What is mhc class ii

Within cells, tapasin is a key protein that mediates the binding of high-affinity peptides to most class I proteins. Two major functions have been proposed for tapasin: i a chaperone-like stabilization of empty class I proteins 20 — 22 , 24 , and ii a peptide-editing function through peptide-exchange catalysis 26 , , Several computational models have been published to describe the mechanism of action of tapasin on MHC class I 28 , 29 , Most researchers agree on the importance of the F-pocket region for peptide exchange 14 , 21 , 37 , 80 , However, the association of F-pocket dynamics and the peptide-exchange mechanism remain a matter of debate.

So far, dynamics in the F-pocket region in the presence of peptide have not revealed any significant conformational exchange phenomena in most MD simulations Table 1. Using a computational systems model 73 , , it was shown that peptide exchange seems to depend on the opening and closing rate of the binding groove in the presence of peptide. Consequently, a low-affinity peptide complex would display fast opening rates, but only if the MHC allele variant has an F-pocket signature more plasticity that allows for fast closing in the presence of a high-affinity peptide as B , it would lead to efficient peptide exchange in the absence of catalyst.

Allele variants with a rigid F-pocket conformation as B in contrast depend on tapasin to sample the necessary conformational states to close the binding groove quickly. It has to be considered that as a default, tapasin is present in the cell and that it may also provide the necessary function as a chaperone to prevent the collapse of empty MHC class I molecules into a non-receptive state 29 , as it is experimentally measured in tapasin-deficient cells 21 , Two seminal studies made it unambiguously clear that HLA-DM recognizes complexes showing a P1-destabilized conformation 13 , However, since DM-susceptible structures rarely show any of the changes present in the DM-bound structure e.

Interestingly, increased fluctuations of this region could be observed by other computational and experimental studies, implying the existence of higher conformational entropy within this region 46 , However, a considerable influence of P1-remote sites on conformational dynamics and DM-dependence was recently demonstrated Similarly, and as already mentioned above, Ferrante et al.

According to their experimental and computational results, higher conformational entropy of pMHCII complexes correlates with DM susceptibility. A recent study by our group in the MHC class II field explored internal motions of pMHC class II molecules along the conformational peptide-exchange pathway in a more conceptual model In agreement with the general view, the catalyzed pathway depends on the particular destabilization of the region surrounding the P1 pocket, sharing in part features of MHC class II bound to DM.

The non-catalyzed pathway, however, was correlated to the ground state of the pMHCII complex and, therefore, is directly correlated with thermodynamic stability. However, a similar intermediate state can be defined for the very stable WT protein, where peptide release from the pockets was not mandatory for the observation of the early intermediates.

Thus, if the pMHCII forms a stable complex, the peptide editing depends on the population of rare conformations that can be selected by the catalyst DM for binding. In conclusion, this model helps to reconcile discrepancies in the hypothesized correlations of peptide affinity, pMHC stability, DM susceptibility, and catalytic effect Major histocompatibility complex proteins are encoded by oligogenic and highly polymorphic genes and most polymorphisms map to the regions important for peptide binding.

The pMHC complexes display various degrees of flexibility along the binding groove, and these dynamic features seem to correlate with the propensity for peptide exchange.

Of interest is the fact that tapasin and DM both bind their MHC targets in regions of enhanced dynamics. Short, destabilized helical segments together with their adjacent structural elements seem to represent the requirements for transient binding of the respective catalyst. The degree of these local flexibilities can be correlated to a higher dependence of a particular pMHC complex on tapasin or DM. Polymorphic substitutions might not only change the binding preference for certain ligands but also the overall stability and dynamics of the corresponding allelic variants.

In turn, this will affect the conformational ensemble recognized by the peptide editors and in principle should be able to explain why certain alleles seem to possess a generally lower taspasin or DM dependence. In this way, MHC molecules may become a paradigmatic example of how differences in the dynamic landscape of protein complexes translate into distinct functional outcomes of physiological relevance.

How far have we come and what has to be done to achieve this goal? Figures 4 and 5 summarize the findings described in this review and also emphasize the most daunting questions in the field that need to be answered in order to formulate a unifying concept of antigen exchange. What seems to be clear is that both type of MHC molecules can exchange peptide along two distinct pathways, with the ratio of spontaneous versus catalyzed exchange certainly being different for the allelic protein variants and pMHC complex.

While dynamics often correlates with thermodynamic stability, it has yet to be seen which type of motions are critical for catalysis and which structural elements are indispensable for these transitions to occur.

However, there are no structural insights about the replacement of DM by incoming peptide, thus requiring experimental and simulation strategies to follow the fate of DM-prebound MHCII molecules. In the case of MHCI, a tapasin-class I complex structure is required in order to provide a reliable framework for further experimental and theoretical studies. Similarly, characterization of empty MHC molecules will certainly aid in defining the dynamic modes that are explored by the peptide-binding domains.

Since it has been shown that empty MHC molecules can be rescued by the chaperoning function of the exchange catalysts , and thus the dynamics that occur upon peptide exchange are likely to show features of the empty state.

It seems, therefore, highly desirable to compare the two systems on time scales down to a few milliseconds. Figure 4. Thermodynamic model for peptide exchange of major histocompatibility complex MHC class I. Figure 5. Thermodynamic model for peptide editing of major histocompatibility complex class II. Binding of peptides which can displace the stabilizing interactions complete the peptide exchange process state 4. Spontaneous non-catalyzed peptide exchange depends on the intrinsic stability of the pMHCII complex and does not rely on the sampling of rare conformations state 2.

Binding of a new peptide would likely require dissociation of the bound peptide, leading to the empty state state 3 which rapidly converts into the non-receptive state state 3b but can also be chaperone by DM state 3c in order to allow for high-affinity peptide binding state 4. For both MHC classes, more sophisticated NMR experiments capitalizing on selective amino acid side-chain labeling protocols are probably required and methods relying on CEST or relaxation dispersion should be able to yield more direct information on the anticipated intermediate states , So far, in-depth NMR experiments are restricted to certain stable pMHC complexes and the investigation of other alleles have been hampered by the in-availability of other variants such as the disease-relevant DQ alleles.

There is a need to expand the experimental basis of dynamically investigated pMHC complexes in order to test the predictions made on the basis of the dynamic features of just a few alleles.

Solutions are most likely to come from protein engineering approaches in combination with the use of different expression systems. The increasing importance of MD simulations arises from the fact that micro-to-milli-second simulations in combination with Markov State Modeling will become more of a standard in the field. This is essential, because the critical intermediates of antigen exchange seem to be populated at this time scale. Once we are able to conceptualize conformational peptide exchange, we will be in the position to better predict MHC peptide occupancies in the context of cellular editing mechanisms and we will understand and be able to manipulate the action of small molecules or biological macromolecules that modulate peptide exchange.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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J Biol Chem — Nat Struct Biol — Biochemistry — Redistribution of MHC class II may allow IECs to influence immune responses during a pathogenic or inflammatory insult, by presenting peptides that promote immune clearance or induce tolerance. Whether these molecules are expressed during inflammation is less clear.

Unlike the gut during ontogeny, fetal lung tissue does not appear to express MHC class II on AEC surfaces during gestation except in the case of active inflammation Interestingly, invariant chain expression without co-expression of MHC class II has been detected on fetal alveolar epithelium by 12—14 weeks' gestational age in humans However, additional studies utilizing clinical specimens have provided conflicting data, especially in primary bronchial EC cultures 96 — Evidence in studies comparing germ-free to conventional rats supports constitutive surface expression of MHC II in lung parenchymal AECs, specifically Type II pneumocytes, but decreased expression in bronchial epithelium of germ-free rats, suggesting site-specific expression Lung tissue obtained from patients with allergy or autoimmunity, including chronic bronchitis, asthma, idiopathic pulmonary fibrosis or lung transplant rejection, shows enhanced expression of MHC class II on AECs 96 , 97 , — Viral infection, including parainfluenza, have demonstrably increased AEC MHC class II expression, whereas bacterial infection appears to have the opposite effect in human lung specimens 91 , 97 , Figure 3.

The airway is composed of the upper airway conducting zone for humidifying and clearing particulates of inhaled air bronchi and bronchioles and lower airway respiratory zone for gas exchange respiratory bronchioles and alveoli.

The polarity of class II expression is not well-defined. Unlike the intestine, organized lymphoid structures are not found in adulthood, except in disease states. Co-stimulatory molecule expression appears to be region-specific in humans, as well. Viral infection, specifically with rhinovirus, upregulates CD80 on alveolar cells and CD86 on bronchial cells In vivo data obtained from lung biopsies in patients with a variety of autoimmune pathologies, including lung transplant rejection and idiopathic pulmonary fibrosis, shows increased expression of CD80 and CD86 on AEC from all segments of the respiratory tract 97 , In comparison, in bronchiolitis obliterans organizing pneumonia now known as cryptogenic organizing pneumonia , an idiopathic interstitial lung disease believed to be secondary to epithelial damage, CD80 is upregulated in AECs without concurrent upregulation of CD86 or MHC class II expression 97 , Like gut, CD58 is constitutively expressed on alveolar ECs, though expression has not been demonstrated in isolated Type II pneumocytes T cell hybridomas do not need co-stimulation, which arguably mimics the reduced costimulatory requirements of the majority of T cells in the lamina propria, which are antigen-experienced memory cells , When the epithelium is breached, IECs may interact with antigen along both the apical and basolateral surfaces, raising the possibility that novel peptide epitopes can be generated.

Dotan et al. Another mechanism by which ECs may modulate antigen presentation is through exosomes. Exosomes, cell-derived vesicles laden with MHC class II, are released extracellularly when the limiting membrane of a multi-vesicular endosome fuses with the plasma membrane These exosomes express late-endosomal markers, consistent with their origin in multi-vesicular bodies. Defining the relative contributions of direct IEC antigen presentation vs.

Additionally, investigations by Cunningham et al. Further characterization by other groups shows that purified allogeneic T cells are stimulated in response to bronchial ECs, which is abolished by the addition of anti-DR antibody Bronchial ECs have also been shown to present protein antigens to antigen-specific sensitized T cells, suggesting the ability of AECs to process and present foreign antigen to the underlying lymphoid tissue Co-localization studies further demonstrate the trafficking of these antigens through early and late endosomes to acid vesicles and lysosomes In vitro studies have important caveats.

Therefore, studies using these cell lines may be more representative of EC antigen presentation during inflammation rather than homeostasis. Colorectal cancer cells are also susceptible to genetic and epigenetic abnormalities, including changes in DNA methylation that affect CIITA expression Small intestinal EC lines, such as HEC-6 and H4, exist, but are derived from fetal tissue and are more representative of crypt stem cells than fully differentiated ECs Additionally, AECs are often derived from bronchoalveolar lavage brushings or fluid in patients with additional underlying pathologies, which are highly operator- and patient-dependent and may not be representative of the entire airway epithelium.

Furthermore, in vitro experiments using peripheral blood T cells may not recapitulate interactions between ECs and organ-specific T cells. Therefore, the complexity of the epithelium and the arrangements of the many cell types found within may not be well-represented in cultures of primary purified cell lines.

Several in vivo studies of IEC antigen presentation have focused on IBD, where inflammatory responses to the gut microbiota are believed to elicit tissue damage, yet the role of IECs themselves remain poorly defined.

Maggio-Price et al. In a different murine colitis model, Thelemann et al. Similar in vivo data has not been collected in the respiratory tract of animal models, and effects on the lung epithelium were not evaluated in the above models. These findings have been re-capitulated in human AECs in vivo , as well 99 , One candidate is IL, an IL superfamily cytokine released by activated DCs and elevated during intestinal inflammation Another potential candidate is IL IL has been shown to be elevated in autoimmune colitis including IBD and celiac disease and is a key mediator of intestinal homeostasis , — Interestingly, tissue explants from patients with active celiac disease show IL expression only in the crypts Recent evidence in humans shows that AEC also constitutively produce IL in vitro in animal models , Therefore, further investigation is needed to determine if these or other region-specific cytokines upregulate EC MHC class II expression.

Commensal bacteria reside within the lumen of the gut, reaching a density of up to 10 12 cells per cm 3 in the large intestine It is well-established that these microbes contribute to the development of the intestinal immune system; gnotobiotic mice, for example, do not form isolated lymphoid structures in the small intestine Though the lung and gut share a common origin at the oropharynx, microbial populations are vastly different. The lung is not completely sterile but has a much lower bacterial burden without a characteristic microbiome like the gut; rather, lung flora tends to resemble oral flora and may change in response to a variety of stimuli and pathologies , There is limited but interesting evidence that specific classes of commensals, such as segmented filamentous bacteria, are sufficient to induce MHC class II in IECs Additionally, the roles of viruses and fungi within the microbiome and their effects on EC MHC class II expression remain largely unexplored.

Studies in natural fish populations link MHC class II allelic variation with the abundance of certain microbial taxa These findings corroborate studies in laboratory mice, which show that MHC class II-linked changes in the microbiome mediate risk of enteric infection and autoimmune disease, such as type 1 diabetesc , The precise mechanisms behind these effects remain poorly understood, though there is evidence that MHC class II polymorphisms control microbial populations through IgA phenotype and thus modify susceptibility to pathogens The gut microbiome has been shown to affect lung susceptibility to infection with viral, fungal and bacterial pathogens — The severity of ozone-induced asthma in mice appears to be regulated by the gut microbiome through short chain fatty acid production The microbiome may even affect predisposition to lung cancer as evidenced through murine studies focused on probiotic use, though further mechanistic and human studies are still needed in this area, as well , Though much of the available evidence on MHC class II expression by ECs was obtained decades ago, this is an exciting time for research into the role of ECs in mucosal immunology.

Renewed awareness of the role played by epithelial cells in homeostasis and disease and technical advances in different areas open up several new avenues for research and clinical applications. Celiac disease, in which blunting of the villous tips on biopsy is pathognomonic, provides an example of a disease in which the role of the EC should be re-visited. Levels of MHC class II that are below the limit of detection by immunohistochemistry used in many early papers may therefore be sufficient to activate T cells.

More sensitive techniques, such as flow cytometry or electron microscopy, are more informative, as evidenced by more recent papers. Another novel possibility is investigation utilizing multiplexed ion beam imaging MIBI to visualize large panels of cell-surface proteins tagged with elemental metals that may allow improved detection of MHC II isoforms and co-localization of various co-stimulatory molecules on tissue sections Using these technologies to study celiac disease, a model disease in which the inciting immunogen and the presenting MHC class II-molecules are known, may provide important insights into the role of ECs in antigen presentation.

The function of co-stimulatory molecules in this process is another area that requires more investigation. While some description of EC surface expression of classic B7 molecules, CD80 and CD86, is found in the literature above , their roles during homeostasis and inflammation remain unclear. The lack of expression of CD86 found in the gut, compared to constitutive expression in the airway, may suggest a diminished role of IECs in interactions with Tregs Work on the ICOS co-stimulation pathway in the airway already has provided promising results, with anti-ICOS treatment leading to prevention of chronic lung transplant rejection and obliterative bronchiolitis as well as ICOS being shown as an important player in asthma , However, the contribution of the aerodigestive epithelium in mediating these interactions remains to be explored.

Further delineation of the subsets and character of ECs are needed as well. The epithelium is composed of both stem cells and specialized subtypes as described above, many of which remain poorly understood. Both MHC II expression and antigen presenting capabilities and function may therefore differ among these cells. Work reviewed here has shown that, for example, M cells in the gut or type II pneumocytes in the lung may have roles in antigen presentation and expression of HLA-DR 9 , 11 , Furthermore, the polarity and anatomic localization of intestinal and pulmonary ECs also likely bear significant implications for antigen uptake, processing and presentation and warrant further investigation 53 , 55 , 71 — 73 , 78 — Defining the roles of these various cell types and their locoregional interactions thus may provide additional important insights.

The work by Westendorf et al. Moreover, it is plausible that MHC class II on ECs not only allows ECs to modulate immune responses, but also in fact allows the immune system to regulate the epithelium. Cytokines released by adjacent mucosal and intraepithelial immune cells in response to EC presentation of MHC class II-bound peptides may alter cell renewal, barrier integrity, cell type composition, and the innate immune functions of the epithelium.

A promising approach to explore these questions is in organoids derived from stem cells or induced pluripotent stem cells that can differentiate into specialized cell types mimicking the physiological structure of the epithelium — Organoids offer a reductionist setting for testing the role of immune cells, cytokines, pathogens, and other regulatory factors on MHC class II in primary ECs in a way that appears to model organs physiologically.

Intestinal organoids can be readily infected with human strains of enteric pathogens, such as rotavirus, norovirus, and Salmonella to allow exploration of MHC class II internalization and polarity during infection and inflammation — The study of lung organoids remains, comparatively, in its infancy, though work has been done to create structures resembling fetal lung buds in the second trimester of gestation for the study of respiratory syncytial virus Organoids may provide a model system to study the aforementioned hypotheses to provide evidence more pertinent to humans.

Finally, current research is actively exploring the contributions of the microbiome to systemic immunity. However, how the microbiome changes EC structure and function, especially through MHC class II and co-stimulatory molecule expression, and whether this affects development of disease and ultimate outcomes are also key questions. Highlighting the importance of co-stimulatory molecules, recent clinical work has demonstrated that the efficacy of cancer immunotherapies targeting B7 molecules PD-L1 or CTLA-4 in epithelial cancers including non-small cell lung carcinoma as well as colon cancer appear keenly dependent on the gut microbiome; lack of or depletion of commensals using oral antibiotics appears to attenuate tumor response to these therapies , Ultimately, systems that integrate immunological, microbial, and environmental signals to study EC MHC class II expression and function are likely to advance our understanding of mucosal immunity and the epithelium of the aerodigestive tract.

How these findings can be manipulated to affect infectious, autoimmune or even neoplastic diseases will likely be pursued in the coming years. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. DM is supported by the Gupta Family Foundation.

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The authors also thank the anonymous referees who provided excellent advice in the preparation of this manuscript. You can also search for this author in PubMed Google Scholar. Correspondence to Paul A. Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus and B cells in the bone marrow that strongly recognize self antigen undergo deletion or marked suppression.

Refers to mechanisms that control the reactivity of self antigen-specific lymphocytes that have escaped central tolerance. These mechanisms include 'active' suppression by cells that have immunomodulatory functions such as regulatory T cells , as well as the induction of anergy or deletion, for example, through antigen presentation to T cells in the absence of co-stimulation.

A protein that binds to newly synthesized MHC class II molecules and promotes their egress from the endoplasmic reticulum. Forms of late endosomes that contain numerous intraluminal vesicles. MVBs can either fuse with lysosomes degrading the intraluminal vesicles and associated cargo proteins or with the plasma membrane releasing the intracellular vesicles from the cell in the form of exosomes.

A nonspecific endocytosis pathway that facilitates the uptake of extracellular material that can vary in size from small molecules to intact cells. Plasma membrane ruffles entrap extracellular material and the resulting macropinosomes internalize and deliver their cargo to the endosomal—lysosomal pathway. The specific uptake of extracellular material that binds to membrane receptors and enters the cell through clathrin-coated vesicles. Integral membrane proteins directly bind to clathrin-associated adaptor molecules to facilitate their uptake.

Immature dendritic cells DCs with a morphology that resembles that of plasma cells. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection. The process by which antigen-presenting cells APCs load peptides that are derived from extracellular antigens onto MHC class I molecules.

Cross-presentation is essential for the initiation of immune responses to pathogens that do not infect APCs. A process by which intracellular proteins, organelles and invading microorganisms are encapsulated in cytosolic vacuoles. These vacuoles known as autophagosomes fuse with lysosomes and degrade encapsulated cargo for antigen presentation. Bulk cytoplasmic autophagy occurs as a starvation response.

A junctional structure that is formed at the interface between T cells and target cells including antigen-presenting cells. The molecular organization within this structure concentrates signalling molecules and directs the release of cytokines and lytic granules towards the target cell. Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres.

These dendritic cells DCs have long dendrites and carry intact antigens on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies. Structures that arise from phase separation of different plasma membrane lipids as a result of their physical properties. This results in the formation of distinct and stable lipid domains in membranes, which might provide a platform for membrane-associated protein organization. Reprints and Permissions. Nat Rev Immunol 15, — Download citation.

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Skip to main content Thank you for visiting nature. Subjects Antigen-presenting cells Antigen processing and presentation Dendritic cells. Key Points MHC class II molecules bind antigenic peptides that are generated in endosomal—lysosomal antigen-processing compartments. Access through your institution. Buy or subscribe. Rent or Buy article Get time limited or full article access on ReadCube. Figure 2: Pathways of antigen endocytosis in antigen-presenting cells.

References 1 Banchereau, J. Acknowledgements The authors acknowledge the many investigators in the field whose primary data could not be cited in this Review owing to space limitations. Roche View author publications.

View author publications. Ethics declarations Competing interests The authors declare no competing financial interests. PowerPoint slides. PowerPoint slide for Fig. Glossary Central tolerance Self-tolerance that is created at the level of the central lymphoid organs. Peripheral tolerance Refers to mechanisms that control the reactivity of self antigen-specific lymphocytes that have escaped central tolerance. Invariant chain Ii. Multivesicular bodies MVBs.

Macropinocytosis A nonspecific endocytosis pathway that facilitates the uptake of extracellular material that can vary in size from small molecules to intact cells. Clathrin-mediated endocytosis The specific uptake of extracellular material that binds to membrane receptors and enters the cell through clathrin-coated vesicles.

Cross-presentation The process by which antigen-presenting cells APCs load peptides that are derived from extracellular antigens onto MHC class I molecules. Macroautophagy A process by which intracellular proteins, organelles and invading microorganisms are encapsulated in cytosolic vacuoles. Immunological synapse A junctional structure that is formed at the interface between T cells and target cells including antigen-presenting cells.

Follicular DCs Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres.