Advertisement

Genes of the Antigen Processing Pathways

Abstract

There is overwhelming evidence that a bimodal system exists for processing and presenting antigen to T lymphocytes. This system involves the endogenous and exogenous pathways, responsible for processing and targeting antigen from internal and external sources for presentation on class I and class II major histocompatibility complex (MHC) molecules, respectively. The endogenous route supplies antigen predominately from cytosolic sources, such as virus-encoded proteins, whereas the exogenous route facilitates the processing and presentation of antigens captured at the cell surface, such as through endocytosis of antibody-bound (opsonized) pathogens. Such a discrete division of labor in antigen processing is, like most other conceptual models in biology, something of a caricature. However, besides being fundamentally accurate, the bimodal model is an important framework from which to appreciate larger issues of the immune system, such as immunoregulation. For example, distinct and separate pathways for antigen collection and presentation on class I and class II MHC provide an elegantly simple way by which we can imagine the autonomous regulation of antigen presentation to CD8+ and CD4+ T-cell subsets. Nonetheless, reality never quite fully surrenders itself to models and the processing of antigen for class I and class II molecules does appear to overlap. Moreover, the immunoregulatory mechanisms governing CD4 and CDS T-cell-mediated immunity are considerably more complex than can be explained by understanding antigen presentation alone.

Keywords

Major Histocompatibility Complex Major Histocompatibility Complex Class Antigen Presentation Antigen Processing Proteasome Subunit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jentsch, S., and Schlenker, S. 1995. Selective protein—degradation A journey’s end within the proteasome. Cell 82:881–884.PubMedGoogle Scholar
  2. 2.
    Wlodawei, A. 1995. Proteasome: A complex protease with a new told and a distinct mechanism. Structure 3:417–420.Google Scholar
  3. 3.
    Chen, P., and Hochstrasser, M. 1995. Biogenesis, structure and function of the yeast 20s proteasome. EMBO J. 14:2620–2630.PubMedGoogle Scholar
  4. 4.
    Hochstrasser, M. 1995. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr. Opin. Cell Biol. 7:215–223.PubMedGoogle Scholar
  5. 5.
    Yang, Y., Fruh, K., Ahn, K., and Peterson, P. A. 1995. In vivo assembly of the proicasomul complexes, implications for antigen processing. J. Biol. Chem. 270:27687–27694.PubMedGoogle Scholar
  6. 6.
    Momburg, F., Ortiz-Navarrete, V., Neefjes, J., Goulmy, E., van de Wal, Y., Spits, H., Powis, S. J., Butcher, G. W., Howard, J. C., Walden, P., and Hammerling, G. U. 1992. Proteasome subunits encoded by the major histoxcompatibility complex are not essential for antigen presentation. Nature 360:174–177.PubMedGoogle Scholar
  7. 7.
    Yewdell, J., Lapham, C., Bacik, I., Spies, T., and Bennink, J. 1994. MHC-encoded proteasome subunits LMP2 and LMP7 are not required for efficient antigen presentation. J. Immunol. 152:1163–1170.PubMedGoogle Scholar
  8. 8.
    Arnold, D., Driscoll, J., Androlewicz, M., Hughes, E., Cresswell, P., and Spies, T. 1992. Proteasome subunits encoded in the MHC are not generally required for the processing of peptides bound by MHC class 1 molecules. Nature 360:171–174.PubMedGoogle Scholar
  9. 9.
    Rock, K. L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D., and Goldberg, A. I., 1994. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class 1 molecules. Cell 78:761–771.PubMedGoogle Scholar
  10. 10.
    Niedermann, G., Butz, S., Ihlenfeldt, H. G., Grimm, R., Lucchiari, M., Hoschuetzky, H., Jung, G., Maier, B., and Eichmann, K. 1995. Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules. Immunity 2:289–299.PubMedGoogle Scholar
  11. 11.
    Yang, B., Hahn, Y. S., Hahn, C. S., and Braciale, T. J. 1996. The requirement for proteasome activity class I major histocompatibility complex antigen presentation is dictated by the length of preprocessed antigen. J. Exp. Med. 183:1545–1552.PubMedGoogle Scholar
  12. 12.
    Loewe, J., Stock, D., Jap, B., Zwickl, P., Baumeister, W., and Huber, R. 1995. Crystal structure of the 20 S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science 268:533–539.Google Scholar
  13. 13.
    Frentzel, S., Kuhn Hartmann, I., Gernold, M., Gott, P., Seelig, A., and Kloetzel, P. M. 1993. The major-histocompatibility-complex-encoded beta-type proteasome subunits bdLMP2 and LMP7. Evidence that LMP2 and LMP7 are synthesized as proproteins and that cellular levels of both mRNA and LMP-containing 20 S proteasomes are differentially regulated. Eur. J. Biochem. 216:119–126.PubMedGoogle Scholar
  14. 14.
    Frentzel, S., Pesold Hurt, B., Seelig, A., and Kloetzel, P. M. 1994. 20 S proteasomes are assembled via distinct precursor complexes. Processing of LMP2 and LMP7 proproteins takes place in 13-16 S preproteasome complexes. J. Mol. Biol. 236:975–981.PubMedGoogle Scholar
  15. 15.
    Rechsteiner, M., Hoffman, L., and Dubiel, W. 1993. The multicatalytic and 26 S proteases. J. Biol. Chem. 268:6065–6068.PubMedGoogle Scholar
  16. 16.
    Rousset, R., Desbois, C., Bantignies, F., and Jalinot, P. 1996. Effects on NF-kappa B/pO5 processing of the interaction between the HTEV-1 transactivator Tax and the proteasome. Nature 381:328–331.PubMedGoogle Scholar
  17. 17.
    Nandi, D., Jiang, H., and Monaco, J. J. 1996. Identification of MECL-I (LMP-I0) as the third IFN-gamma-inducible proteasome subunit. J. Immunol. 156:2361–2364.PubMedGoogle Scholar
  18. 18.
    Seulert, W., Futcher, B., and Jentsch, S. 1995. Role of a ubiquitin-conjugating enzyme in degradation of S-and M-phase cyclins. Nature 373:78–81.Google Scholar
  19. 19.
    Scheffner, M., Nuber, U., and Huibregtse, J. M. 1995. Protein ubiquitination involving an E1-E2 E3 enzyme ubiquilin thioester cascade. Nature 373:81–83.PubMedGoogle Scholar
  20. 20.
    Stancovski, I., Gonen, H., Orian, A., Schwartz, A. L., and Ciechanover, A. 1995. Degradation of the protooncogene product c-fos by the ubiquitin proteolytic system in vivo and in vitro-Identification and characterization of the conjugating enzymes. Mol. Cell. Biol. 15:7106–7116.PubMedGoogle Scholar
  21. 21.
    King, R. W., Peters, J. M., Tugendreich, S., Rolfe, M., Hieter, P., and Kirschner, M. W. 1995. A 20 S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 81:279–288.PubMedGoogle Scholar
  22. 22.
    Hershko, A., Ganoth, D., Pehrson, J., Palazzo, R. E., and Cohen, L. H. 1991. Methylated ubiquitin inhibits cyclin degradation in calm embryo extracts. J. Biol. Chem. 266:16376–16379.PubMedGoogle Scholar
  23. 23.
    Glotzer, M., Murray, A. W., and Kirschner, M. W. 1991. Cyclin is degraded by the ubiquitin pathway. Nature 349:132–138.PubMedGoogle Scholar
  24. 24.
    Pagano, M., Tam, S. W., Theodoras, A. M., Beer Romero, P., Del Sal, G., Chau, V., Yew, P. R., Draetta, G. F., and Rolfe, M. 1995. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269:682–685.PubMedGoogle Scholar
  25. 25.
    Ciechanover, A., and Schwartz, A. L. 1994. The ubiquitin-mediated proteolytic pathway: Mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins. FASEB J. 8:182–191.PubMedGoogle Scholar
  26. 26.
    Seemueller, E., Lupas, A., Stock, D., Loewe, J., Huber, R., and Baumeister, W. 1995. Proteasome from Thermoplasma acidophilum: A threonine protease. Science 268:579–582.Google Scholar
  27. 27.
    Frueh, K., Gossen, M., Wang, K., Bujard, H., Peterson, P. A., and Yang, Y. 1994. Displacement of housekeeping proteasome subunits by MHC-encoded LMPs: A newly discovered mechanism for modulating the multicatalytic proteinase complex. EMBO J. 13:3236–3244.Google Scholar
  28. 28.
    Belich, M. P., Glynne, R. J., Senger, G., Sheer, D., and Trowsdale, J. 1994. Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins. Curr. Biol. 4:769–776.PubMedGoogle Scholar
  29. 29.
    Akiyama, K., Yokota, K., Kagawa, S., Shimbara, N., Tamura, T., Akioka, H., Nothwang, H. G., Noda, C., Tanaka, K., and Ichihara, A. 1994. cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. Science 265:1231–1234.PubMedGoogle Scholar
  30. 30.
    Akiyama, K., Kagawa, S., Tamura, T., Shimbara, N., Takashina, M., Kristensen, P., Hendil, K. B., Tanaka, K., and Ichihara, A. 1994. Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon-gamma for acquirement of the functional diversity responsible for antigen processing. FEBS Lett. 343:85–88.PubMedGoogle Scholar
  31. 31.
    Kelly, A., Powis, S. H., Glynne, R., Radley, E., Beck, S., and Trowsdale, J. 1991. Second proteasome-related gene in the human MHC class II region. Nature 353:667–668.PubMedGoogle Scholar
  32. 32.
    Martinez, C. K., and Monaco, J. J. 1991. Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene. Nature 353:664–667.PubMedGoogle Scholar
  33. 33.
    Glynne, R., Powis, S. H., Beck, S., Kelly, A., Kerr, L. A., and Trowsdale, J. 1991. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature 353:357–360.PubMedGoogle Scholar
  34. 34.
    Ortiz-Navarrete, V., Seelig, A., Gernold, M., Frentzel, S., Kloetzel, P. M., and Hammerling, G. J. 1991. Subunit of the ‘20S’ proteasome (multicatalytic protease) encoded by the major histocompatibility rnplex. Nature 353:662–664.PubMedGoogle Scholar
  35. 35.
    Aki, M., Shimbara, N., Takashina, M., Akiyama, K., Kagawa, S., Tamura, T., Tanahashi, N., Yoshimura, T., Tanaka, K., and Ichihara, A. 1994. Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J. Biochem. 115:257–269.PubMedGoogle Scholar
  36. 36.
    Gaczynska, M., Goldberg, A. L., Tanaka, K., Hendil, K. B., and Rock, K. L. 1996. Proteasome subunits X and Y alter peptidase activities in opposite ways to the interferon-gamma-induced subunils LMP2 and LMP7. J. Biol. Chem. 271:17275–17280.PubMedGoogle Scholar
  37. 37.
    Gaczynska, M., Rock, K. L., Spies, T., and Goldberg, A. L. 1994. Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proc. Natl. Acad. Sci. USA 91:9213–9217.PubMedGoogle Scholar
  38. 38.
    Gaczynska, M., Rock, K. L., and Goldberg, A. L. 1993. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365:264–267.PubMedGoogle Scholar
  39. 39.
    Boes, B., Hengel, H., Ruppert, T., Multhaup, G., Koszinowski, U. H., and Kloetzel, P. M. 1994. Interferon gamma stimulation modulates the proteolytic activity and cleavage site preference of 20 S mouse proteasomes. J. Exp. Med. 179:901–909.PubMedGoogle Scholar
  40. 40.
    Driscoll, J., Brown, M. G., Finley, D., and Monaco, J. J. 1993. MHC-linked LMP gene products specifically after peptidase activities of the proteasome. Nature 365:262–264.PubMedGoogle Scholar
  41. 41.
    Zanelli, E., Zhou, P., Cao, H., Smart, M. K., and David, C. S. 1993. Genomic organization and tissue expression of the mouse proteasome gene Lmp-7. Immunogenetics 38:400–407.PubMedGoogle Scholar
  42. 42.
    Glynne, R., Kerr, L. A., Mockridge, I., Beck, S., Kelly, A., and Trowsdale, J. 1993. The major histocompatibility complex-encoded proteasome component LMP7: Alternative first exons and post-translational processing. Eur. J. Immunol. 23:860–866.PubMedGoogle Scholar
  43. 43.
    Martinez., C. K., and Monaco, J. J. 1993. Post-translational processing of a major histocompatibility complex-encoded proteasome subunit, LMP-2. Mol. Immunol. 30:1177–1183.PubMedGoogle Scholar
  44. 44.
    Fehling, H. J., Swat, W., Laplace, C., Kuehn, R., Rajewsky, K., Mueller, U., and von Boehmer, H. 1994. MHC class I expression in mice lacking the proteasome subunit LMP-7. Science 265:1234–1237.PubMedGoogle Scholar
  45. 45.
    Van Kaer, L., Ashton Rickardt, P. G., Eichelberger, M., Gaczynska, M., Nagashima, K., Rock, K. L., Goldberg, A. L., Doherty, P. C., and Tonegawa, S. 1994. Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity 1:533–541.PubMedGoogle Scholar
  46. 46.
    Ahn, K., Erlander, M., Lelurcq, D., Peterson, P. A., Frueh, K., and Yang, Y. 1996. In vivo characterization of the proteasome regulator PA28. J. Biol. Chem. 271:18237–18242.PubMedGoogle Scholar
  47. 47.
    Kania, M. A., Demartino, G. N., Baumeister, W., and Goldberg, A. L. 1996. The proteasome subunit, C2. contains an important site for binding of the PA28 (IIS) activator. Eur. J. Biochem. 236:510–516.PubMedGoogle Scholar
  48. 48.
    Groettrup, M., Ruppert, T., Kuehn, L., Seeger, M., Standera, S., Koszinowski, U., and Kloetzel, P. M. 1995. The interferon-XgX-inducible IIS-regulator (PA28) and the LMP2/LMP7 subunits govern the peptide production by the 20S proteasome in vitro. J. Biol. Chem. 270:23808–23815.PubMedGoogle Scholar
  49. 49.
    Li, N. X., Lerea, K. M., and Etlinger, J. D. 1996. Phosphorylation of the proteasome activator PA28 is required for proteasome activation. Biochem. Biophys. Res. Commun. 225:855–860.PubMedGoogle Scholar
  50. 50.
    Mott, J. D., Pramanik, B. C., Moomaw, C. R., Afendis, S. J., Demartino, G. N., and Slaughter, C. A. 1994. PA28, an activator of the 20S proteasome, is composed of two nonidentical but homologous subunits. J. Biol. Chem. 269:31466–31471.PubMedGoogle Scholar
  51. 51.
    Ahn, J. Y., Tanahashi, N., Akiyama, K. Y., Hisamatsu, H., Noda, C., Tanaka, K., Chung, C. H., Shimbara, N., Willy, P. J., Mott, J. D., Slaughter, C. A., and Demartino, G. N. 1995. Primary structures of 2 homologous subunits of PA28, a XgX-interferon-inducible protein activator of the 20S proteasome. FEBS Lett. 366:37–42.PubMedGoogle Scholar
  52. 52.
    Dick, T. P., Ruppert, T., Groettrup, M., Kloetzel, P. M., Kuehn, L., Koszinowski, U. H., Stevanovic, S., Schild, H., and Rammensee, H. G. 1996. Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands. Cell 86:253–262.PubMedGoogle Scholar
  53. 53.
    Groettrup, M., Soza, A., Eggers, M., Kuehn, L., Dick, T. P., Schild, H., Rammensee, H. G., Koszinowski, U. H., and Kloetzel, P. M. 1996. A role for lhe proteasome regulator PA28alpha in antigen presentation. Nature 381:166–168.PubMedGoogle Scholar
  54. 54.
    Muller, K. M., Ebensperger, C., and Tampe, R. 1994. Nucleotide binding to the hydrophilic C-terminal domain of the transporter associated with antigen processing (TAP). J. Biol. Chem. 269:14032–14037.PubMedGoogle Scholar
  55. 55.
    Momburg, F., Roelse, J., Howard, J. C., Butcher, G. W., Hammerling, G. J., and Neefjes, J. J. 1994. Selectivity of MHC-encoded peptide transporters from human, mouse and rat. Nature 367:648–651.PubMedGoogle Scholar
  56. 56.
    Androlewicz, M. J., Anderson, K. S., and Cresswell, P. 1993. Evidence that transporters associated with antigen processing translocate a major histocompatibility complex class I-binding peptide into the endoplasmic reticulum in an ATP-dependent manner. Proc. Natl. Acad. Sci. USA 90:9130–9134.PubMedGoogle Scholar
  57. 57.
    Carmichael, P., Kerr, L. A., Kelly, A., and Lombardi, G. 1996. The TAP complex influences allorecognition of class-11 MHC molecules. Hum. Immunol. 50:70–77.PubMedGoogle Scholar
  58. 58.
    Min, W., Pober, J. S., and Johnson, D. R. 1996. Kinetically coordinated induction of TAPl and HLA class l by IFN-gamma: The rapid induction of TAPl by IFN-gamma is mediated by Statl alpha. J. Immunol. 156:3174–3183.PubMedGoogle Scholar
  59. 59.
    Powis, S. H., Mockridge, I., Kelly, A., Kerr, L. A., Glynne, R., Gileadi, U., Beck, S., and Trowsdale, J. 1992. Polymorphism in a second ABC transporter gene located within the class II region of the human major histocompatibility complex. Proc. Natl. Acad. Sci. USA 89:1463–1467.PubMedGoogle Scholar
  60. 60.
    Gros, P., Croop, J., and Housman, D. 1986. Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47:371–380.PubMedGoogle Scholar
  61. 61.
    Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M. L., Iannuzzi, M. C. Collins, F, S., and Tsui, L. S. 1989. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245:1066–1073.PubMedGoogle Scholar
  62. 62.
    Androlewicz, M. J., Ortmann, B., van Endert, P. M., Spies, T., and Cresswell, P. 1994. Characteristics of peptide and MHC class I/β2 microglobulin binding to the transporters associated with antigen processing. Proc. Natl. Acad. Sci. USA 91:12716–12720.PubMedGoogle Scholar
  63. 63.
    Suh, W. K., Mitchell, E. K., Yang, Y., Peterson, P. A., Waneck, G. L., and Williams, D. B. 1996. MHC class I molecules form ternary complexes with calnexin and TAP and undergo peptide-regulated interaction with TAP via their extracellular domains. J. Exp. Med. 184:337–348.PubMedGoogle Scholar
  64. 64.
    Suh, W. L., Cohen Doyle, M. F., Fruh, K., Wang, K., Peterson, P. A., and Williams, D. B. 1994. Interaction of MHC class I molecules with the transporter associated with antigen processing. Science 264:1322–1326.PubMedGoogle Scholar
  65. 65.
    Ortmann, B., Androlewicz, M. J., and Cresswell, P. 1994. MHC class I/beta 2-microglobulin complexes associate with TAP transporters before peptide binding. Nature 368:864–867.PubMedGoogle Scholar
  66. 66.
    Peace-Brewer, A. L., Tussey, L. G., Matsui, M., Li, G., Quinn, D. G., and Frelinger, J. A. 1996. A point mutation in HLA-A *0201 results in failure to bind the TAP complex and to present virus-derived peptides to CTL. Immunity 4:505–514.PubMedGoogle Scholar
  67. 67.
    Sadasivan, B., Lehner, P. J., Ortmann, B., Spies, T., and Cresswell, P. 1996. Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class molecules with TAP. Immunity 5:103–114.PubMedGoogle Scholar
  68. 68.
    Carreno, B. M., Solheim, J. C., Harris, M., Stroynowski, I., Connolly, J. M., and Hansen, T. H. 1995. TAP associates with a unique class-I conformation, whereas calnexin associates with multiple class-I forms in mouse and man. J. Immunol. 155:4726–4733.PubMedGoogle Scholar
  69. 69.
    Nossal, G. J. 1983. Cellular mechanisms of immunologic tolerance. Annu. Rev. Immunol. 1:33–62.PubMedGoogle Scholar
  70. 70.
    Colonna, M., Bresnahan, M., Bahrain, S., Strominger, J. L., and Spies, T. 1992. Allelic variants of the human putative peptide transporter involved in antigen processing. Proc. Natl. Acad. Sci. USA 89:3932–3936.PubMedGoogle Scholar
  71. 71.
    Livingstone, A. M., Powis, S. J., Gunther, E., Cramer, D. V., Howard, J. C., and Butcher, G. W. 1991. Cim: An MHC class II-linked allelism affecting the antigenicity of a classical class I molecule for T lymphocytes. Immunogenetics 34:157–163.PubMedGoogle Scholar
  72. 72.
    Heemels, M. T., Schumacher, T. N., Wonigeit, K., and Ploegh, H. L. 1993. Peptide translation by variants of the transporter associated with antigen processing. Science 262:2059–2063.PubMedGoogle Scholar
  73. 73.
    Powis, S. J., Deverson, E. V., Coadwell, W. J., Ciruela, A., Huskisson, N. S., Smith, H., Butcher, G. W., and Howard, J. C. 1992. Effect of polymorphism of an MHC-linked transporter on the peptides assembled in class I molecule. Nature 357:211–215.PubMedGoogle Scholar
  74. 74.
    Androlewicz, M. J., and Cresswell, P. 1994. Human transporters associated with antigen processing possess a promiscuous peptide-binding site. Immunity 1:7–14.PubMedGoogle Scholar
  75. 75.
    Momburg, F., Neefjes, J. J., and Hammerling, G. J. 1994. Peptide selection by MHC-encoded TAP transporters. Curr. Opin. Immunol. 6:32–37.PubMedGoogle Scholar
  76. 76.
    Momburg, F., Roelse, J., Hammerling, G. J., and Neefjes, J. J. 1994. Peptide size selection by the major histocompatibility complex-encoded peptide transporter. J. Exp. Med. 179:1613–1623.PubMedGoogle Scholar
  77. 77.
    Schumacher, T. N., Kantesaria, D. V., Heemels, M. T., Ashton Rickardt, P. G., Shepherd, J. C, Fruh, K., Yang, Y., Peterson, P. A., Tonegawa, S., and Ploegh, H. L. 1994. Peptide length and sequence specificity of the mouse TAPl/TAP2 translocator. J. Exp. Med. 179:533–540.PubMedGoogle Scholar
  78. 78.
    Cease, K. B., Berkower, I., York-Jolley, J., and Berzofsky, J. A. 1986. T cell clones specific for an amphipathic alpha-helical region of sperm whale myoglobin show differing fine specificities for synthetic peptides. A multiview/single structure interpretation of immunodominance. J. Exp. Med. 164:1779–1784.PubMedGoogle Scholar
  79. 79.
    Berkower, I., Buckenmeyer, G. K., and Berzofsky, J. A. 1986. Molecular mapping of a histocompatibility-restricted immunodominant T cell epitope with synthetic and natural peptides: Implications for T cell antigenic structure. J. Immunol. 136:2498–2503.PubMedGoogle Scholar
  80. 80.
    Carreno, B. M., Turner, R. V., Biddison, W. E., and Coligan, J. E. 1992. Overlapping epitopes that are recognized by CD8+ HLA class I-restricted and CD4+ class II-restricted cytotoxic T lymphocytes are contained within an influenza nucleoprotein peptide. J. Immunol. 148:894–899.PubMedGoogle Scholar
  81. 81.
    Schwartz, R. H., Fox, B. S., Fraga, E., Chen, C., and Singh, B. 1985. The T lymphocyte response to cytochrome c. V. Determination of the minimal peptide size required for stimulation of T cell clones and assessment of the contribution of each residue beyond this size to anligenic potency. J. Immunol. 135:2598–2608.PubMedGoogle Scholar
  82. 82.
    Engelhard, V. H., Appella, E., Benjamin, D. C., Bodnar, W. M., Cox, A. L., Chen, Y., Henderson, R. A., Huczko, E. L., Michel, H., Sakaguchi, K., Shabanowitz, J., Sevilir, N., Slingluff, C. L., and Hunt, D. F. 1993. Mass spectrometric analysis of peptides associated with the human class I MHC molecules HLA-A2.1 and HLA-B7 and identification of structural features that determine binding. Chem. Immunol. 57:39–62.PubMedGoogle Scholar
  83. 83.
    Henderson, R. A., Michel, H., Sakaguchi, K., Shabanowitz, J., Appella, E., Hunt, D. F., and Engelhard, V. H. 1992. HLA-A2.1-associated peptides from a mutant cell line: A second pathway of antigen presentation. Science 255:1264–1266.PubMedGoogle Scholar
  84. 84.
    Wei, M. L., and Cresswell, P. 1992. HLA-A2 molecules in an antigen-processing mutant cell contain signal sequence-derived peptides. Nature 356:443–446.PubMedGoogle Scholar
  85. 85.
    Franksson, L., George, E., Powis, S., Butcher, G., Howard, J., and Karre, K. 1993. Tumorigenicity conferred to lymphoma mutant by major histocompatibility complex-encoded transporter gene. J. Exp. Med. 177:201–205.PubMedGoogle Scholar
  86. 86.
    Kaklamanis, L., Townsend, A., Doussis Anagnostopoulou, I. A., Mortensen, N., Harris, A. L., and Gatter, K. C. 1994. Loss of major histocompatibility complex-encoded transporter associated with antigen presentation (TAP) in colorectal cancer. Am. J. Pathol. 145:505–509.PubMedGoogle Scholar
  87. 87.
    Cromme, F. V., Airey, J., Heemeis, M. T., Ploegh, H. L., Keating, P. J., Stern, P. I., Meijer, C. J., and Walboomers, J. M. 1994. Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas. J. Exp. Med. 179:335–340.PubMedGoogle Scholar
  88. 88.
    Restifo, N. P., Esquivel, F., Kawakami, Y., Yewdell, J. W., Mule, J. J., Rosenberg, S. A., and Bennink, J. R. 1993. Identification of human cancers deficient in antigen processing. J. Exp. Med. 177:265–272.Google Scholar
  89. 89.
    Rotem Yehudar, R., Groettrup, M., Soza, A., Kloetzel, P. M., and Ehrlich, R. 1996. LMP-associated proteolytic activities and TAP-dependent peptide transport for class I MHC molecules are suppressed in cell lines transformed by the highly oncogenic adenovirus 12. J. Exp. Med. 183:499–514.PubMedGoogle Scholar
  90. 90.
    York, I. A., Roop, C., Andrews, D. W., Riddell, S. R., Graham, F. L., and Johnson, D. C. 1994. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 77:525–535.PubMedGoogle Scholar
  91. 91.
    Hill, A., Jugovic, P., York, I., Russ, G., Bennink, J., Yewdell, J., Ploegh, H., and Johnson, D. 1995. Herpes simplex virus turns of the TAP to evade host immunity. Nature 375:411–415.PubMedGoogle Scholar
  92. 92.
    Frueh, K., Ahn, K., Djaballah, H., Sempe, P., van Ended, P. M., Tampe, R., Peterson, P. A., and Yang, Y. 1995. A viral inhibitor of peptide transporters for antigen presentation. Nature 375:415–418.Google Scholar
  93. 93.
    Tomazin, R., Hill, A. B., Jugovic, P., York, I., van Endert, P., Ploegh, H. L., Andrews, D. W., and Johnson, D. C. 1996. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO J. 15:3256–3266.PubMedGoogle Scholar
  94. 94.
    Ahn, K., Meyer, T. H., Uebel, S., Sempe, P., Djaballah, H., Yang, Y., Peterson, P. A., Frueh, K., and Tampe, R. 1996. Molecular mechanisms and species specificity of TAP inhibition of herpes simplex virus 1CP47. EMBO J. 15:3247–3255.PubMedGoogle Scholar
  95. 95.
    Ou, W. J., Cameron, P. H., Thomas, D. Y., and Bergeron, J. J. 1993. Association of folding intermediates of glycoproteins with calnexin during protein maturation. Nature 364:771–776.PubMedGoogle Scholar
  96. 96.
    Ware, F. E., Vassilakos, A., Peterson, P. A., Jackson, M. R., Lehrman, M. A., and Williams, D. B. 1995. The molecular chaperone calnexin binds Glc lMan9GlcNAc2 oligosaccharide as an initial step in recognizing unfolded glycoproteins. J. Biol. Chem. 270:4697–4704.PubMedGoogle Scholar
  97. 97.
    Hammond, C., Braakman, I., and Helenius, A. 1994. Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control. Proc. Natl. Acad. Sci. USA 91:913–917.PubMedGoogle Scholar
  98. 98.
    Tjoelker, L. W., Seyfried, C. E., Eddy, R. L., Jr., Byers, M. G., Shows, T. B., Calderon, J., Schreiber, R. B., and Gray, P. W. 1994. Human, mouse, and rat calnexin cDNA cloning: Identification of potential calcium binding motifs and gene localization to human chromosome 5. Biochemistry 33:3229–3236.PubMedGoogle Scholar
  99. 99.
    Herbert, D. N., Foellmer, B., and Helenius, A. 1995. Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 81:425–433.Google Scholar
  100. 100.
    Ora, A., and Helenius, A. 1995. Calnexin fails to associate with substrate proteins in glucosidase-deficient cell lines. J. Biol. Chem. 270:26060–26062.PubMedGoogle Scholar
  101. 101.
    Degen, E., and Williams, D. B. 1991. Participation of a novel 88-kD protein in the biogenesis of murine class 1 histocompatibility molecules. J. Cell Biol. 112:1099–1115.PubMedGoogle Scholar
  102. 102.
    Jackson, M. R., Cohen Doyle, M. F., Peterson, P. A., and Williams, D. B. 1994. Regulation of MHC class 1 transport by the molecular chaperone, calnexin (p88, IP90). Science 263:384–387.PubMedGoogle Scholar
  103. 103.
    Rajagopalan, S., and Brenner, M. B. 1994, Calnexin retains unassembled major histocompatibility complex class 1 free heavy chains in the endoplasmic reticulum. J. Exp. Med. 180:407–412.PubMedGoogle Scholar
  104. 104.
    Degen, E., Cohen Doyle, M. F., and Williams, D. B. 1992. Efficient dissociation of the p88 chaperone from major histocompatibility complex class 1 molecules requires both β2-microglobulin and peptide. J. Exp. Med. 175:1653–1661.PubMedGoogle Scholar
  105. 105.
    Williams, D. B., and Watts, T. H. 1995. Molecular chaperones in antigen processing. Curr. Opin. Immunol. 7:77–84.PubMedGoogle Scholar
  106. 106.
    Sugita, M., and Brenner, M. B. 1994. An unstable beta 2-microglobulin: major histocompatibility complex class I heavy chain intermediate dissociates from calnexin and then is stabilized by binding peptide. J. Exp. Med. 180:2163–2171.PubMedGoogle Scholar
  107. 107.
    Noessner, E., and Parham, P. 1995. Species-specific differences in chaperone interaction of human and mouse major histocompatibility complex class I molecules. J. Exp. Med. 181:327–337.Google Scholar
  108. 108.
    Bergeron, J. J., Brenner, M. B., Thomas, D. Y., and Williams, D. B. 1994. Calnexin: A membrane-bound chaperone of the endoplasmic reticulum. Trends Biochem. Sci. 19:124–128.PubMedGoogle Scholar
  109. 109.
    Hochstenbach, F., David, V., Watkins, S., and Brenner, M. B. 1992. Endoplasmic reticulum resident protein of 90 kilodaltons associates with the T-and B-cell antigen receptors and major hislocompatibility complex antigens during their assembly. Proc. Natl. Acad. Sci. USA 89:4734–4738.PubMedGoogle Scholar
  110. 110.
    David, V., Hochstenbach, F., Rajagopalan, S., and Brenner, M. B. 1993. Interaction with newly synthesized and retained proteins in the endoplasmic reticulum suggests a chaperone function for human integral membrane protein IP90 (calnexin). J. Biol. Chem. 268:9585–9592.PubMedGoogle Scholar
  111. 111.
    Wiest, D. L., Burgess, W. H., McKean, D., Kearse, K. P., and Singer, A. 1995. The molecular chaperone calnexin is expressed on the surface of immature thymocytes in association with clonotype-independent CD3 complexes. EMBO J. 14:3425–3433.PubMedGoogle Scholar
  112. 112.
    Lenter, M., and Vestweber, D. 1994. The integrin chains beta 1 and alpha 6 associate with the chaperone calnexin prior to integrin assembly. J. Biol. Chem. 269:12263–12268.PubMedGoogle Scholar
  113. 113.
    Roche, P. A., Marks, M. S., and Cresswell, P. 1991. Formation of a nine-subunit complex by HLA class II glycoproteins and the invariant chain. Nature 354:392–394.PubMedGoogle Scholar
  114. 114.
    Kvist, S., Wiman, K., Claesson, L., Peterson, P. A., and Dobberstein, B. 1982. Membrane insertion and oligomeric assembly of HLA-DR histocompatibility antigens. Cell 29:61–69.PubMedGoogle Scholar
  115. 115.
    Neefjes, J. J., Stollorz, V., Peters, P. J., Geuze, H. J., and Ploegh, H. L. 1990. The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell 61:171–183.PubMedGoogle Scholar
  116. 116.
    Viville, S., Neefjes, J., Lotteau, V., Dierich, A., LeMeur, M., Ploegh, H., Benoist, C., and Mathis, D. 1993. Mice lacking the MHC class II-associated invariant chain. Cell 72:635–648.PubMedGoogle Scholar
  117. 117.
    Bikoff, E. K., Huang, L. Y., Episkopou, V., van Meerwijk, J., Germain, R. N., and Robertson, E. J. 1993. Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression. J. Exp. Med. 117:1699–1712.Google Scholar
  118. 118.
    Elliott, E. A., Drake, J. R., Amigorena, S., Elsemore, J., Webster, P., Mellman, I., and Flavell, R. A. 1994. The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules. J. Exp. Med. 179:681–694.PubMedGoogle Scholar
  119. 119.
    Roche, P. A., and Cresswell, P. 1991. Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules. Proc. Natl. Acad. Sci. USA 88:3150–3154.PubMedGoogle Scholar
  120. 120.
    Teyton, L., O’Sullivan, D., Dickson, P. W., Lotteau, V., Sette, A., Fink, P., and Peterson, P. A. 1990. Invariant chain distinguishes between the exogenous and endogenous antigen presentation pathways. Nature 348:39–44.PubMedGoogle Scholar
  121. 121.
    Newcomb, J. R., and Cresswell, P. 1993. Characterization of endogenous peptides bound to purified HLA-DR molecules and their absence from invariant chain-associated alpha beta dimers. J. Immunol. 150:499–507.PubMedGoogle Scholar
  122. 122.
    Bakke, O., and Dobberstein, B. 1990. MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell 63:707–716.PubMedGoogle Scholar
  123. 123.
    Swier, K., and Miller, J. 1995. Efficient internalization of MHC class II-invariant chain complexes is not sufficient for invariant chain proteolysis and class II antigen presentation. J. Immunol. 155:630–643.PubMedGoogle Scholar
  124. 124.
    Odorizzi, C. G., Trowbridge, I. S., Xue, L., Hopkins, C. R., Davis, C. D., and Collawn, J. F. 1994. Sorting signals in the MHC class II invariant chain cytoplasmic tail and transmembrane region determine trafficking to an endocytic processing compartment. J. Cell Biol. 126:317–330.PubMedGoogle Scholar
  125. 125.
    Blum, J. S., and Cresswell, P. 1988. Role for intracellular proteases in the processing and transport of class II HLA antigens. Proc. Natl. Acad. Sci. USA 85:3975–3979.PubMedGoogle Scholar
  126. 126.
    Maric, M. A., Taylor, M. D., and Blum, J. S. 1994. Endosomal aspartic proteinases are required for invariant-chain processing. Proc. Natl. Acad. Sci. USA 91:2171–2175.PubMedGoogle Scholar
  127. 127.
    Arunachalam, B., Lamb, C. A., and Cresswell, P. 1994. Transport properties of free and MHC class IIassociated oligomers containing different isoforms of human invariant chain. Int. Immunol. 6:439–451.PubMedGoogle Scholar
  128. 128.
    Romagnoli, P., Layet, C., Ycwdell, J., Bakke, O., and Germain, R. N. 1993. Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments. J. Exp. Med. 177:583–596.PubMedGoogle Scholar
  129. 129.
    Anderson, M. S., Swier, K., Arneson, L., and Miller, J. 1993. Enhanced antigen presentation in the absence of the invariant chain endosomal localization signal. J. Exp. Med. 178:1959–1969.PubMedGoogle Scholar
  130. 130.
    Layet, C., and Germain, R. N. 1991. Invariant chain promotes egress of poorly expressed, haplotype-mismatched class II major histocompatibility complex A alpha A beta dimers from the endoplasmic reticulum/cis-Golgi compartment. Proc. Natl. Acad. Sci. USA 88:2346–2350.PubMedGoogle Scholar
  131. 131.
    Schaiff, W. T., Hruska, K. A., Jr., Bono, C., Shuman, S., and Schwartz, B. D. 1991. Invariant chain influences post-translational processing of HLA-DR molecules. J. Immunol 147:603–608.PubMedGoogle Scholar
  132. 132.
    Anderson, M. S., and Miller, J. 1992. Invariant chain can function as a chaperone protein tor class II major histocompatibility complex molecules. Proc. Natl. Acad. Sri. USA 89:2282–2285.Google Scholar
  133. 133.
    Schaiff, W. T., Hruska, K. A., Jr., McCourt, D. W., Green, M., and Schwartz, B. D. 1992. HLA-DK associates with specific stress proteins and is retained in the endoplasmic rcticulum in invariant chain negative cells. J. Exp. Med. 176:657–666.PubMedGoogle Scholar
  134. 134.
    Rath, S., Lin, R. H., Rudensky, A., and Janeway, C. A., Jr. 1992. T and B cell receptors discriminate major histocompatibility complex class II conformations influenced hy the invariant chain. Eur. J. Immunol. 22: 2121–2127.PubMedGoogle Scholar
  135. 135.
    Peterson, M., and Miller, J. 1990. Invariant chain influences the immunological recognition of MHC class II molecules. Nauture 345:172–174.Google Scholar
  136. 136.
    Peterson, M., and Miller, J. 1992. Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41. Nature 357:596–598.PubMedGoogle Scholar
  137. 137.
    Bakke, O., and Dobberstein, B. 1990. MHC class II-associated invariant chain contains a sorting signal lor endosomal compartments. Cell 63:707–716.PubMedGoogle Scholar
  138. 138.
    Lotteau, V., Teyton, L., Pelcraux, A., Nilsson, T., Karlsson, L., Schmid, S. L., Quaranta, V., and Peterson, P. A. 1990. Intracellular transport of class II MHC molecules directed by invariant chain. Nature 348:600–605.PubMedGoogle Scholar
  139. 139.
    Simonis, S., Miller, J., and Cullen, S. E. 1989. The role of the Ia-invariant chain complex in the posttranslational processing and transport of la and invariant chain glycoproteins. J. Immunol. 143:3619–3625.PubMedGoogle Scholar
  140. 140.
    Marks, M. S., Blum, J. S., and Cresswell, P. 1990. Invariant chain trimers are sequestered in the rough endoplasmic reticulum in the absence of association with HLA class II antigens. J. Cell Biol. 111:839–855.PubMedGoogle Scholar
  141. 141.
    Roche, P. A., and Cresswell, P. 1990. Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding. Nature 345:615–618.PubMedGoogle Scholar
  142. 142.
    Teyton, L., O’Sullivan, D., Dickson, P. W., Lotteau, V., Sette, A., Fink, P., and Peterson, P. A. 1990. Invariant chain distinguishes between the exogenous and endogenous antigen presentation pathways. Nauture 348:39–44.Google Scholar
  143. 143.
    Roche, P. A., Teletski, C. L., Karp, D. R., Pinet, V., Bakke, O., and Long, E. O. 1992. Stable surface expression of invariant chain prevents peptide presentation by HLA-DR. EMBO J. 11:2841–2847.PubMedGoogle Scholar
  144. 144.
    Lamb, C. A., Yewdell, J. W., Bennink, J. R., and Cresswell, P. 1991. Invariant chain targets HLA class II molecules to acidic endosomes containing internalized influenza virus. Proc. Natl. Acad. Sci. USA 88:5998–6002.PubMedGoogle Scholar
  145. 145.
    Romagnoli, P., Layet, C., Yewdell, J., Bakke, O., and Germain, R. N. 1993. Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments. J. Exp. Med. 177:583–596.PubMedGoogle Scholar
  146. 146.
    Neefjes, J. J., and Ploegh, H. L. 1992. Inhibition of endosomal proteolytic activity by leupeptin blocks surface expression of MHC class II molecules and their conversion to SDS resistant alpha beta heterodimers in endosomes. EMHO J. 11:411–416.Google Scholar
  147. 147.
    Loss, G. F., Jr., and Sant, A. J. 1993. Invariant chain retains MHC class II molecules in the endocytic pathway. J. Immunol. 150:3187–3197.PubMedGoogle Scholar
  148. 148.
    Simonsen, A., Momburg, F., Drexler, J., Hummerling, G. J., and Bakke, O. 1993. Intracellular distribution of the MHC class II molecules and the associated invariant chain (Ii) in different cell lines. Int. Immunol. 5:903–917.PubMedGoogle Scholar
  149. 149.
    Loss, G. E., Jr., Elias, C. G., Fields, P. E., Ribaudo, R. K., McKisic, M., and Sant, A. J. 1993. Major histocompatihility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways. J. Exp. Med. 178:73–85.PubMedGoogle Scholar
  150. 150.
    Roche, P. A., Teletski, C. L., Stang, E., Bakke, O., and Long, E. O. 1993. Cell surface HLA-DR-invariant chain complexes are targeted to endosomes by rapid internalization. Proc. Natl. Acad. Sci. USA 90:8581–8585.PubMedGoogle Scholar
  151. 151.
    Nadimi, F., Moreno, J., Momburg, F., Heuser, A., Fuchs, S., Adorini, L., and Hammerling, G. J. 1991. Antigen presentation of hen egg-white lysozyme but not of ribonuclease A is augmented by the major histocompatibility complex class II-associatcd invariant chain. Eur. J. Immunol. 21:1255–1263.PubMedGoogle Scholar
  152. 152.
    Stockinger, B., Pessara, U., Lin, R. H., Habicht, J., Grez, M., and Koch, A. 1989. A role of Ia-associated invariant chains in antigen processing and presentation. Cell 56:683–689.PubMedGoogle Scholar
  153. 153.
    Beriolino, P., Forquet, F., Pont, S., Koch, N., Gerlier, D., and Rabourdin-Combe, C. 1991. Correlation between invariant chain expression level and capability to present antigen to MHC class II-restricted T cells. Int. Immunol. 3:435–443.Google Scholar
  154. 154.
    Naujokas, M. F., Morin, M., Anderson, M. S., Peterson, M., and Miller, J. 1993. The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44. Cell 74:257–268.PubMedGoogle Scholar
  155. 155.
    Kaempgen, E., Koch, N., Koch, F., Stoeger, P., Heufler, C., Schuler, G., and Romani, N. 1991. Class II major histocompatibility complex molecules of murine dendritic cells: Synthesis, sialylalion of invariant chain, and antigen processing capacity are down-regulated upon culture. Proc. Natl. Acad. Sci. USA 88:3014–3018.Google Scholar
  156. 156.
    Fineschi, B., Arneson, L. S., Naujokas, M. F., and Miller, J. 1995. Proteolysis of major histocompatibility complex class II-associaled invariant chain is regulated by the alternatively spliced gene-product, p41. Proc. Natl. Acad. Sci. USA 92:10257–10261.PubMedGoogle Scholar
  157. 157.
    Peterson, M., and Miller, J. 1992. Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41. Nature 357:596–598.PubMedGoogle Scholar
  158. 158.
    Bevec, T., Stoka, V., Pungercic, G., Dolenc, I., and Turk, V. 1996. Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J. Exp. Med. 183:1331–1338.PubMedGoogle Scholar
  159. 159.
    Freisewinkel, I. M., Schenck, K., and Koch, N. 1993. The segment of invariant chain that is critical for association with major histocompatibility complex class II molecules contains the sequence of a peptide eluted from class II polypeplides. Proc. Natl. Acad. Sci. USA 90:9703–9706.PubMedGoogle Scholar
  160. 160.
    Lombard-Platet, S., Bertolino, P., Gimenez, C., Humbert, M., Gerlier, D., and Rabourdin-Combe, C. 1993. Invariant chain expression similarly controls presentation of endogenously synthesized and exogenous antigens by MHC class II molecules. Cell. Immunol. 148:60–70.PubMedGoogle Scholar
  161. 161.
    Romagnoli, P., and Germain, R. N. 1994. The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy. J. Exp. Med. 180:1107–1113.PubMedGoogle Scholar
  162. 162.
    Ghosh, P., Amaya, M., Mellins, E., and Wiley, D. C. 1995. The structure of an intermediate in class-II MHC maturation: CLIP bound to HLA-DR3. Nature 378:457–462.PubMedGoogle Scholar
  163. 163.
    Cresswell, P. 1996. Invariant chain structure and MHC class II function. Cell 84:505–507.PubMedGoogle Scholar
  164. 164.
    Kropshofer, H., Vogt, A. B., and Haemmerling, G. J. 1995. Structural features of the invariant chain fragment CLIP controlling rapid release from HLA-DR molecules and inhibition of peptide binding. Proc. Natl. Acad. Sci. USA 92:8313–8317.PubMedGoogle Scholar
  165. 165.
    Bangia, N., and Watts, T. H. 1995. Evidence for invariant chain-85-101 (CLIP) binding in the antigenbinding site of MHC class-II molecules. Int. Immunol. 7:1585–1591.PubMedGoogle Scholar
  166. 166.
    Rudensky, A. Y., Preston Hurlburt, P., Hong, S. C., Barlow, A., and Janeway, C. A., Jr. 1991. Sequence analysis of peptides bound to MHC class II molecules. Nature 353:622–627.PubMedGoogle Scholar
  167. 167.
    Chicz, R. M., Urban, R. G., Lane, W. S., Gorga, J. C., Stern, L. J., Vignali, D. A., and Strominger, J. L. 1992. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature 358:764–768.PubMedGoogle Scholar
  168. 168.
    Chicz, R. M., Urban, R. G., Gorga, J. C., Vignali, D. A., Lane, W. S., and Strominger, J, L. 1993. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J. Exp. Med. 178:27–47.PubMedGoogle Scholar
  169. 169.
    Fling, S. P., Arp, B., and Pious, D. 1994. HLA-DMA and-DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells. Nature 368:554–558.PubMedGoogle Scholar
  170. 170.
    Morris, P., Shaman, J., Attaya, M., Amaya, M., Goodman, S., Bergman, C, Monaco, J. J., and Mellins, E. 1994. An essential role for HLA-DM in antigen presentation by class II major histocompatibility molecules. Nature 368:551–554.PubMedGoogle Scholar
  171. 171.
    Kelly, A. P., Monaco, J. J., Cho, S. G., and Trowsdale, J. 1991. A new human HLA class II-related locus, DM. Nature 353:571–573.PubMedGoogle Scholar
  172. 172.
    Riberdy, J. M., Newcomb, J. R., Surman, M. J., Barbosa, J. A., and Cresswell, P. 1992. HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides. Nature 360:474–477.PubMedGoogle Scholar
  173. 173.
    Sette, A., Ceman, S., Kubo, R. T., Sakaguchi, K., Appella, E., Hunt, D. F., Davis, T. A., Michel, H., Shabanowitz, J., Rudersdorf, R., Grey, H. M., and DeMars, R. 1992. Invariant chain peptides in most HLA-DR molecules of an antigen-processing mutant. Science 258:1801–1804.PubMedGoogle Scholar
  174. 174.
    Morkowski, S., Goldrath, A. W., Eastman, S., Ramachandra, L., Freed, D. C, Whiteley, P., and Rudensky, A. Y. 1995. T-cell recognition of major histocompatibility complex class-II complexes with invariant chain processing intermediates. J. Exp. Med. 182:1403–1413.PubMedGoogle Scholar
  175. 175.
    Riese, R. J., Wolf, P. R., Broemme, D., Nalkin, L. R., Villadangos, J. A., Ploegh, H. L., and Chapman, H. A. 1996. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity 4:357–366.PubMedGoogle Scholar
  176. 176.
    Cho, S. G., Attaya, M., and Monaco, J. J. 1991. New class II-like genes in the murine MHC. Nature 353:573–576.PubMedGoogle Scholar
  177. 177.
    Mellins, E., Kempin, S., Smilh, L., Monji, T., and Pious, D. 1991. A gene required for class II-re.stricted antigen presentation maps to the major histocompatibility complex. J. Exp. Med. 174:1607–1615.PubMedGoogle Scholar
  178. 178.
    Denzin, L. K., Robbins, N. F., and Carboynewcomb, C. 1994. Assembly and intracellular-transport of HLA-DM and correction of the class-II antigen-processing defect in T2 cells. Immunity 1:595–606.PubMedGoogle Scholar
  179. 179.
    Sanderson, F., Kleijmeer, M. J., Kelly, A., Verwoerd, D., Tulp, A., Neefjes, J. J., Geuze, H. J., and Trowsdale, J. 1994. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science 266:1566–1569.PubMedGoogle Scholar
  180. 180.
    Robbins, N. F., Hammond, C., Denzin, L. K., Pan, M., and Cresswell, P. 1996. Trafficking of major histocompatibility complex class II molecules through intracellular compartments containing HLA-DM. Hum. Immunol. 45:13–23.PubMedGoogle Scholar
  181. 181.
    Sanderson, F., Thomas, C., Neefjes, J., and Trowsdale, J. 1996. Association between HLA-DM and HLA-DR in vivo. Immunity 4:87–96.PubMedGoogle Scholar
  182. 182.
    Pierre, P., Denzin, L. K., Hammond, C., Drake, J. R., Amigorena, S., Cresswell, P., and Mellman, I. 1996. HLA-DM is localized to conventional and unconventional MHC class II-containing endocylic compartments. Immunity 4:229–239.PubMedGoogle Scholar
  183. 183.
    Brown, J. H., Jardetzky, T., Saper, M. A., Samraoui, B., Bjorkman, P. J., and Wiley, D. C. 1988. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature 332:845–850.PubMedGoogle Scholar
  184. 184.
    Denzin, L. K., and Cresswell, P. 1995. HLA-DM induces CLIP dissociation from MHC class-II αβ dimers and facilitates peptide loading. Cell 82:155–165.PubMedGoogle Scholar
  185. 185.
    Sloan, V. S., Cameron, P., Porter, G., Gammon, M., Amaya, M., Mellins, E., and Zaller, D. M. 1995. Mediation by HLA-DM of dissociation of peptides from HLA-DR. Nature 375:802–806.PubMedGoogle Scholar
  186. 186.
    Vogt, A. B., Kropshofer, H., Moldenhauer, G., and Hammerling, G. J. 1996. Kinetic-analysis of peptide loading onto HLA-DR molecules mediated by HLA-DM. Proc. Natl. Acad. Sci. USA 93:9724–9729.PubMedGoogle Scholar
  187. 187.
    Sherman, M. A., Weber, D, A., and Jensen, P. E. 1995. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity 3:197–205.PubMedGoogle Scholar
  188. 188.
    Miyazaki, T., Wolf, P., Tourne, S., Waltzinger, C., Dicrich, A., Barois, N., and Mathis, D. 1996. Mice lacking H2-M complexes, enigmatic elements of the MHC class II peptide-loading pathway. Cell 84:531–541.PubMedGoogle Scholar
  189. 189.
    Martin, W. D., Hicks, G. G., Mindiratta, S. K., Leva, H. I., Ruley, H. E., and Van Kaer, L. 1996. H-2M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Celt 84:543–550.Google Scholar

Copyright information

© Plenum Press, New York 1998

Personalised recommendations