Abstract
Immune responses are initiated and primed by dendritic cells (DCs) that cross-present exogenous antigen. The chaperone CD74 (invariant chain) is thought to promote DC priming exclusively in the context of major histocompatibility complex (MHC) class II. However, we demonstrate here a CD74-dependent MHC class I cross-presentation pathway in DCs that had a major role in the generation of MHC class I–restricted, cytolytic T lymphocyte (CTL) responses to viral protein– and cell-associated antigens. CD74 associated with MHC class I in the endoplasmic reticulum of DCs and mediated the trafficking of MHC class I to endolysosomal compartments for loading with exogenous peptides. We conclude that CD74 has a previously undiscovered physiological function in endolysosomal DC cross-presentation for priming MHC class I–mediated CTL responses.
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References
Guagliardi, L.E. et al. Co-localization of molecules involved in antigen processing and presentation in an early endocytic compartment. Nature 343, 133–139 (1990).
Kovacsovics-Bankowski, M. & Rock, K.L. A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules. Science 267, 243–246 (1995).
Ackerman, A.L., Kyritsis, C., Tampe, R. & Cresswell, P. Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens. Proc. Natl. Acad. Sci. USA 100, 12889–12894 (2003).
Guermonprez, P. et al. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425, 397–402 (2003).
Houde, M. et al. Phagosomes are competent organelles for antigen cross-presentation. Nature 425, 402–406 (2003).
Pfeifer, J.D. et al. Phagocytic processing of bacterial antigens for class I MHC presentation to T cells. Nature 361, 359–362 (1993).
Song, R. & Harding, C.V. Roles of proteasomes, transporter for antigen presentation (TAP), and β2-microglobulin in the processing of bacterial or particulate antigens via an alternate class I MHC processing pathway. J. Immunol. 156, 4182–4190 (1996).
Lizée, G. et al. Control of dendritic cell cross-presentation by the major histocompatibility complex class I cytoplasmic domain. Nat. Immunol. 4, 1065–1073 (2003).
Gagnon, E. et al. Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110, 119–131 (2002).
Touret, N. et al. Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell 123, 157–170 (2005).
Shen, L., Sigal, L.J., Boes, M. & Rock, K.L. Important role of cathepsin S in generating peptides for TAP-independent MHC class I crosspresentation in vivo. Immunity 21, 155–165 (2004).
Cebrian, I. et al. Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells. Cell 147, 1355–1368 (2011).
Basha, G. et al. MHC class I endosomal and lysosomal trafficking coincides with exogenous antigen loading in dendritic cells. PLoS ONE 3, e3247 (2008).
Chiu, I., Davis, D.M. & Strominger, J.L. Trafficking of spontaneously endocytosed MHC proteins. Proc. Natl. Acad. Sci. USA 96, 13944–13949 (1999).
Reid, P.A. & Watts, C. Cycling of cell-surface MHC glycoproteins through primaquine-sensitive intracellular compartments. Nature 346, 655–657 (1990).
Bakke, O. & Dobberstein, B. MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell 63, 707–716 (1990).
Sugita, M. & Brenner, M.B. Association of the invariant chain with major histocompatibility complex class I molecules directs trafficking to endocytic compartments. J. Biol. Chem. 270, 1443–1448 (1995).
Vigna, J.L., Smith, K.D. & Lutz, C.T. Invariant chain association with MHC class I: preference for HLA class I/β2-microglobulin heterodimers, specificity, and influence of the MHC peptide-binding groove. J. Immunol. 157, 4503–4510 (1996).
Kleijmeer, M.J. et al. Antigen loading of MHC class I molecules in the endocytic tract. Traffic 2, 124–137 (2001).
Zwickey, H.L. & Potter, T.A. Antigen secreted from noncytosolic Listeria monocytogenes is processed by the classical MHC class I processing pathway. J. Immunol. 162, 6341–6350 (1999).
MacAry, P.A. et al. Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells. Proc. Natl. Acad. Sci. USA 98, 3982–3987 (2001).
Tourne, S. et al. Biosynthesis of major histocompatibility complex molecules and generation of T cells in Ii TAP1 double-mutant mice. Proc. Natl. Acad. Sci. USA 93, 1464–1469 (1996).
Reber, A.J., Turnquist, H.R., Thomas, H.J., Lutz, C.T. & Solheim, J.C. Expression of invariant chain can cause an allele-dependent increase in the surface expression of MHC class I molecules. Immunogenetics 54, 74–81 (2002).
Vitalis, T.Z. et al. Using the TAP component of the antigen-processing machinery as a molecular adjuvant. PLoS Pathog. 1, e36 (2005).
van Kaer, L., Ashton-Rickardt, P.G., Ploegh, H.L. & Tonegawa, S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4−8+ T cells. Cell 71, 1205–1214 (1992).
McAdam, A.J., Farkash, E.A., Gewurz, B.E. & Sharpe, A.H. B7 costimulation is critical for antibody class switching and CD8+ cytotoxic T-lymphocyte generation in the host response to vesicular stomatitis virus. J. Virol. 74, 203–208 (2000).
Marzo, A.L. et al. Fully functional memory CD8 T cells in the absence of CD4 T cells. J. Immunol. 173, 969–975 (2004).
Faure-Andre, G. et al. Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 322, 1705–1710 (2008).
Benvenuti, F. et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science 305, 1150–1153 (2004).
Shastri, N. & Gonzalez, F. Endogenous generation and presentation of the ovalbumin peptide/Kb complex to T cells. J. Immunol. 150, 2724–2736 (1993).
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).
Brossart, P. & Bevan, M.J. Presentation of exogenous protein antigens on major histocompatibility complex class I molecules by dendritic cells: pathway of presentation and regulation by cytokines. Blood 90, 1594–1599 (1997).
Merzougui, N., Kratzer, R., Saveanu, L. & van Endert, P. A proteasome-dependent, TAP-independent pathway for cross-presentation of phagocytosed antigen. EMBO Rep. 12, 1257–1264 (2011).
Loss, G.E. Jr. & Sant, A.J. Invariant chain retains MHC class II molecules in the endocytic pathway. J. Immunol. 150, 3187–3197 (1993).
Stockinger, B. et al. A role of Ia-associated invariant chains in antigen processing and presentation. Cell 56, 683–689 (1989).
Kornfeld, R. & Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664 10.1146/annurev.bi.54.070185.003215 (1985).
Rock, K.L., Gamble, S. & Rothstein, L. Presentation of exogenous antigen with class I major histocompatibility complex molecules. Science 249, 918–921 (1990).
van Lith, M., van Ham, M. & Neefjes, J. Stable expression of MHC class I heavy chain/HLA-DO complexes at the plasma membrane. Eur. J. Immunol. 33, 1145–1151 (2003).
Nuchtern, J.G., Biddison, W.E. & Klausner, R.D. Class II MHC molecules can use the endogenous pathway of antigen presentation. Nature 343, 74–76 10.1038/343074a0 (1990).
Cerundolo, V., Elliott, T., Elvin, J., Bastin, J. & Townsend, A. Association of the human invariant chain with H-2 Db class I molecules. Eur. J. Immunol. 22, 2243–2248 (1992).
Powis, S. J. CLIP-region mediated interaction of Invariant chain with MHC class I molecules. FEBS Lett 580, 3112–3116 (2006).
Sigal, L.J. & Rock, K.L. Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation. J. Exp. Med. 192, 1143–1150 (2000).
Buller, R.M., Holmes, K.L., Hugin, A., Frederickson, T.N. & Morse, H.C. III. Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328, 77–79 10.1038/328077a0 (1987).
Janssen, E.M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).
Machold, R.P. & Ploegh, H.L. Intermediates in the assembly and degradation of class I major histocompatibility complex (MHC) molecules probed with free heavy chain-specific monoclonal antibodies. J. Exp. Med. 184, 2251–2259 (1996).
Reinicke, A.T., Omilusik, K.D., Basha, G. & Jefferies, W.A. Dendritic cell cross-priming is essential for immune responses to Listeria monocytogenes. PLoS ONE 4, e7210 10.1371/journal.pone.0007210 (2009).
Luckey, C.J. et al. Differences in the expression of human class I MHC alleles and their associated peptides in the presence of proteasome inhibitors. J. Immunol. 167, 1212–1221 (2001).
Krüger, T. et al. Lessons to be learned from primary renal cell carcinomas: novel tumor antigens and HLA ligands for immunotherapy. Cancer Immunol. Immunother. 54, 826–836 (2005).
Busch, R., Cloutier, I., Sekaly, R.P. & Hammerling, G.J. Invariant chain protects class II histocompatibility antigens from binding intact polypeptides in the endoplasmic reticulum. EMBO J. 15, 418–428 (1996).
Savina, A. et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126, 205–218 (2006).
Rashid, A., Auchincloss, H. Jr. & Sharon, J. Comparison of GK1.5 and chimeric rat/mouse GK1.5 anti-CD4 antibodies for prolongation of skin allograft survival and suppression of alloantibody production in mice. J. Immunol. 148, 1382–1388 (1992).
Acknowledgements
We thank D. Mathis (Institut de Génétique et de Biologie Moléculaire et Cellulaire and The Harvard Stem Cell Institute) for Cd74−/− (H-2Kb) mice; N. Shastri (University of California, Berkeley) for the B3Z T cell hybridoma; J. Yewdell (US National Institutes of Health) for antibody 25.D1.16; I. Shachar (Weizmann Institute of Sciences) for the CD74 constructs; and B. Barber and D. Williams (University of Toronto) for antiserum directed toward the region of H-2Kb encoded by exon 8. Supported by the Canadian Institutes of Health Research (K.O.; and MOP-77631 and MOP-86739 to W.A.J.).
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G.B. and K.O. designed, did and analyzed experiments; A.C.S. did DC-transfection experiments; A.T.R. did experiments and provided intellectual input; N.L. provided intellectual input and bioinformatics; K.B.C. did experiments; W.A.J. conceived of the research project, designed experiments, supervised the research and analyzed the data; and G.B., K.O. and W.A.J. wrote the manuscript.
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Basha, G., Omilusik, K., Chavez-Steenbock, A. et al. A CD74-dependent MHC class I endolysosomal cross-presentation pathway. Nat Immunol 13, 237–245 (2012). https://doi.org/10.1038/ni.2225
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DOI: https://doi.org/10.1038/ni.2225
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