What is mhc 2

Tuft cells, a rare EC with a distinctive tufted morphology, express chemosensory receptors and may have roles in type 2 immunity and mucosal immunity, but remain poorly understood 17 , Figure 1. MHC class II and invariant chain form nonamers—or, according to recent studies, pentamers and heptamers—that traffic into an acidic endosomal compartment. IECs have a known role in innate immune responses via expression of a variety of pattern recognition receptors PRRs.

PRRs trigger intracellular pathways that lead to cytokine and chemokine release. PRRs important in the gut include Toll-like receptors 1—9 TLRs and nucleotide-binding oligomerization domain-containing proteins NODs that recognize pathogen-associated molecular patterns PAMPs derived from microbial components 19 — The bronchial epithelium is composed of basal cells, columnar ciliated epithelial cells, mucous goblet cells, brush or tuft cells and Clara cells 24 , Neuroendocrine cells, similar to the gut, promote the vasomotor function of the airways Basal cells, similar to Paneth cells, are important for epithelial regeneration and produce bioactive molecules including endopeptidase, lipoxygenase products and cytokines 28 , Goblet cells, like those of the gut, secrete mucus in order to trap foreign particles and pathogens 24 , Columnar ciliated cells account for the majority of AECs in the bronchial lumen and are responsible mainly for mucus clearance Clara cells produce surfactants and antiproteases including secretory leukocyte protease inhibitor and p mono-oxygenases Type I pneumocytes are mainly responsible for gas exchange and make up the majority of the alveolar surface, though recent evidence suggests they may have additional roles in remodeling, regulation and defense Type II pneumocytes are responsible for surfactant production and reuptake though they also act as progenitor cells and enhance immune responses 33 , Unlike the gut, an integrated mucosal immune system does not exist in the healthy adult human lung, though bronchus-associated lymphoid tissue BALT is present in young children and also develops in many disease states in adulthood 35 , The class II pathway for processing and presenting antigen is complex but involves interaction with accessory molecules and trafficking through intracellular compartments 42 — In humans, cell surface expression of class II is first detected around 18 weeks' gestation and increases through development 15 , 58 , At homeostasis, MHC class II appears to be constitutively expressed on small intestinal enterocytes, most densely in the upper villus 15 , 53 , Conversely, MHC class II is absent from small intestinal crypts as well as colonic epithelium under normal physiologic conditions but is upregulated in specimens obtained from patients with active inflammatory bowel disease IBD , celiac disease, and graft vs.

Exposure to inflammatory antigens, such as gliadin in celiac disease, has also been shown to cause the upregulation of cell surface MHC class II 62 , These changes are dependent on active disease; celiac patients in remission have IEC MHC class II levels comparable to those of non-celiac controls Figure 2. At homeostasis left , MHC class II is constitutively expressed in the upper villi of the small intestine. At the crypt base, intestinal stem cells self-renew and differentiate into specialized cell types: antimicrobial-producing Paneth cells, mucus-producing Goblet cells, hormone-producing enteroendocrine cells, and nutrient-absorptive enterocytes Epithelial barrier integrity decreases, which may result in ECs encountering antigen along both the apical and basolateral surfaces.

Organized lymphoid structures, known as Peyer's Patches, contain dense concentrations of professional antigen presenting cells B cells, macrophages, dendritic cells. These cells encounter antigen delivered by microfold M cells, which transcytose luminal antigens. IECs are polarized, with brush border enzymes localized to the apical luminal surface to break down dietary antigens and poly-Ig receptors restricted to the basolateral surface to translocate IgA into the intestinal lumen This polarity is important as peptide-presentation to the resident immune cells of the GALT is necessary for systemic crosstalk.

However, other reports, including a comparatively recent study, show lateral and basolateral MHC class II 73 — These contradictory observations may be due to variability in methods of tissue processing and labeling, which has a significant effect on antigen stability and labeling efficiency 68 , 76 , Both conventional and electron microscopy have been used to show redistribution of IEC MHC class II from multivesicular bodies late endosomes to the basolateral membrane located on the submucosal side of the epithelial membrane in both celiac disease and IBD 74 , 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 — Immunol Rev — MHC class II complexes sample intermediate states along the peptide exchange pathway.

Nat Commun Conformational variation in structures of classical and non-classical MHCII proteins and functional implications. Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle.

Structural analysis of MHC class I molecules with bound peptide antigens. Semin Immunol — A subset of HLA-B27 molecules contains peptides much longer than nonamers. High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I.

Implications for T-cell receptor engagement and T-cell immunodominance. J Biol Chem —9. Haematologica —8. Peptide linkage to the alpha-subunit of MHCII creates a stably inverted antigen presentation complex. A novel pathway of presentation by class II-MHC molecules involving peptides or denatured proteins important in autoimmunity. Mol Immunol —8. Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion.

J Exp Med — Zhou Z, Jensen PE. Front Immunol Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide.

Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet —6. Molecular mechanisms for contribution of MHC molecules to autoimmune diseases.

Stability of empty and peptide-loaded class II major histocompatibility complex molecules at neutral and endosomal pH: comparison to class I proteins. Comparative molecular dynamics analysis of tapasin-dependent and -independent MHC class I alleles.

Protein Sci — Differential tapasin dependence of MHC class I molecules correlates with conformational changes upon peptide dissociation: a molecular dynamics simulation study. Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides. Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins.

PLoS One 9:e Selector function of MHC I molecules is determined by protein plasticity. The peptide-receptive transition state of MHC class I molecules: insight from structure and molecular dynamics. J Immunol —9. Not all empty MHC class I molecules are molten globules: tryptophan fluorescence reveals a two-step mechanism of thermal denaturation.

Thermal stability comparison of purified empty and peptide-filled forms of a class I MHC molecule. Structural and functional mosaic nature of MHC class I molecules in their peptide-free form. Mol Immunol —9. Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro. Cell —7. The crystal structure of H-2D b complexed with a partial peptide epitope suggests a major histocompatibility complex class I assembly intermediate.

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control. J Cell Sci — Stable peptide binding to MHC class II molecule is rapid and is determined by a receptive conformation shaped by prior association with low affinity peptides. J Immunol —6. Empty class II major histocompatibility complex created by peptide photolysis establishes the role of DM in peptide association. Empty and peptide-loaded class II major histocompatibility complex proteins produced by expression in Escherichia coli and folding in vitro.

Protein Expr Purif — Probing the ligand-induced conformational change in HLA-DR1 by selective chemical modification and mass spectrometric mapping. Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket.

PLoS One 3:e Characterization of structural features controlling the receptiveness of empty class II MHC molecules. PLoS One 6:e Flexibility of the MHC class II peptide binding cleft in the bound, partially filled, and empty states: a molecular dynamics simulation study. Biopolymers — Monoclonal antibodies specific for the empty conformation of HLA-DR1 reveal aspects of the conformational change associated with peptide binding.

Differential peptide dynamics is linked to major histocompatibility complex polymorphism. HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution. How T cell receptors interact with peptide-MHCs: a multiple steered molecular dynamics study.

Proteins — PLoS Comput Biol 8:e PLoS One 7:e Proline substitution independently enhances H-2D b complex stabilization and TCR recognition of melanoma-associated peptides. Chem Pharm Bull Tokyo — A comparative approach linking molecular dynamics of altered peptide ligands and MHC with in vivo immune responses.

PLoS One 5:e Association of HLA-DR1 with the allergic response to the major mugwort pollen allergen: molecular background. BMC Immunol Bello M, Correa-Basurto J. Molecular dynamics simulations to provide insights into epitopes coupled to the soluble and membrane-bound MHC-II complexes. PLoS One 8:e Chem Pharm Bull Tokyo —8. Dynamic influence of the two membrane-proximal immunoglobulin-like domains upon the peptide-binding platform domain in class I and class II major histocompatibility complexes: normal mode analysis.

Chem Pharm Bull Tokyo —9. Influence of inflammation-related changes on conformational characteristics of HLA-B27 subtypes as detected by IR spectroscopy.

FEBS J — J Biomol NMR — Dynamics of free versus complexed beta2-microglobulin and the evolution of interfaces in MHC class I molecules. Immunogenetics — Peptide modulation of class I major histocompatibility complex protein molecular flexibility and the implications for immune recognition.

Peptide-dependent conformational fluctuation determines the stability of the human leukocyte antigen class I complex. Madden DR. The three-dimensional structure of peptide-MHC complexes.

Annu Rev Immunol — Nature —4. Before elimination of infected cells can begin, APCs must first activate the T cells involved in cellular immunity. If an intracellular pathogen directly infects the cytoplasm of an APC, then the processing and presentation of antigens can occur as described in proteasomes and on the cell surface with MHC I. However, if the intracellular pathogen does not directly infect APCs, an alternative strategy called cross-presentation is utilized.

The exact mechanisms by which cross-presentation occur are not yet well understood, but it appears that cross-presentation is primarily a function of dendritic cells and not macrophages or B cells. Which type of antigen-presenting molecule is found only on macrophages, dendritic cells, and B cells?

Skip to main content. Adaptive Specific Host Defenses. Search for:. What is the role of antigen presentation in adaptive immunity? What is cross-presentation, and when is it likely to occur? Key Concepts and Summary Major histocompatibility complex MHC is a collection of genes coding for glycoprotein molecules expressed on the surface of all nucleated cells. Cells that become infected by intracellular pathogens can present foreign antigens on MHC I as well, marking the infected cell for destruction.

MHC II molecules are expressed only on the surface of antigen-presenting cells macrophages, dendritic cells, and B cells. Ireland, J. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells.

Wegner, N. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Nedjic, J. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Aichinger, M. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. Lee, H. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32 , — Manoury, B.

Immunity 18 , — Shi, G. Immunity 10 , — Nakagawa, T. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice.

Lautwein, A. Inflammatory stimuli recruit cathepsin activity to late endosomal compartments in human dendritic cells. Activation of lysosomal function during dendritic cell maturation. Inaba, K. The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. Turley, S. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP.

Nature Immunol. Delamarre, L. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. This important study shows that DCs are better APCs than macrophages, partly because their late endosomal—lysosomal compartments are less proteolytic, thereby limiting the complete destruction of internalized antigens and promoting antigenic peptide generation.

Chatterjee, B. Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells. Savina, A. Immunity 30 , — Romao, S. Reith, W. Steimle, V. Wilson, N. Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells.

LeibundGut-Landmann, S. MHC class II expression is differentially regulated in plasmacytoid and conventional dendritic cells. Villadangos, J.

Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29 , — Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces. Kleijmeer, M. MHC class II compartments and the kinetics of antigen presentation in activated mouse spleen dendritic cells. Harding, C.

Class II MHC molecules are present in macrophage lysosomes and phagolysosomes that function in the phagocytic processing of Listeria monocytogenes for presentation to T cells. Pierre, P. Endosomally stored MHC class II does not contribute to antigen presentation by dendritic cells at inflammatory conditions. Traffic 12 , — Cella, M.

Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. Boes, M. Chow, A. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. References 77—79 show that maturation of DCs promotes tubulation of antigen-processing compartments, which results in the delivery of peptide—MHC class II to the plasma membrane. Lankar, D. Dynamics of major histocompatibility complex class II compartments during B cell receptor-mediated cell activation.

Siemasko, K. Vascotto, F. Le Roux, D. Syk-dependent actin dynamics regulate endocytic trafficking and processing of antigens internalized through the B-cell receptor. Cell 18 , — Nashar, T. Mohan, J. Amigorena, S. Yuseff, M. Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. Immunity 35 , — This study shows that the engagement of B cells with an immobilized antigen leads to polarized lysosome exocytosis, delivery of lysosomal enzymes into the B cell—antigen interface and allows antigen extraction from the immobilized surface into the B cell.

Rocha, N. MHC class II molecules on the move for successful antigen presentation. EMBO J. Kamon, H. Ocana-Morgner, C. Paul, P. Thery, C. Segura, E. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming.

Muntasell, A. Buschow, S. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10 , — Bastos-Amador, P. Capture of cell-derived microvesicles exosomes and apoptotic bodies by human plasmacytoid dendritic cells. Leukocyte Biol. Denzer, K. Viaud, S. Dendritic cell-derived exosomes for cancer immunotherapy: what's next? Cancer Res.