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

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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.

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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.


  1. 1

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

  2. 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).

  3. 3

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

  4. 4

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

  5. 5

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

  6. 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).

  7. 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).

  8. 8

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

  9. 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).

  10. 10

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

  11. 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).

  12. 12

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

  13. 13

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

  14. 14

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

  15. 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).

  16. 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).

  17. 17

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

  18. 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).

  19. 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).

  20. 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).

  21. 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).

  22. 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).

  23. 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).

  24. 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).

  25. 25

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

  26. 26

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

  27. 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).

  28. 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).

  29. 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).

  30. 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).

  31. 31

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

  32. 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).

  33. 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).

  34. 34

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

  35. 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).

  36. 36

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

  37. 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).

  38. 38

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

  39. 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).

  40. 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).

  41. 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).

  42. 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).

  43. 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).

  44. 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).

  45. 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. 46

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

  47. 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).

  48. 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).

  49. 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).

  50. 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).

  51. 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).

  52. 52

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

  53. 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).

  54. 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).

  55. 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).

  56. 56

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

  57. 57

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

  58. 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).

  59. 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).

  60. 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).

  61. 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).

  62. 62

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

  63. 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).

  64. 64

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

  65. 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).

  66. 66

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

  67. 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).

  68. 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).

  69. 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).

  70. 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).

  71. 71

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

  72. 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).

  73. 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).

  74. 74

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

  75. 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).

  76. 76

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

  77. 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).

  78. 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).

  79. 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).

  80. 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).

  81. 81

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

  82. 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).

  83. 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).

  84. 84

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

  85. 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).

  86. 86

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

  87. 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).

  88. 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).

  89. 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).

  90. 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).

  91. 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).

  92. 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).

  93. 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).

  94. 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).

  95. 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).

  96. 96

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

  97. 97

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

  98. 98

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

  99. 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).

  100. 100

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

  101. 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).

  102. 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).

  103. 103

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

  104. 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).

  105. 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).

  106. 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).

  107. 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).

  108. 108

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

  109. 109

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

  110. 110

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

  111. 111

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

  112. 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).

  113. 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).

  114. 114

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

  115. 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).

  116. 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).

  117. 117

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

  118. 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).

  119. 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).

  120. 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).

  121. 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).

  122. 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).

  123. 123

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

  124. 124

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

  125. 125

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

  126. 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).

  127. 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).

  128. 128

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

  129. 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).

  130. 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).

  131. 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).

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

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