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.

  • Review Article
  • Published:

The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules

Nature Immunology volume 5, pages 685–692 (2004)Cite this article

Abstract

The endosomes and lysosomes of antigen-presenting cells host the processing and assembly reactions that result in the display of peptides on major histocompatibility complex (MHC) class II molecules and lipid-linked products on CD1 molecules. This environment is potentially hostile for T cell epitope and MHC class II survival, and the influence of regulators of protease activity and specialized chaperones that assist MHC class II assembly is crucial. At present, evidence indicates that individual proteases make both constructive and destructive contributions to antigen processing for MHC class II presentation to CD4 T cells. Some features of CD1 antigen capture within the endocytic pathway are also discussed.

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: Ii processing proceeds in a C-terminal–to–N-terminal direction.
Figure 2: Alternative scenarios and fates of T cell epitopes during antigen processing.
Figure 3: Multiple influences on protease activity in the endocytic compartment.

Similar content being viewed by others

References

  1. Germain, R.N. & Margulies, D.H. The biochemistry and cell biology of antigen processing and presentation. Annu. Rev. Immunol. 11, 403–450 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Wolf, P.R. & Ploegh, H.L. How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. Annu. Rev. Cell Cev. Biol. 11, 267–306 (1995).

    Article  CAS  Google Scholar 

  3. Cresswell, P. Invariant chain structure and MHC class II function. Cell 84, 505–507 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Watts, C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu. Rev. Immunol. 15, 821–850 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Engelhard, V.H. Structure of peptides associated with class I and class II MHC molecules. Annu. Rev. Immunol. 12, 181–207 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Hiltbold, E.M. & Roche, P.A. Trafficking of MHC class II molecules in the late secretory pathway. Curr. Opin. Immunol. 14, 30–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Lanzavecchia, A., Reid, P.A. & Watts, C. Irreversible association of peptides with class II MHC molecules in living cells. Nature 357, 249–252 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Robinson, J.H. & Delvig, A.A. Diversity in MHC class II antigen presentation. Immunology 105, 252–262 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bennett, K. et al. Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E. Eur. J. Immunol. 22, 1519–1524 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Santambrogio, L. et al. Extracellular antigen processing and presentation by immature dendritic cells. Proc. Natl. Acad. Sci. USA 96, 15056–15061 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Musson, J.A., Walker, N., Flick-Smith, H., Williamson, E.D. & Robinson, J.H. Differential processing of CD4 T-cell epitopes from the protective antigen of Bacillus anthracis. J. Biol. Chem. 278, 52425–52431 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Watts, C. Antigen processing in the endocytic compartment. Curr. Opin. Immunol. 13, 26–31 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Honey, K. & Rudensky, A.Y. Lysosomal cysteine proteases regulate antigen presentation. Nat. Rev. Immunol. 3, 472–482 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Bryant, P. & Ploegh, H. Class II MHC peptide loading by the professionals. Curr. Opin. Immunol. 16, 96–102 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Blum, J.S. & Cresswell, P. Role for intracellular proteases in the processing and transport of class II HLA antigens. Proc. Natl. Acad. Sci. USA 85, 3975–3979 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Amigorena, S. et al. Invariant chain cleavage and peptide loading in major histocompatibility complex class II vesicles. J. Exp. Med. 181, 1729–1741 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Manoury, B. et al. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Immunity 18, 489–498 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Riese, R.J. et al. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity 4, 357–366 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Brachet, V., Raposo, G., Amigorena, S. & Mellman, I. Ii chain controls the transport of major histocompatibility complex class II molecules to and from lysosomes. J. Cell. Biol. 137, 51–65 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Driessen, C. et al. Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J. Cell. Biol. 147, 775–790 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakagawa, T. et al. Cathepsin L: critical role in li degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Tolosa, E. et al. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J. Clin. Invest. 112, 517–526 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bania, J. et al. Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs. Proc. Natl. Acad. Sci. USA 100, 6664–6669 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Shi, G.P. et al. Role for cathepsin F in invariant chain processing and major Histocompatibility complex class II peptide loading by macrophages. J. Exp. Med. 191, 1177–1185 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saegusa, K. et al. Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J. Clin. Invest. 110, 361–369 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Riese, R.J. et al. Cathepsin S activity regulates antigen presentation and immunity. J. Clin. Invest. 101, 2351–2363 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nakagawa, T.Y. et al. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity 10, 207–217 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Villadangos, J.A., Riese, R.J., Peters, C., Chapman, H.A. & Ploegh, H.L. Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism. J. Exp. Med. 186, 549–560 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wiendl, H. et al. Antigen processing and presentation in human muscle: cathepsin S is critical for MHC class II expression and upregulated in inflammatory myopathies. J. Neuroimmunol. 138, 132–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Matza, D. et al. Invariant chain induces B cell maturation in a process that is independent of its chaperonic activity. Proc. Natl. Acad. Sci. USA 99, 3018–3023 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Matza, D., Kerem, A. & Shachar, I. Invariant chain, a chain of command. Trends Immunol. 24, 264–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Shi, G.P. et al. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10, 197–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Denzin, L.K. & Cresswell, P. HLA-DM induces CLIP dissociation from MHC class II αβ dimers and facilitates peptide loading. Cell 82, 155–165 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Sloan, V.S. et al. Mediation by HLA-DM of dissociation of peptides from HLA-DR. Nature 375, 802–806 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Sherman, M.A., Weber, D.A. & Jensen, P.E. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity 3, 197–205 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Busch, R. & Mellins, E.D. Developing and shedding inhibitions: how MHC class II molecules reach maturity. Curr. Opin. Immunol. 8, 51–58 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Kropshofer, H., Hammerling, G.J. & Vogt, A.B. How HLA-DM edits the MHC class II peptide repertoire: survival of the fittest? Immunol. Today 18, 77–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Alfonso, C. & Karlsson, L. Nonclassical MHC class II molecules. Annu. Rev. Immunol. 18, 113–142 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Brocke, P., Garbi, N., Momburg, F. & Hammerling, G.J. HLA-DM, HLA-DO and tapasin: functional similarities and differences. Curr. Opin. Immunol. 14, 22–29. (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Belmares, M.P., Busch, R., Wucherpfennig, K.W., McConnell, H.M. & Mellins, E.D. Structural factors contributing to DM susceptibility of MHC class II/peptide complexes. J. Immunol. 169, 5109–5117 (2002).

    Article  PubMed  Google Scholar 

  41. Stratikos, E., Wiley, D.C. & Stern, L.J. Enhanced catalytic action of HLA-DM on the exchange of peptides lacking backbone hydrogen bonds between their N-terminal region and the MHC class II alpha-chain. J. Immunol. 172, 1109–1117 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Pu, Z., Lovitch, S.B., Bikoff, E.K. & Unanue, E.R. T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM. Immunity 20, 467–476 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Stebbins, C.C., Loss, G.E., Jr., Elias, C.G., Chervonsky, A. & Sant, A.J. The requirement for DM in class II-restricted antigen presentation and SDS-stable dimer formation is allele and species dependent. J. Exp. Med. 181, 223–234 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Wolf, P.R. et al. The phenotype of H-2M-deficient mice is dependent on the MHC class II molecules expressed. Eur. J. Immunol. 28, 2605–2618 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Brooks, A.G., Campbell, P.L., Reynolds, P., Gautam, A.M. & McCluskey, J. Antigen presentation and assembly by mouse I-Ak class II molecules in human APC containing deleted or mutated HLA DM genes. J. Immunol. 5382–5392 (1994).

  46. Koonce, C.H. et al. DM loss in k haplotype mice reveals isotype-specific chaperone requirements. J. Immunol. 170, 3751–3761 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Pashine, A. et al. Interaction of HLA-DR with an acidic face of HLA-DM disrupts sequence-dependent interactions with peptides. Immunity 19, 183–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Liljedahl, M. et al. HLA-DO is a lysosomal resident which requires association with HLA-DM for efficient intracellular transport. EMBO J. 15, 4817–4824 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Chen, X. et al. Regulated expression of human histocompatibility leukocyte antigen (HLA)-DO during antigen-dependent and antigen-independent phases of B cell development. J. Exp. Med. 195, 1053–1062 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Glazier, K.S. et al. Germinal center B cells regulate their capability to present antigen by modulation of HLA-DO. J. Exp. Med. 195, 1063–1069 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Perraudeau, M. et al. Altered major histocompatibility complex class II peptide loading in H2-O-deficient mice. Eur. J. Immunol. 30, 2871–2880 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Liljedahl, M. et al. Altered antigen presentation in mice lacking H2-O. Immunity 8, 233–243 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. van Ham, M. et al. Modulation of the major histocompatibility complex class II-associated peptide repertoire by human histocompatibility leukocyte antigen (HLA)-DO. J. Exp. Med. 191, 1127–1136 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Watts, C., West, M.A., Reid, P.A. & Davidson, H.W. Processing of immunoglobulin-associated antigen in B lymphocytes. Cold Spring Harb. Symp. Quant. Biol. 1, 345–352 (1989).

    Article  Google Scholar 

  55. Brocke, P., Armandola, E., Garbi, N. & Hammerling, G.J. Downmodulation of antigen presentation by H2-O in B cell lines and primary B lymphocytes. Eur. J. Immunol. 33, 411–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Alfonso, C. et al. Analysis of H2-O influence on antigen presentation by B cells. J. Immunol. 171, 2331–2337 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Sercarz, E.E. et al. Dominance and crypticity of T cell antigenic determinants. Annu. Rev. Immunol. 11, 729–766 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Driessen, C., Lennon-Dumenil, A.M. & Ploegh, H.L. Individual cathepsins degrade immune complexes internalized by antigen-presenting cells via Fcγ receptors. Eur. J. Immunol. 31, 1592–1601 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Pluger, E.B. et al. Specific role for cathepsin S in the generation of antigenic peptides in vivo. Eur. J. Immunol. 32, 467–476 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Hsieh, C.S., deRoos, P., Honey, K., Beers, C. & Rudensky, A.Y. A Role for cathepsin L and cathepsin S in peptide generation for MHC class II presentation. J. Immunol. 168, 2618–2625 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Honey, K., Nakagawa, T., Peters, C. & Rudensky, A. Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195, 1349–1358 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Manoury, B. et al. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 396, 695–699 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Chen, J.M., Rawlings, N.D., Stevens, R.A.E. & Barrett, A.J. Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cystein endopeptidases. FEBS Lett. 441, 461–465 (1998).

    Google Scholar 

  64. Watts, C. et al. Roles for asparagine endopeptidase in class II MHC-restricted antigen processing. Biochem. Soc. Symp. 70, 31–38 (2003).

    Article  CAS  Google Scholar 

  65. Antoniou, A.N., Blackwood, S.L., Mazzeo, D. & Watts, C. Control of antigen presentation by a single protease cleavage site. Immunity 12, 391–398 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Loak, K. et al. Novel cell-permeable acyloxymethylketone inhibitors of asparaginyl endopeptidase. Biol. Chem. 384, 1239–1246 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Manoury, B. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat. Immunol. 3, 169–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Krogsgaard, M. et al. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. J. Exp. Med. 191, 1395–1412. (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Brooks, K. & Knight, A.M. Lowering the affinity between antigen and the B cell receptor can enhance antigen presentation. Eur. J. Immunol. 34, 837–843 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Collins, D.S., Unanue, E.R. & Harding, C.V. Reduction of disulfide bonds within lysosomes is a key step in antigen processing. J. Immunol. 147, 4054–4059 (1991).

    CAS  PubMed  Google Scholar 

  71. Jensen, P.E. Antigen unfolding and disulfide reduction in antigen presenting cells. Semin. Immunol. 7, 347–353 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Arunachalam, B., Phan, U.T., Geuze, H.J. & Cresswell, P. Enzymatic reduction of disulfide bonds in lysosomes: characterization of a γ-interferon-inducible lysosomal thiol reductase (GILT). Proc. Natl. Acad. Sci. USA 97, 745–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Haque, M.A. et al. Absence of γ-interferon-inducible lysosomal thiol reductase in melanomas disrupts T cell recognition of select immunodominant epitopes. J. Exp. Med. 195, 1267–1277 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Maric, M. et al. Defective antigen processing in GILT-free mice. Science 294, 1361–1365 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Li, P., Haque, M.A. & Blum, J.S. Role of disulfide bonds in regulating antigen processing and epitope selection. J. Immunol. 169, 2444–2450 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Kalka-Moll, W.M. et al. Zwitterionic polysaccharides stimulate T cells by MHC class II-dependent interactions. J. Immunol. 169, 6149–6153 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Cobb, B.A., Wang, Q., Tzianabos, A.O. & Kasper, D.L. Polysaccharide processing and presentation by the MHCII pathway. Cell 117, 677–687 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Shirahama-Noda, K. et al. Biosynthetic processing of cathepsins and lysosomal degradation are abolished in asparaginyl endopeptidase-deficient mice. J. Biol. Chem. 278, 33194–33199 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Honey, K. et al. Cathepsin S regulates the expression of cathepsin L and the turnover of γ-interferon-inducible lysosomal thiol reductase in B lymphocytes. J. Biol. Chem. 276, 22573–22578 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Lennon-Dumenil, A.M. et al. The p41 isoform of invariant chain is a chaperone for cathepsin L. EMBO J. 20, 4055–4064 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Honey, K. et al. Thymocyte expression of cathepsin L is essential for NKT cell development. Nat. Immunol. 3, 1069–1074 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Guncar, G., Pungercic, G., Klemencic, I., Turk, V. & Turk, D. Crystal structure of MHC class II-associated p41 Ii fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S. EMBO J. 18, 793–803 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ogrinc, T., Dolenc, I., Ritonja, A. & Turk, V. Purification of the complex of cathepsin L and the MHC class II-associated invariant chain fragment from human kidney. FEBS Lett. 336, 555–559 (1993).

    Article  CAS  PubMed  Google Scholar 

  84. Fiebiger, E. et al. Invariant chain controls the activity of extracellular cathepsin L. J. Exp. Med. 196, 1263–1269 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Beers, C., Honey, K., Fink, S., Forbush, K. & Rudensky, A. Differential regulation of cathepsin S and cathepsin L in interferon-γ-treated macrophages. J. Exp. Med. 197, 169–179 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Peterson, M. & Miller, J. Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41. Nature 357, 596–598 (1992).

    Article  CAS  PubMed  Google Scholar 

  87. Fiebiger, E. et al. Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells. J. Exp. Med. 193, 881–892 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Trombetta, E.S., Ebersold, M., Garrett, W., Pypaert, M. & Mellman, I. Activation of lysosomal function during dendritic cell maturation. Science 299, 1400–1403 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Li, D.N., Matthews, S.P., Antoniou, A.N., Mazzeo, D. & Watts, C. Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. J. Biol. Chem. 278, 38980–38990 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Kleijmeer, M. et al. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. J. Cell. Biol. 155, 53–63 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chow, A., Toomre, D., Garrett, W. & Mellman, I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418, 988–994 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Cella, M., Engering, A., Pinet, V., Pieters, J. & Lanzavecchia, A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388, 782–787 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Steinman, R.M. & Nussenzweig, M.C. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. USA 99, 351–358 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Veeraswamy, R.K., Cella, M., Colonna, M. & Unanue, E.R. Dendritic cells process and present antigens across a range of maturation states. J. Immunol. 170, 5367–5372 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Wilson, N.S., El-Sukkari, D. & Villadangos, J.A. 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. Blood 103, 2187–2195 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Turley, S.J. et al. Transport of peptide-MHC class II complexes in developing dendritic cells. Science 288, 522–527 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418, 983–988 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Bertho, N. et al. Requirements for T cell-polarized tubulation of class II+ compartments in dendritic cells. J. Immunol. 171, 5689–5696 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. 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).

    Article  CAS  PubMed  Google Scholar 

  100. Kropshofer, H. et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes. Nat. Immunol. 3, 61–68 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Lee, P., Matsueda, G.R. & Allen, P.M. T cell recognition of fibrinogen. A determinant on the A α-chain does not require processing. J. Immunol. 140, 1063–1068 (1988).

    CAS  PubMed  Google Scholar 

  102. Davidson, H.W., Reid, P.A., Lanzavecchia, A. & Watts, C. Processed antigen binds to newly synthesized MHC class II molecules in antigen-specific B lymphocytes. Cell 67, 105–116 (1991).

    Article  CAS  PubMed  Google Scholar 

  103. Lindner, R. & Unanue, E.R. Distinct antigen MHC class II complexes generated by separate processing pathways. EMBO J. 15, 6910–6920 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Villadangos, J.A., Driessen, C., Shi, G.-P., Chapman, H.A. & Ploegh, H.L. Early endosomal maturation of MHC class II molecules independently of cysteine proteases and H-2DM. EMBO J. 19, 882–891 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nelson, C.A., Vidavsky, I., Viner, N.J., Gross, M.L. & Unanue, E.R. Amino-terminal trimming of peptides for presentation on major histocompatibility complex class II molecules. Proc. Natl. Acad. Sci. USA 94, 628–633 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Lippolis, J.D. et al. Analysis of MHC class II antigen processing by quantitation of peptides that constitute nested sets. J. Immunol. 169, 5089–5097 (2002).

    Article  PubMed  Google Scholar 

  107. Carson, R.T., Vignali, K.M., Woodland, D.L. & Vignali, D.A. T cell receptor recognition of MHC class II-bound peptide flanking residues enhances immunogenicity and results in altered TCR V region usage. Immunity 7, 387–399 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Sercarz, E.E. & Maverakis, E. MHC-guided processing: binding of large antigen fragments. Nat. Rev. Immunol. 3, 621–629 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Joyce, S. & Van Kaer, L. CD1-restricted antigen presentation: an oily matter. Curr. Opin. Immunol. 15, 95–104 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Brigl, M. & Brenner, M.B. CD1: Antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–90 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Gadola, S.D. et al. Structure of human CD1b with bound ligands at 2.3 Å, a maze for alkyl chains. Nat. Immunol. 3, 721–726 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Zajonc, D.M., Elsliger, M.A., Teyton, L. & Wilson, I.A. Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15 Å. Nat. Immunol. 4, 808–815 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Sugita, M. et al. Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 16, 697–706 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Elewaut, D. et al. The adaptor protein AP-3 is required for CD1d-mediated antigen presentation of glycosphingolipids and development of Vα14i NKT cells. J. Exp. Med. 198, 1133–1146 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Cernadas, M. et al. Lysosomal localization of murine CD1d mediated by AP-3 is necessary for NK T cell development. J. Immunol. 171, 4149–4155 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Moody, D.B. & Porcelli, S.A. CD1 trafficking: invariant chain gives a new twist to the tale. Immunity 15, 861–865 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Kang, S.J. & Cresswell, P. Regulation of intracellular trafficking of human CD1d by association with MHC class II molecules. EMBO J. 21, 1650–1660 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jayawardena-Wolf, J., Benlagha, K., Chiu, Y.H., Mehr, R. & Bendelac, A. CD1d endosomal trafficking is independently regulated by an intrinsic CD1d-encoded tyrosine motif and by the invariant chain. Immunity 15, 897–908 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Chiu, Y.H. et al. Multiple defects in antigen presentation and T cell development by mice expressing cytoplasmic tail-truncated CD1d. Nat. Immunol. 3, 55–60 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Riese, R.J. et al. Regulation of CD1 function and NK1.1+ T cell selection and maturation by cathepsin S. Immunity 15, 909–919 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Kang, S.J. & Cresswell, P. Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Nat. Immunol. 5, 175–181 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Zhou, D. et al. Editing of CD1d-bound lipid antigens by endosomal lipid transfer proteins. Science 303, 523–527 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Winau, F. et al. Saposin C is required for lipid presentation by human CD1b. Nat. Immunol. 5, 169–174 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Leonova, T. et al. Proteolytic processing patterns of prosaposin in insect and mammalian cells. J. Biol. Chem. 271, 17312–17320 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Vielhaber, G., Hurwitz, R. & Sandhoff, K. Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP) precursor in cultured human fibroblasts. Mannose 6-phosphate receptor-independent endocytosis of SAP precursor. J. Biol. Chem. 271, 32438–32446 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Kyewski, B., Derbinski, J., Gotter, J. & Klein, L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol. 23, 364–371 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Anderson, M.S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 10, 1395–1401 (2002).

    Article  CAS  Google Scholar 

  129. Newcomb, J.R. & Cresswell, P. Structural analysis of proteolytic products of MHC class II-invariant chain complexes generated in vivo. J. Immunol. 151, 4153–4163 (1993).

    CAS  PubMed  Google Scholar 

  130. Denzin, L.K., Hammond, C. & Cresswell, P. HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules. J. Exp. Med. 184, 2153–2165 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Simitsek, P.D., Campbell, D.G., Lanzavecchia, A., Fairweather, N. & Watts, C. Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. J. Exp. Med. 181, 1957–1963 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by The Wellcome Trust, Medical Research Council and European Union.

Author information

Authors and Affiliations

  1. Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

    Colin Watts

Authors
  1. Colin Watts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Colin Watts.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watts, C. The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules. Nat Immunol 5, 685–692 (2004). https://doi.org/10.1038/ni1088

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1088

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