histocompatibility complex class I and costimulatory molecule upregulation on respiratory epithelial cells. J Infect Dis. (2000) 181:1780𠄴. doi: 10.1086/315463

99. Tanaka H, Maeda K, Nakamura Y, Azuma M, Yanagawa H, Sone S. CD40 and IFN-gamma dependent T cell activation by human bronchial epithelial cells. J Med Invest. (2001) 48:109�.

100. Steiniger B, Sickel E. Class II MHC molecules and monocytes/macrophages in the respiratory system of conventional, germ-free and interferon-gamma-treated rats. Immunobiology (1992) 184:295�. doi: 10.1016/S0171-2985(11)80588-7

101. Sacco O, Lantero S, Scarso L, Galietta LJ, Spallarossa D, Silvestri M, et al. Modulation of HLA-DR antigen and ICAM-1 molecule expression on airway epithelial cells by sodium nedocromil. Ann Allergy Asthma Immunol. (1999) 83:49�. doi: 10.1016/S1081-1206(10)63512-0

102. Chang SC, Hsu HK, Perng RP, Shiao GM, Lin CY. Increased expression of MHC class II antigens in rejecting canine lung allografts. Transplantation (1990) 49:1158�.

103. Vignola AM, Campbell AM, Chanez P, Bousquet J, Paul-Lacoste P, Michel FB, et al. HLA-DR and ICAM-1 expression on bronchial epithelial cells in asthma and chronic bronchitis. Am Rev Respir Dis. (1993) 148:689�. doi: 10.1164/ajrccm/148.3.689

104. Gao J, De BP, Banerjee AK. Human parainfluenza virus type 3 up-regulates major histocompatibility complex class I and II expression on respiratory epithelial cells: involvement of a STAT1- and CIITA-independent pathway. J Virol. (1999) 73:1411𠄸.

105. Elssner A, Jaumann F, Wolf WP, Schwaiblmair M, Behr J, Furst H, et al. Bronchial epithelial cell B7-1 and B7-2 mRNA expression after lung transplantation: a role in allograft rejection? Eur Respir J. (2002) 20:165𠄹. doi: 10.1183/09031936.02.00268102

106. King TE. Cryptogenic Organizing Pneumonia (2017). Available online at:

107. Hershberg RM, Framson PE, Cho DH, Lee LY, Kovats S, Beitz J, et al. Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. J Clin Invest. (1997) 100:204�.

108. London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4 + T cells. J Immunol. (2000) 164:265�. doi: 10.4049/jimmunol.164.1.265

109. Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol. (1994) 152:2675�.

110. Hollander D. Crohn's disease𠄺 permeability disorder of the tight junction? Gut (1988) 29:1621𠄴. doi: 10.1136/gut.29.12.1621

111. Arnott ID, Kingstone K, Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol. (2000) 35:1163𠄹. doi: 10.1080/003655200750056637

112. Smecuol E, Bai JC, Vazquez H, Kogan Z, Cabanne A, Niveloni S, et al. Gastrointestinal permeability in celiac disease. Gastroenterology (1997) 112:1129�.

113. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles & friends. J Cell Biol. (2013) 200:373�. doi: 10.1083/jcb.201211138

114. van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology (2001) 121:337�. doi: 10.1053/gast.2001.26263

115. Van Niel G, Mallegol J, Bevilacqua C, Candalh C, Brugiere S, Tomaskovic-Crook E, et al. Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice. Gut (2003) 52:1690𠄷. doi: 10.1136/gut.52.12.1690

116. Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, et al. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology (2007) 132:1866�. doi: 10.1053/j.gastro.2007.02.043

117. Cunningham AC, Zhang JG, Moy JV, Ali S, Kirby JA. A comparison of the antigen-presenting capabilities of class II MHC-expressing human lung epithelial and endothelial cells. Immunology (1997) 91:458�.

118. Kalb TH, Chuang MT, Marom Z, Mayer L. Evidence for accessory cell function by class II MHC antigen-expressing airway epithelial cells. Am J Respir Cell Mol Biol. (1991) 4:320𠄹. doi: 10.1165/ajrcmb/4.4.320

119. Suda T, Sato A, Sugiura W, Chida, K. Induction of MHC class II antigens on rat bronchial epithelial cells by interferon-gamma and its effect on antigen presentation. Lung (1995) 173:127�.

120. Salik E, Tyorkin M, Mohan S, George I, Becker K, Oei E, et al. Antigen trafficking and accessory cell function in respiratory epithelial cells. Am J Respir Cell Mol Biol. (1999) 21:365�. doi: 10.1165/ajrcmb.21.3.3529

121. Satoh A, Toyota M, Ikeda H, Morimoto Y, Akino K, Mita H, et al. Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-[gamma]-induced HLA-DR expression in colorectal and gastric cancer cells. Oncogene (2004) 23:8876�. doi: 10.1038/sj.onc.1208144

122. Cencič A, Langerholc T. Functional cell models of the gut and their applications in food microbiology𠅊 review. Int J Food Microbiol. (2010) 141:S4�. doi: 10.1016/j.ijfoodmicro.2010.03.026

123. Hatano R, Yamada K, Iwamoto T, Maeda N, Emoto T, Shimizu M, et al. Antigen presentation by small intestinal epithelial cells uniquely enhances IFN-gamma secretion from CD4 + intestinal intraepithelial lymphocytes. Biochem Biophys Res Commun. (2013) 435:592𠄶. doi: 10.1016/j.bbrc.2013.05.024

124. Thome JJ, Bickham KL, Ohmura Y, Kubota M, Matsuoka N, Gordon C, et al. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat Med. (2016) 22:72�. doi: 10.1038/nm.4008

125. Maggio-Price L, Seamons A, Bielefeldt-Ohmann H, Zeng W, Brabb T, Ware C, et al. Lineage targeted MHC-II transgenic mice demonstrate the role of dendritic cells in bacterial-driven colitis. Inflamm Bowel Dis. (2013) 19:174�. doi: 10.1002/ibd.23000

126. Loschko J, Schreiber HA, Rieke GJ, Esterhazy D, Meredith MM, Pedicord VA, et al. Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation. J Exp Med. (2016) 213:517�. doi: 10.1084/jem.20160062

127. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, et al. A functionally specialized population of mucosal CD103 + DCs induces Foxp3 + regulatory T cells via a TGF-β-and retinoic acid�pendent mechanism. J Exp Med. (2007) 204:1757�. doi: 10.1084/jem.20070590

128. Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12-and IL-15-responsive IFN-γ-producing cells. Immunity (2013) 38:769�. doi: 10.1016/j.immuni.2013.02.010

129. Ferrick DA, Schrenzel MD, Mulvania T, Hsieh B. Differential production of interferon-gamma and interleukin-4 in response to Th1-and Th2-stimulating pathogens by gammadelta T cells in vivo. Nature (1995) 373:255.

130. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. (2008) 9:503�. doi: 10.1038/ni1582

131. Skeen MJ, Ziegler HK. Activation of gamma delta T cells for production of IFN-gamma is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J Immunol. (1995) 154:5832�.

132. Loh L, Ivarsson M, Michaelsson J, Sandberg J, Nixon DF. Invariant natural killer T cells developing in the human fetus accumulate and mature in the small intestine. Mucosal Immunol. (2014) 7:1233�. doi: 10.1038/mi.2014.13

133. Reith W, LeibundGut-Landmann S, Waldburger JM. Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol. (2005) 5:793�. doi: 10.1038/nri1708

134. Sanderson IR, Bustin SA, Dziennis S, Paraszczuk J, Stamm DS. Age and diet act through distinct isoforms of the class II transactivator gene in mouse intestinal epithelium. Gastroenterology (2004) 127:203�. doi: 10.1053/j.gastro.2004.04.014

135. Ibrahim L, Dominguez M, Yacoub M. Primary human adult lung epithelial cells in vitro: response to interferon-gamma and cytomegalovirus. Immunology (1993) 79:119�.

136. Radosevich M, Ono SJ. MHC class II gene expression is not induced in HPIV3-infected respiratory epithelial cells. Immunol Res. (2004) 30:125�. doi: 10.1385/IR:30:2:125

137. Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. (2014) 14:667�. doi: 10.1038/nri3738

138. Jarvinen TT, Collin P, Rasmussen M, Kyrönpalo S, Mäki M, Partanen J, et al. Villous tip intraepithelial lymphocytes as markers of early-stage coeliac disease. Scand J Gastroenterol. (2004) 39:428�. doi: 10.1080/00365520310008773

139. Spits H, Bernink JH, Lanier L. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat Immunol. (2016) 17:758�. doi: 10.1038/ni.3482

140. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. IL-27, a Heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4 + T cells. Immunity (2002) 16:779�. doi: 10.1016/S1074-7613(02)00324-2

141. Diegelmann J, Olszak T, Goke B, Blumberg RS, Brand S. A novel role for interleukin-27 (IL-27) as mediator of intestinal epithelial barrier protection mediated via differential signal transducer and activator of transcription (STAT) protein signaling and induction of antibacterial and anti-inflammatory proteins. J Biol Chem. (2012) 287:286�. doi: 10.1074/jbc.M111.294355

142. Feng XM, Chen XL, Liu N, Chen Z, Zhou YL, Han ZB, et al. Interleukin-27 upregulates major histocompatibility complex class II expression in primary human endothelial cells through induction of major histocompatibility complex class II transactivator. Hum Immunol. (2007) 68:965�. doi: 10.1016/j.humimm.2007.10.004

143. Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol. (2005) 5:521�. doi: 10.1038/nri1648

144. Lopetuso LR, Chowdhry S, Pizarro TT. Opposing functions of classic and novel IL-1 family members in gut health and disease. Front Immunol. (2013) 4:181. doi: 10.3389/fimmu.2013.00181

145. Okamura H, Nagata K, Komatsu T, Tanimoto T, Nukata Y, Tanabe F, et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun. (1995) 63:3966�.

146. Kohno K, Kataoka J, Ohtsuki T, Suemoto Y, Okamoto I, Usui M, et al. IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J Immunol. (1997) 158:1541�.

147. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. (2001) 12:53�. doi: 10.1016/S1359-6101(00)00015-0

148. Pizarro TT, Michie MH, Bentz M, Woraratanadharm J, Smith MF Jr., Foley E, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol. (1999) 162:6829�.

149. Monteleone G, Trapasso F, Parrello T, Biancone L, Stella A, Iuliano R, et al. Bioactive IL-18 expression is up-regulated in Crohn's disease. J Immunol. (1999) 163:143𠄷.

150. Kanai T, Watanabe M, Okazawa A, Nakamaru K, Okamoto M, Naganuma M, et al. Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease. Gastroenterology (2000) 119:1514�. doi: 10.1053/gast.2000.20260

151. Leon AJ, Garrote JA, Blanco-Quiros A, Calvo C, Fernandez-Salazar L, Del Villar A, et al. Interleukin 18 maintains a long-standing inflammation in coeliac disease patients. Clin Exp Immunol. (2006) 146:479�. doi: 10.1111/j.1365-2249.2006.03239.x

152. Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med. (2010) 207:1625�. doi: 10.1084/jem.20100199

153. Maerten P, Shen C, Colpaert S, Liu Z, Bullens DA, van Assche G, et al. Involvement of interleukin 18 in Crohn's disease: evidence from in vitro analysis of human gut inflammatory cells and from experimental colitis models. Clin Exp Immunol. (2004) 135:310𠄷. doi: 10.1111/j.1365-2249.2004.02362.x

154. Kolinska J, Lisa V, Clark JA, Kozakova H, Zakostelecka M, Khailova L, et al. Constitutive expression of IL-18 and IL-18R in differentiated IEC-6 cells: effect of TNF-alpha and IFN-gamma treatment. J Interferon Cytokine Res. (2008) 28:287�. doi: 10.1089/jir.2006.0130

155. Weiss ES, Girard-Guyonvarc'h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood (2018) 131:1442�. doi: 10.1182/blood-2017-12-820852

156. Cameron LA, Taha RA, Tsicopoulos A, Kurimoto M, Olivenstein R, Wallaert B, et al. Airway epithelium expresses interleukin-18. Eur Respir J. (1999) 14:553𠄹.

157. Muneta Y, Goji N, Tsuji NM, Mikami O, Shimoji Y, Nakajima Y, et al. Expression of interleukin-18 by porcine airway and intestinal epithelium. J Interferon Cytokine Res. (2002) 22:883𠄹. doi: 10.1089/107999002760274908

158. Wittmann M, Purwar R, Hartmann C, Gutzmer R, Werfel T. Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases. J Invest Dermatol. (2005) 124:1225�. doi: 10.1111/j.0022-202X.2005.23715.x

159. Englyst HN, Macfarlane GT. Breakdown of resistant and readily digestible starch by human gut bacteria. J Sci Food Agric. (1986) 37:699�. doi: 10.1002/jsfa.2740370717

160. Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin β receptor & TNF receptor I function. J Immunol. (2003) 170:5475�. doi: 10.4049/jimmunol.170.11.5475

161. Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med. (2011) 184:957�. doi: 10.1164/rccm.201104-0655OC

162. Wu BG, Segal LN. Lung microbiota and its impact on the mucosal immune phenotype. Microbiol Spectr. (2017) 5. doi: 10.1128/microbiolspec.BAD-0005-2016

163. Matsumoto S, Setoyama H, Imaoka A, Okada Y, Amasaki H, Suzuki K, et al. Gamma delta TCR-bearing intraepithelial lymphocytes regulate class II major histocompatibility complex molecule expression on the mouse small intestinal epithelium. Epithelial Cell Biol. (1995) 4:163�.

164. Matsumoto S, Nanno M, Watanabe N, Miyashita M, Amasaki H, Suzuki K, et al. Physiological roles of gammadelta T-cell receptor intraepithelial lymphocytes in cytoproliferation and differentiation of mouse intestinal epithelial cells. Immunology (1999) 97:18�.

165. Umesaki Y, Okada Y, Matsumoto S, Imaoka A, Setoyama H. Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class II molecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse. Microbiol Immunol. (1995) 39:555�.

166. Sydora BC, Mixter PF, Houlden B, Hershberg R, Levy R, Comay M, et al. T-cell receptor gamma delta diversity and specificity of intestinal intraepithelial lymphocytes: analysis of IEL-derived hybridomas. Cell Immunol. (1993) 152:305�. doi: 10.1006/cimm.1993.1293

167. Jarry A, Cerf-Bensussan N, Brousse N, Selz F, Guy-Grand D. Subsets of CD3 + (T cell receptor alpha/beta or gamma/delta) and CD3 − lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur J Immunol. (1990) 20:1097�. doi: 10.1002/eji.1830200523

168. Bolnick DI, Snowberg LK, Caporaso JG, Lauber C, Knight R, Stutz WE. Major histocompatibility complex class IIb polymorphism influences gut microbiota composition and diversity. Mol Ecol. (2014) 23:4831�. doi: 10.1111/mec.12846

169. Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, et al. MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun. (2015) 6:8642. doi: 10.1038/ncomms9642

170. Silverman M, Kua L, Tanca A. Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny. Proc Natl Acad Sci USA. (2017) 114:9671𠄶. doi: 10.1073/pnas.1712280114

171. Bingula R, Filaire M. Desired turbulence? Gut-lung axis, immunity, and lung cancer. J Oncol. (2017) 2017:5035371. doi: 10.1155/2017/5035371

172. Tsay TB, Yang MC, Chen PH, Hsu CM, Chen LW. Gut flora enhance bacterial clearance in lung through toll-like receptors 4. J Biomed Sci. (2011) 18:68. doi: 10.1186/1423-0127-18-68

173. Fagundes CT, Amaral FA, Vieira AT, Soares AC, Pinho V, Nicoli JR, et al. Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J Immunol. (2012) 188:1411�. doi: 10.4049/jimmunol.1101682

174. Yitbarek A, Alkie T, Taha-Abdelaziz K, Astill J, Rodriguez-Lecompte JC, Parkinson J, et al. Gut microbiota modulates type I interferon and antibody-mediated immune responses in chickens infected with influenza virus subtype H9N2. Benef Microbes (2018) 9:417�. doi: 10.3920/BM2017.0088

175. Tweedle JL, Deepe GS Jr. TNFalpha antagonism reveals a gut/lung axis that amplifies regulatory T cells in a pulmonary fungal infection. Infect Immun. (2018) 86. doi: 10.1128/IAI.00109-18

176. Bradley CP, Teng F, Felix KM, Sano T, Naskar D, Block KE, et al. Segmented filamentous bacteria provoke lung autoimmunity by inducing gut-lung axis Th17 cells expressing dual TCRs. Cell Host Microbe (2017) 22:697� e694. doi: 10.1016/j.chom.2017.10.007

177. Cho Y, Abu-Ali G, Tashiro H, Kasahara DI, Brown TA, Brand JD, et al. The microbiome regulates pulmonary responses to ozone in mice. Am J Respir Cell Mol Biol. (2018) 59:346�. doi: 10.1165/rcmb.2017-0404OC

178. Gui QF, Lu HF, Zhang CX, Xu ZR, Yang YH. Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model. Genet Mol Res. (2015) 14:5642�. doi: 10.4238/2015.May.25.16

179. Lundin KEA, Gjertsen HA, Scott H, Sollid LM, Thorsby E. Function of DQ2 and DQ8 as HLA susceptibility molecules in celiac disease. Hum Immunol. (1994) 41:24𠄷. doi: 10.1016/0198-8859(94)90079-5

180. Sarna VK, Skodje GI, Reims HM, Risnes LF, Dahal-Koirala S, Sollid LM, et al. HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge. Gut (2017) 67:1606�. doi: 10.1136/gutjnl-2017-314461

181. Brottveit M, Raki M, Bergseng E, Fallang LE, Simonsen B, Lovik A, et al. Assessing possible celiac disease by an HLA-DQ2-gliadin tetramer test. Am J Gastroenterol. (2011) 106:1318�. doi: 10.1038/ajg.2011.23

182. Sollid LM, Lie BA. Celiac disease genetics: current concepts and practical applications. Clin Gastroenterol Hepatol. (2005) 3:843�. doi: 10.1016/S1542-3565(05)00532-X

183. Irvine DJ, Purbhoo MA, Krogsgaard M, Davis MM. Direct observation of ligand recognition by T cells. Nature (2002) 419:845𠄹. doi: 10.1038/nature01076

184. Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, et al. Multiplexed ion beam imaging of human breast tumors. Nat Med. (2014) 20:436�. doi: 10.1038/nm.3488

185. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4 + CD25 + regulatory T cells. J Immunol. (2003) 171:3348�. doi: 10.4049/jimmunol.171.7.3348

186. KleinJan A, Willart MA, Kuipers H, Coyle AJ, Hoogsteden HC, Lambrecht BN. Inducible costimulator blockade prolongs airway luminal patency in a mouse model of obliterative bronchiolitis. Transplantation (2008) 86:1436�. doi: 10.1097/TP.0b013e3181886baa

187. Lombardi V, Singh AK, Akbari O. The role of costimulatory molecules in allergic disease and asthma. Int Arch Allergy Immunol. (2010) 151:179�. doi: 10.1159/000242355

188. Westendorf AM, Bruder D, Hansen W, Buer J. Intestinal epithelial antigen induces CD4 + T cells with regulatory phenotype in a transgenic autoimmune mouse model. Ann N Y Acad Sci. (2006) 1072:401𠄶. doi: 10.1196/annals.1326.035

189. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature (2009) 459:262𠄵. doi: 10.1038/nature07935

190. Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. (2009) 15:701𠄶. doi: 10.1038/nm.1951

191. McCracken KW, Howell JC, Wells JM, Spence JR. Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc. (2011) 6:1920𠄸. doi: 10.1038/nprot.2011.410

192. Rouch JD, Scott A, Lei NY, Solorzano-Vargas RS, Wang J, Hanson EM, et al. Development of functional microfold (M) cells from intestinal stem cells in primary human enteroids. PLoS ONE (2016) 11:e0148216. doi: 10.1371/journal.pone.0148216

193. Farin HF, Karthaus WR, Kujala P, Rakhshandehroo M, Schwank G, Vries RG, et al. Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell�rived IFN-γ. J Exp Med. (2014) 211:1393�. doi: 10.1084/jem.20130753

194. Ettayebi K, Crawford SE, Murakami K, Broughman JR, Karandikar U, Tenge VR, et al. Replication of human noroviruses in stem cell-derived human enteroids. Science (2016) 353:1387�. doi: 10.1126/science.aaf5211

195. Saxena K, Blutt SE, Ettayebi K, Zeng XL, Broughman JR, Crawford SE, et al. Human intestinal enteroids: a new model to study human rotavirus infection, host restriction & pathophysiology. J Virol. (2015) 90:43�. doi: 10.1128/jvi.01930-15

196. Forbester JL, Goulding D, Vallier L, Hannan N, Hale C, Pickard D, et al. Interaction of salmonella enterica serovar typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun. (2015) 83:2926�. doi: 10.1128/iai.00161-15

197. Chen YW, Huang SX, de Carvalho A, Ho SH, Islam MN, Volpi S, et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol. (2017) 19:542𠄹. doi: 10.1038/ncb3510

198. Routy B, Le Chatelier E. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (2018) 359:91𠄷. doi: 10.1126/science.aan3706

199. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science (2015) 350:1079�. doi: 10.1126/science.aad1329

200. Van der Flier LG, Clevers H. Stem cells, self-renewal & differentiation in the intestinal epithelium. Annu Rev Physiol. (2009) 71:241�. doi: 10.1146/annurev.physiol.010908.163145

Keywords: epithelial cells, MHC class II, antigen presentation, intestine, respiratory

Citation: Wosen JE, Mukhopadhyay D, Macaubas C and Mellins ED (2018) Epithelial MHC Class II Expression and Its Role in Antigen Presentation in the Gastrointestinal and Respiratory Tracts. Front. Immunol. 9:2144. doi: 10.3389/fimmu.2018.02144

Received: 18 June 2018 Accepted: 30 August 2018
Published: 25 September 2018.

Diane Bimczok, Montana State University, United States
Claudio Nicoletti, Università degli Studi di Firenze, Italy

Copyright © 2018 Wosen, Mukhopadhyay, Macaubas and Mellins. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


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