- Review Article
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The ins and outs of MHC class II-mediated antigen processing and presentation
Nature Reviews Immunologyvolume 15, pages203–216 (2015)Cite this article
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Key Points
MHC class II molecules bind antigenic peptides that are generated in endosomal–lysosomal antigen-processing compartments. These peptides are derived from proteins that access these compartments using various endocytic pathways and also as a result of autophagy.
Proteolysis in antigen-processing compartments is regulated in antigen-presenting cells (APCs) to favour the formation of antigenic peptides that can bind to MHC class II and to avoid the complete hydrolysis of proteins to very short peptides or to amino acids.
Nonspecific endocytosis processes are terminated following dendritic cell (DC) activation, but mature DCs can still internalize antigen by receptor-mediated endocytosis or phagocytosis. Using these pathways, mature DCs can generate peptide–MHC class II complexes and activate naive CD4+ T cells.
The formation of antigen-processing compartments is regulated during APC activation. B cell activation results in MHC class II recruitment to endosomes and lysosomes to form these compartments, whereas in DCs, lysosomal proteases relocalize to antigen-processing compartments and enhance antigen proteolysis.
APC activation leads to efficient generation of peptide–MHC class II complexes and markedly increases the expression of these complexes on the APC plasma membrane. Increased surface expression of peptide–MHC class II complexes on activated APCs is a result of enhanced MHC class II transcription and/or translation, movement of intracellular peptide–MHC class II complexes to the APC plasma membrane and reduced lysosomal MHC class II degradation.
Expression of the E3 ubiquitin ligase MARCH1 by immature APCs promotes rapid turnover of peptide–MHC class II complexes. DC activation terminates MARCH1 expression and ubiquitylation of peptide–MHC class II complexes, thus increasing the half-life of peptide–MHC class II complexes.
Abstract
Antigenic peptide-loaded MHC class II molecules (peptide–MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4+ T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide–MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide–MHC class II complexes, the intracellular trafficking of peptide–MHC class II complexes to the APC plasma membrane and their ultimate degradation.
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References
Banchereau, J. et al. Immunobiology of dendritic cells.Annu. Rev. Immunol.18, 767–811 (2000).
Harwood, N. E. & Batista, F. D. Early events in B cell activation.Annu. Rev. Immunol.28, 185–210 (2010).
Trombetta, E. S. & Mellman, I. Cell biology of antigen processingin vitro andin vivo.Annu. Rev. Immunol.23, 975–1028 (2005).
Blum, J. S., Wearsch, P. A. & Cresswell, P. Pathways of antigen processing.Annu. Rev. Immunol.31, 443–473 (2013).
Bozzacco, L. et al. Mass spectrometry analysis and quantitation of peptides presented on the MHC II molecules of mouse spleen dendritic cells.J. Proteome Res.10, 5016–5030 (2011).
Cresswell, P. Invariant chain structure and MHC class II function.Cell84, 505–507 (1996).
Dugast, M., Toussaint, H., Dousset, C. & Benaroch, P. AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes.J. Biol. Chem.280, 19656–19664 (2005).
McCormick, P. J., Martina, J. A. & Bonifacino, J. S. Involvement of clathrin and AP-2 in the trafficking of MHC class II molecules to antigen-processing compartments.Proc. Natl Acad. Sci. USA102, 7910–7915 (2005).
Roche, P. A., Teletski, C. L., Stang, E., Bakke, O. & Long, E. O. Cell surface HLA-DR-invariant chain complexes are targeted to endosomes by rapid internalization.Proc. Natl Acad. Sci. USA90, 8581–8585 (1993).
Roche, P. A. & Cresswell, P. Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding.Nature345, 615–618 (1990).
Castellino, F. & Germain, R. N. Extensive trafficking of MHC class II-invariant chain complexes in the endocytic pathway and appearance of peptide-loaded class II in multiple compartments.Immunity.2, 73–88 (1995).
Neefjes, J. CIIV, MIIC and other compartments for MHC class II loading.Eur. J. Immunol.29, 1421–1425 (1999).
Busch, R. et al. Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression.Immunol. Rev.207, 242–260 (2005).
Denzin, L. K., Fallas, J. L., Prendes, M. & Yi, W. Right place, right time, right peptide: DO keeps DM focused.Immunol. Rev.207, 279–292 (2005).
Lim, J. P. & Gleeson, P. A. Macropinocytosis: an endocytic pathway for internalising large gulps.Immunol. Cell Biol.89, 836–843 (2011).
Mercer, J. & Helenius, A. Virus entry by macropinocytosis.Nature Cell Biol.11, 510–520 (2009).
Clement, C. C., Rotzschke, O. & Santambrogio, L. The lymph as a pool of self-antigens.Trends Immunol.32, 6–11 (2011).
Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.J. Exp. Med.182, 389–400 (1995).
West, M. A. et al. Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling.Science305, 1153–1157 (2004).This study shows that acute activation of DCs leads to a transient burst of macropinocytosis, which enables DCs to internalize a large 'gulp' of exogenous antigens.
Garrett, W. S. et al. Developmental control of endocytosis in dendritic cells by Cdc42.Cell102, 325–334 (2000).
Reis e Sousa, C., Stahl, P. D. & Austyn, J. M. Phagocytosis of antigens by Langerhans cellsin vitro.J. Exp. Med.178, 509–519 (1993).
Platt, C. D. et al. Mature dendritic cells use endocytic receptors to capture and present antigens.Proc. Natl Acad. Sci. USA107, 4287–4292 (2010).In this study, the authors show that mature DCs maintain the ability to capture exogenous antigens if the antigen binds to endocytic receptors that are present on the mature DC surface.
Young, L. J. et al. Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens.Proc. Natl Acad. Sci. USA104, 17753–17758 (2007).
Drutman, S. B. & Trombetta, E. S. Dendritic cells continue to capture and present antigens after maturationin vivo.J. Immunol.185, 2140–2146 (2010).This intriguing study challenges the dogma that mature DCs are incapable of nonspecific endocytosis by showing thatin vivo-matured DCs are capable of internalizing, processing and presenting various 'soluble' antigens to CD4+ T cells.
Rock, K. L., Benacerraf, B. & Abbas, A. K. Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors.J. Exp. Med.160, 1102–1113 (1984).
Fearon, D. T. & Carroll, M. C. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex.Annu. Rev. Immunol.18, 393–422 (2000).
Antoniou, A. N. & Watts, C. Antibody modulation of antigen presentation: positive and negative effects on presentation of the tetanus toxin antigen via the murine B cell isoform of FcγRII.Eur. J. Immunol.32, 530–540 (2002).
Bonifaz, L. C. et al.In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination.J. Exp. Med.199, 815–824 (2004).
Leung, C. S. et al. Robust T-cell stimulation by Epstein–Barr virus-transformed B cells after antigen targeting to DEC-205.Blood121, 1584–1594 (2013).
Stuart, L. M. & Ezekowitz, R. A. Phagocytosis: elegant complexity.Immunity22, 539–550 (2005).
Bonaccorsi, I. et al. Membrane transfer from tumor cells overcomes deficient phagocytic ability of plasmacytoid dendritic cells for the acquisition and presentation of tumor antigens.J. Immunol.192, 824–832 (2014).
Steinman, R. M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells.J. Exp. Med.191, 411–416 (2000).
Tse, S. M. et al. Differential role of actin, clathrin, and dynamin in Fcγ receptor-mediated endocytosis and phagocytosis.J. Biol. Chem.278, 3331–3338 (2003).
Guermonprez, P. et al. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells.Nature425, 397–402 (2003).
Houde, M. et al. Phagosomes are competent organelles for antigen cross-presentation.Nature425, 402–406 (2003).
Joffre, O. P., Segura, E., Savina, A. & Amigorena, S. Cross-presentation by dendritic cells.Nature Rev. Immunol.12, 557–569 (2012).
Blander, J. M. & Medzhitov, R. Regulation of phagosome maturation by signals from toll-like receptors.Science304, 1014–1018 (2004).
Blander, J. M. & Medzhitov, R. Toll-dependent selection of microbial antigens for presentation by dendritic cells.Nature440, 808–812 (2006).This study shows that individual phagosomes in a single DC behave autonomously, and that only phagosomes containing TLR ligands process and present their antigens to CD4+ T cells.
Russell, D. G. & Yates, R. M. TLR signalling and phagosome maturation: an alternative viewpoint.Cell. Microbiol.9, 849–850 (2007).
Mantegazza, A. R. et al. Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4+ T cells.Immunity36, 782–794 (2012).
Hoffmann, E. et al. Autonomous phagosomal degradation and antigen presentation in dendritic cells.Proc. Natl Acad. Sci. USA109, 14556–14561 (2012).
Mantegazza, A. R. et al. TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation.Proc. Natl Acad. Sci. USA111, 15508–15513 (2014).
Adamopoulou, E. et al. Exploring the MHC-peptide matrix of central tolerance in the human thymus.Nature Commun.4, 2039 (2013).
Crotzer, V. L. & Blum, J. S. Autophagy and adaptive immunity.Immunology131, 9–17 (2010).
Schmid, D., Pypaert, M. & Munz, C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes.Immunity26, 79–92 (2007).
Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy.Science307, 593–596 (2005).
Ireland, J. M. & Unanue, E. R. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells.J. Exp. Med.208, 2625–2632 (2011).
Wegner, N. et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis.Immunol. Rev.233, 34–54 (2010).
Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance.Nature455, 396–400 (2008).
Aichinger, M., Wu, C., Nedjic, J. & Klein, L. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance.J. Exp. Med.210, 287–300 (2013).References 49 and 50 reveal an important role for macroautophagy in the generation of peptides required for both the positive and the negative selection of the CD4+ T cell repertoire.
Lee, H. K. et al.In vivo requirement for Atg5 in antigen presentation by dendritic cells.Immunity32, 227–239 (2010).
Manoury, B. et al. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone.Immunity18, 489–498 (2003).
Shi, G. P. et al. Cathepsin S required for normal MHC class II peptide loading and germinal center development.Immunity10, 197–206 (1999).
Nakagawa, T. Y. et al. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice.Immunity10, 207–217 (1999).
Lautwein, A. et al. Inflammatory stimuli recruit cathepsin activity to late endosomal compartments in human dendritic cells.Eur. J. Immunol.32, 3348–3357 (2002).
Trombetta, E. S., Ebersold, M., Garrett, W., Pypaert, M. & Mellman, I. Activation of lysosomal function during dendritic cell maturation.Science299, 1400–1403 (2003).
Inaba, K. et al. The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli.J. Exp. Med.191, 927–936 (2000).
Turley, S. J. et al. Transport of peptide-MHC class II complexes in developing dendritic cells.Science288, 522–527 (2000).
Manoury, B. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP.Nature Immunol.3, 169–174 (2002).
Delamarre, L., Pack, M., Chang, H., Mellman, I. & Trombetta, E. S. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate.Science307, 1630–1634 (2005).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. et al. Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells.Blood120, 2011–2020 (2012).
Savina, A. et al. The small GTPase Rac2 controls phagosomal alkalinization and antigen crosspresentation selectively in CD8+ dendritic cells.Immunity30, 544–555 (2009).
Romao, S. et al. Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing.J. Cell Biol.203, 757–766 (2013).
Reith, W., LeibundGut-Landmann, S. & Waldburger, J. M. Regulation of MHC class II gene expression by the class II transactivator.Nature Rev. Immunol.5, 793–806 (2005).
Steimle, V., Siegrist, C. A., Mottet, A., Lisowska-Grospierre, B. & Mach, B. Regulation of MHC class II expression by interferon-γ mediated by the transactivator geneCIITA.Science265, 106–109 (1994).
Wilson, N. S., El-Sukkari, D. & Villadangos, J. A. Dendritic cells constitutively present self antigens in their immature statein vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis.Blood103, 2187–2195 (2004).
Young, L. J. et al. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells.Nature Immunol.9, 1244–1252 (2008).
LeibundGut-Landmann, S., Waldburger, J. M., Reis e Sousa, C., Acha-Orbea, H. & Reith, W. MHC class II expression is differentially regulated in plasmacytoid and conventional dendritic cells.Nature Immunol.5, 899–908 (2004).
Villadangos, J. A. & Young, L. Antigen-presentation properties of plasmacytoid dendritic cells.Immunity29, 352–361 (2008).
Villadangos, J. A., Schnorrer, P. & Wilson, N. S. Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces.Immunol. Rev.207, 191–205 (2005).
Kleijmeer, M. J. et al. MHC class II compartments and the kinetics of antigen presentation in activated mouse spleen dendritic cells.J. Immunol.154, 5715–5724 (1995).
Harding, C. V. & Geuze, H. J. Class II MHC molecules are present in macrophage lysosomes and phagolysosomes that function in the phagocytic processing ofListeria monocytogenes for presentation to T cells.J. Cell Biol.119, 531–542 (1992).
Kleijmeer, M. J., Oorschot, V. M. & Geuze, H. J. Human resident langerhans cells display a lysosomal compartment enriched in MHC class II.J. Invest. Dermatol.103, 516–523 (1994).
Pierre, P. et al. Developmental regulation of MHC class II transport in mouse dendritic cells.Nature388, 787–792 (1997).
ten Broeke, T., van Niel, G., Wauben, M. H., Wubbolts, R. & Stoorvogel, W. Endosomally stored MHC class II does not contribute to antigen presentation by dendritic cells at inflammatory conditions.Traffic12, 1025–1036 (2011).
Cella, M., Engering, A., Pinet, V., Pieters, J. & Lanzavecchia, A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells.Nature388, 782–787 (1997).This seminal study shows that activation of DCs with LPS or tumour necrosis factor transiently increases MHC class II biosynthesis, enhances cell surface MHC class II stability and enables DCs to maintain functional memory of acquired antigens.
Kleijmeer, M. et al. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells.J. Cell Biol.155, 53–63 (2001).
Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport.Nature418, 983–988 (2002).
Chow, A., Toomre, D., Garrett, W. & Mellman, I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane.Nature418, 988–994 (2002).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. et al. Dynamics of major histocompatibility complex class II compartments during B cell receptor-mediated cell activation.J. Exp. Med.195, 461–472 (2002).
Siemasko, K., Eisfelder, B. J., Williamson, E., Kabak, S. & Clark, M. R. Signals from the B lymphocyte antigen receptor regulate MHC class II containing late endosomes.J. Immunol.160, 5203–5208 (1998).
Vascotto, F. et al. The actin-based motor protein myosin II regulates MHC class II trafficking and BCR-driven antigen presentation.J. Cell Biol.176, 1007–1019 (2007).
Le Roux, D. et al. Syk-dependent actin dynamics regulate endocytic trafficking and processing of antigens internalized through the B-cell receptor.Mol. Biol. Cell18, 3451–3462 (2007).
Nashar, T. O. & Drake, J. R. The pathway of antigen uptake and processing dictates MHC class II-mediated B cell survival and activation.J. Immunol.174, 1306–1316 (2005).
Mohan, J. F., Calderon, B., Anderson, M. S. & Unanue, E. R. Pathogenic CD4+ T cells recognizing an unstable peptide of insulin are directly recruited into islets bypassing local lymph nodes.J. Exp. Med.210, 2403–2414 (2013).
Amigorena, S., Drake, J. R., Webster, P. & Mellman, I. Transient accumulation of new class II MHC molecules in a novel endocytic compartment in B lymphocytes.Nature369, 113–120 (1994).
Yuseff, M. I. et al. Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation.Immunity35, 361–374 (2011).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. & Neefjes, J. MHC class II molecules on the move for successful antigen presentation.EMBO J.27, 1–5 (2008).
Kamon, H. et al. TRIF–GEFH1–RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation.EMBO J.25, 4108–4119 (2006).
Ocana-Morgner, C., Wahren, C. & Jessberger, R. SWAP-70 regulates RhoA/RhoB-dependent MHCII surface localization in dendritic cells.Blood113, 1474–1482 (2009).
Paul, P. et al. A genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation.Cell145, 268–283 (2011).
Thery, C. et al. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes.Nature Immunol.3, 1156–1162 (2002).
Segura, E. et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming.Blood106, 216–223 (2005).
Muntasell, A., Berger, A. C. & Roche, P. A. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes.EMBO J.26, 4263–4272 (2007).
Buschow, S. I. et al. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways.Traffic10, 1528–1542 (2009).
Bastos-Amador, P. et al. Capture of cell-derived microvesicles (exosomes and apoptotic bodies) by human plasmacytoid dendritic cells.J. Leukocyte Biol.91, 751–758 (2012).
Denzer, K. et al. Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface.J. Immunol.165, 1259–1265 (2000).
Viaud, S. et al. Dendritic cell-derived exosomes for cancer immunotherapy: what's next?Cancer Res.70, 1281–1285 (2010).
Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes.Nature Med.4, 594–600 (1998).
Mahaweni, N. M., Kaijen-Lambers, M. E., Dekkers, J., Aerts, J. G. & Hegmans, J. P. Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma.J. Extracell. Vesicles2, 22492 (2013).
Anderson, H. A. & Roche, P. A. MHC class II association with lipid rafts on the antigen presenting cell surface.Biochim. Biophys. Actahttp://dx.doi.org/10.1016/j.bbamcr.2014.09.019 (2014).
Kropshofer, H. et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide- MHC class II complexes.Nature Immunol.3, 61–68 (2002).
Anderson, H. A., Hiltbold, E. M. & Roche, P. A. Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation.Nature Immunol.1, 156–162 (2000).In this study, we show that MHC class II molecules are constitutive residents of lipid raft membrane microdomains and that raft association is important for CD4+ T cell activation under conditions of limiting antigen dose.
Eren, E. et al. Location of major histocompatibility complex class II molecules in rafts on dendritic cells enhances the efficiency of T-cell activation and proliferation.Scand. J. Immunol.63, 7–16 (2006).
Bosch, B., Heipertz, E. L., Drake, J. R. & Roche, P. A. Major histocompatibility complex (MHC) class II-peptide complexes arrive at the plasma membrane in cholesterol-rich microclusters.J. Biol. Chem.288, 13236–13242 (2013).
Poloso, N. J., Muntasell, A. & Roche, P. A. MHC class II molecules traffic into lipid rafts during intracellular transport.J. Immunol.173, 4539–4546 (2004).
Karacsonyi, C., Knorr, R., Fulbier, A. & Lindner, R. Association of major histocompatibility complex II with cholesterol- and sphingolipid-rich membranes precedes peptide loading.J. Biol. Chem.279, 34818–34826 (2004).
Poloso, N. J. & Roche, P. A. Association of MHC class II-peptide complexes with plasma membrane lipid microdomains.Curr. Opin. Immunol.16, 103–107 (2004).
Steinman, R. M., Mellman, I. S., Muller, W. A. & Cohn, Z. A. Endocytosis and the recycling of plasma membrane.J. Cell Biol.96, 1–27 (1983).
Momburg, F. et al. Epitope-specific enhancement of antigen presentation by invariant chain.J. Exp. Med.178, 1453–1458 (1993).
Tewari, M. K., Sinnathamby, G., Rajagopal, D. & Eisenlohr, L. C. A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent.Nature Immunol.6, 287–294 (2005).
Pinet, V., Malnati, M. S. & Long, E. O. Two processing pathways for the MHC class II-restricted presentation of exogenous influenza virus antigen.J. Immunol.152, 4852–4860 (1994).
Griffin, J. P., Chu, R. & Harding, C. V. Early endosomes and a late endocytic compartment generate different peptide-class II MHC complexes via distinct processing mechanisms.J. Immunol.158, 1523–1532 (1997).
Ohmura-Hoshino, M. et al. Inhibition of MHC class II expression and immune responses by c-MIR.J. Immunol.177, 341–354 (2006).
Shin, J. S. et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination.Nature444, 115–118 (2006).
van Niel, G. et al. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination.Immunity25, 885–894 (2006).References 115 and 116 show that selective ubiquitylation of MHC class II in immature DCs regulates intracellular MHC class II localization.
Matsuki, Y. et al. Novel regulation of MHC class II function in B cells.EMBO J.26, 846–854 (2007).This study confirms that MARCH1 is the main E3 ubiquitin ligase that is responsible for MHC class II ubiquitylation and that it regulates MHC class II expression in B cells.
De Gassart, A. et al. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation.Proc. Natl Acad. Sci. USA105, 3491–3496 (2008).
Walseng, E. et al. Ubiquitination regulates MHC class II-peptide complex retention and degradation in dendritic cells.Proc. Natl Acad. Sci. USA107, 20465–20470 (2010).
Gauvreau, M. E. et al. Sorting of MHC class II molecules into exosomes through a ubiquitin-independent pathway.Traffic10, 1518–1527 (2009).
Furuta, K., Ishido, S. & Roche, P. A. Encounter with antigen-specific primed CD4 T cells promotes MHC class II degradation in dendritic cells.Proc. Natl Acad. Sci. USA109, 19380–19385 (2012).
Bartee, E., Mansouri, M., Hovey Nerenberg, B. T., Gouveia, K. & Fruh, K. Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins.J. Virol.78, 1109–1120 (2004).
Oh, J. et al. MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells.J. Exp. Med.210, 1069–1077 (2013).
Baravalle, G. et al. Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells.J. Immunol.187, 2966–2973 (2011).
Corcoran, K. et al. Ubiquitin-mediated regulation of CD86 protein expression by the ubiquitin ligase membrane-associated RING-CH-1 (MARCH1).J. Biol. Chem.286, 37168–37180 (2011).
Thibodeau, J. et al. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes.Eur. J. Immunol.38, 1225–1230 (2008).
Koppelman, B., Neefjes, J. J., de Vries, J. E. & de Waal Malefyt, R. Interleukin-10 down-regulates MHC class II αβ-peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling.Immunity.7, 861–871 (1997).
Walseng, E. et al. Dendritic cell activation prevents MHC class II ubiquitination and promotes MHC class II survival regardless of the activation stimulus.J. Biol. Chem.285, 41749–41754 (2010).
Jabbour, M., Campbell, E. M., Fares, H. & Lybarger, L. Discrete domains of MARCH1 mediate its localization, functional interactions, and posttranscriptional control of expression.J. Immunol.183, 6500–6512 (2009).
Bourgeois-Daigneault, M. C. & Thibodeau, J. Autoregulation of MARCH1 expression by dimerization and autoubiquitination.J. Immunol.188, 4959–4970 (2012).
Furuta, K., Walseng, E. & Roche, P. A. Internalizing MHC class II-peptide complexes are ubiquitinated in early endosomes and targeted for lysosomal degradation.Proc. Natl Acad. Sci. USA110, 20188–20193 (2013).In this study, we show that peptide–MHC class II molecules that are being internalized from the plasma membrane are targets of MARCH1-mediated ubiquitylation and lysosomal degradation.
Tze, L. E. et al. CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation.J. Exp. Med.208, 149–165 (2011).
Klein, E. et al. CD83 localization in a recycling compartment of immature human monocyte-derived dendritic cells.Int. Immunol.17, 477–487 (2005).
Bourgeois-Daigneault, M. C. & Thibodeau, J. Identification of a novel motif that affects the conformation and activity of the MARCH1 E3 ubiquitin ligase.J. Cell Sci.126, 989–998 (2013).
Ma, J. K., Platt, M. Y., Eastham-Anderson, J., Shin, J. S. & Mellman, I. MHC class II distribution in dendritic cells and B cells is determined by ubiquitin chain length.Proc. Natl Acad. Sci. USA109, 8820–8827 (2012).
MacGurn, J. A., Hsu, P. C. & Emr, S. D. Ubiquitin and membrane protein turnover: from cradle to grave.Annu. Rev. Biochem.81, 231–259 (2012).
Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system.Annu. Rev. Immunol.18, 861–926 (2000).
Lapaque, N. et al.Salmonella regulates polyubiquitination and surface expression of MHC class II antigens.Proc. Natl Acad. Sci. USA106, 14052–14057 (2009).
Wilson, J. E., Katkere, B. & Drake, J. R.Francisella tularensis induces ubiquitin-dependent major histocompatibility complex class II degradation in activated macrophages.Infect. Immun.77, 4953–4965 (2009).
Hunt, D. et al.Francisella tularensis elicits IL-10 via a PGE2-inducible factor, to drive macrophage MARCH1 expression and class II down-regulation.PLoS ONE7, e37330 (2012).
Ferrari, G., Langen, H., Naito, M. & Pieters, J. A coat protein on phagosomes involved in the intracellular survival of mycobacteria.Cell97, 435–447 (1999).
Ramachandra, L., Noss, E., Boom, W. H. & Harding, C. V. Processing ofMycobacterium tuberculosis antigen 85B involves intraphagosomal formation of peptide-major histocompatibility complex II complexes and is inhibited by live bacilli that decrease phagosome maturation.J. Exp. Med.194, 1421–1432 (2001).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG andMycobacterium tuberculosis survival in infected macrophages.Cell119, 753–766 (2004).
Lilley, B. N. & Ploegh, H. L. Viral modulation of antigen presentation: manipulation of cellular targets in the ER and beyond.Immunol. Rev.207, 126–144 (2005).
Tomazin, R. et al. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells.Nature Med.5, 1039–1043 (1999).
Hegde, N. R. et al. Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: a novel mechanism for evading major histocompatibility complex class II antigen presentation.J. Virol.76, 10929–10941 (2002).
Odeberg, J., Plachter, B., Branden, L. & Soderberg-Naucler, C. Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain.Blood101, 4870–4877 (2003).
Temme, S., Eis-Hubinger, A. M., McLellan, A. D. & Koch, N. The herpes simplex virus-1 encoded glycoprotein B diverts HLA-DR into the exosome pathway.J. Immunol.184, 236–243 (2010).
Toussaint, H. et al. Human immunodeficiency virus type 1 nef expression prevents AP-2-mediated internalization of the major histocompatibility complex class II-associated invariant chain.J. Virol.82, 8373–8382 (2008).
Stumptner-Cuvelette, P. et al. Human immunodeficiency virus-1 Nef expression induces intracellular accumulation of multivesicular bodies and major histocompatibility complex class II complexes: potential role of phosphatidylinositol 3-kinase.Mol. Biol. Cell14, 4857–4870 (2003).
Zuo, J. et al. Epstein–Barr virus evades CD4+ T cell responses in lytic cycle through BZLF1-mediated downregulation of CD74 and the cooperation of vBcl-2.PLoS Pathog.7, e1002455 (2011).
Ressing, M. E. et al. Epstein–Barr virus gp42 is posttranslationally modified to produce soluble gp42 that mediates HLA class II immune evasion.J. Virol.79, 841–852 (2005).
Acknowledgements
The authors acknowledge the many investigators in the field whose primary data could not be cited in this Review owing to space limitations. The authors also thank the anonymous referees who provided excellent advice in the preparation of this manuscript. This work was supported by the Japan Society for the Promotion of Science (to K.F.) and by the Intramural Research Program of the US National Institutes of Health (to P.A.R.).
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Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892-9760, Maryland, USA
Paul A. Roche
Department of Immunobiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, 7008530, Japan
Kazuyuki Furuta
- Paul A. Roche
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Glossary
- Central tolerance
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.
- Peripheral tolerance
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.
- Invariant chain
(Ii). A protein that binds to newly synthesized MHC class II molecules and promotes their egress from the endoplasmic reticulum. It blocks the peptide-binding site on nascent MHC class II molecules and targets Ii–MHC class II complexes to late endosomal and lysosomal antigen-processing compartments.
- Multivesicular bodies
(MVBs). 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).
- Macropinocytosis
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.
- Clathrin-mediated endocytosis
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.
- Plasmacytoid DCs
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.
- Cross-presentation
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.
- Macroautophagy
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.
- Immunological synapse
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.
- Follicular DCs
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.
- Lipid rafts
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.
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Roche, P., Furuta, K. The ins and outs of MHC class II-mediated antigen processing and presentation.Nat Rev Immunol15, 203–216 (2015). https://doi.org/10.1038/nri3818
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