Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A CD74-dependent MHC class I endolysosomal cross-presentation pathway

Nature Immunology volume 13, pages 237–245 (2012)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cd74−/− mice generate weak antiviral primary immune responses.
Figure 2: The deficiency of Cd74−/− mice in eliciting primary immune responses resides in their antigen-presenting cells and is independent of CD4+ T cells.
Figure 3: Cd74−/− DCs are unable to cross-present cell-associated antigens in vivo to prime antigen-specific CD8+ T cells.
Figure 4: Cross-presentation and cross-priming are defective in Cd74−/− DCs.
Figure 5: Inhibition of CD74-mediated trafficking of MHC class I in DCs by treatment with chloroquine.
Figure 6: CD74 controls the ER-to-endolysosome trafficking of MHC class I in DCs.

Similar content being viewed by others

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Guermonprez, P. et al. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425, 397–402 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Houde, M. et al. Phagosomes are competent organelles for antigen cross-presentation. Nature 425, 402–406 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Pfeifer, J.D. et al. Phagocytic processing of bacterial antigens for class I MHC presentation to T cells. Nature 361, 359–362 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  Google Scholar 

  9. Gagnon, E. et al. Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110, 119–131 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Touret, N. et al. Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell 123, 157–170 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Cebrian, I. et al. Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells. Cell 147, 1355–1368 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Basha, G. et al. MHC class I endosomal and lysosomal trafficking coincides with exogenous antigen loading in dendritic cells. PLoS ONE 3, e3247 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chiu, I., Davis, D.M. & Strominger, J.L. Trafficking of spontaneously endocytosed MHC proteins. Proc. Natl. Acad. Sci. USA 96, 13944–13949 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reid, P.A. & Watts, C. Cycling of cell-surface MHC glycoproteins through primaquine-sensitive intracellular compartments. Nature 346, 655–657 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. Bakke, O. & Dobberstein, B. MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell 63, 707–716 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    CAS  PubMed  Google Scholar 

  19. Kleijmeer, M.J. et al. Antigen loading of MHC class I molecules in the endocytic tract. Traffic 2, 124–137 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Vitalis, T.Z. et al. Using the TAP component of the antigen-processing machinery as a molecular adjuvant. PLoS Pathog. 1, e36 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Marzo, A.L. et al. Fully functional memory CD8 T cells in the absence of CD4 T cells. J. Immunol. 173, 969–975 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Faure-Andre, G. et al. Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 322, 1705–1710 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Benvenuti, F. et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science 305, 1150–1153 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Shastri, N. & Gonzalez, F. Endogenous generation and presentation of the ovalbumin peptide/Kb complex to T cells. J. Immunol. 150, 2724–2736 (1993).

    CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Loss, G.E. Jr. & Sant, A.J. Invariant chain retains MHC class II molecules in the endocytic pathway. J. Immunol. 150, 3187–3197 (1993).

    CAS  PubMed  Google Scholar 

  35. Stockinger, B. et al. A role of Ia-associated invariant chains in antigen processing and presentation. Cell 56, 683–689 (1989).

    Article  CAS  PubMed  Google Scholar 

  36. Kornfeld, R. & Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664 10.1146/annurev.bi.54.070185.003215 (1985).

    Article  CAS  PubMed  Google Scholar 

  37. Rock, K.L., Gamble, S. & Rothstein, L. Presentation of exogenous antigen with class I major histocompatibility complex molecules. Science 249, 918–921 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. Powis, S. J. CLIP-region mediated interaction of Invariant chain with MHC class I molecules. FEBS Lett 580, 3112–3116 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Janssen, E.M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Savina, A. et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126, 205–218 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Author notes

  1. Genc Basha & Anna T Reinicke

    Present address: Present addresses: Nanomedicine Research Unit, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, British Columbia, Vancouver, Canada (G.B.), and Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (A.T.R.).,

  2. Genc Basha and Kyla Omilusik: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Department of Medical Genetics and Department of Zoology, The Biomedical Research Centre, The Michael Smith Laboratories, The Centre for Blood Research, The Brain Research Centre, University of British Columbia, Vancouver, Canada

    Genc Basha, Kyla Omilusik, Ana Chavez-Steenbock, Anna T Reinicke, Nathan Lack, Kyung Bok Choi & Wilfred A Jefferies

Authors
  1. Genc Basha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyla Omilusik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Chavez-Steenbock
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna T Reinicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nathan Lack
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kyung Bok Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wilfred A Jefferies
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Wilfred A Jefferies.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 437 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2225

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing