Role of Ligand Density in T Cell Reactions

  • Theodore J. Tsomides


Studies in the early 1970s revealed a requirement that T lympho-cytes responding to antigens on other cells (B lymphocytes or macrophages) must share MHC specificities with the antigen-bearing cells they recognize in order to become functional helper T cells.1–3 Zinkernagel and Doherty unequivocally showed that virus-specific cytotoxic T lymphocyte (CTL) responses also require shared MHC specificities between the T cell and the virus-infected target cell (“MHC restriction”).4 Subsequently, molecular genetic studies led to characterization of the highly polymorphic genes of the MHC and to sequencing of the genes encoding subunits of the antigen-specific T cell receptor (TCR). Details of the tripartite interaction between antigen, MHC protein, and TCR did not begin to emerge until the mid-1980s, when landmark studies of Townsend et al showed that the antigens recognized by T cells are short peptides (generally 8–25 amino acids in length),5 and x-ray crystallographic structure determinations provided striking images of MHC molecules complexed with mixtures of cellular peptides6,7 or individual synthetic peptides.8–11 The 1990s have seen an explosion of information regarding peptide-MHC interactions and an accompanying heightening of interest in applying this information to clinical areas such as autoimmunity, vaccine design, and immunotherapy (e.g., refs. 12–15).


Cell Epitope Ligand Density Human Melanoma Antigen Sensitize Target Cell Brichard Versus 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kindred B, Shreffler DC. H-2 dependence of co-operation between T and B cells in vivo. J Immunol 1972; 109: 940–943.Google Scholar
  2. 2.
    Katz DH, Hamaoka T, Dorf ME et al. Cell interactions between histoincompatible T and B lymphocytes. The H-2 gene complex determines successful physiologic lymphocyte interactions. Proc Natl Acad Sci USA 1973; 70: 2624–2628.CrossRefGoogle Scholar
  3. 3.
    Rosenthal AS, Shevach EM. Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J Exp Med 1973; 138: 1194–1212.CrossRefGoogle Scholar
  4. 4.
    Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 1974; 248: 701–702.CrossRefGoogle Scholar
  5. 5.
    Townsend ARM, Rothbard J, Gotch FM et al. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 1986; 44: 959–968.CrossRefGoogle Scholar
  6. 6.
    Bjorkman PJ, Saper MA, Samraoui B et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 1987; 329: 506–512.CrossRefGoogle Scholar
  7. 7.
    Brown JH, Jardetzky TS, Gorga JC et al. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 1993; 364: 33–39.CrossRefGoogle Scholar
  8. 8.
    Fremont DH, Matsumura M, Stura EA et al. Crystal stuctures of two viral peptides in complex with murine MHC class I H-2Kb. Science 1992; 257: 919–927.CrossRefGoogle Scholar
  9. 9.
    Zhang W, Young ACM, Imarai M et al. Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: Implications for peptide binding and T-cell receptor recognition. Proc Natl Acad Sci USA 1992; 89: 8403–8407.CrossRefGoogle Scholar
  10. 10.
    Silver ML, Guo H-C, Strominger JL et al. Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature 1992; 360: 367–369.CrossRefGoogle Scholar
  11. 11.
    Stern LJ, Brown JH, Jardetzky TS et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 1994; 368: 215–221.CrossRefGoogle Scholar
  12. 12.
    Feltkamp MCW, Smits HL, Vierboom MPM et al. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol 1993; 23: 2242–2249.CrossRefGoogle Scholar
  13. 13.
    Celis E, Tsai V, Crimi C et al. Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. Proc Natl Acad Sci USA 1994; 91: 2105–2109.CrossRefGoogle Scholar
  14. 14.
    Sette A, Alexander J, Ruppert J et al. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Ann Rev Immunol 1994; 12: 413–431.CrossRefGoogle Scholar
  15. 15.
    Chicz RM, Urban RG. Analysis of MHC-presented peptides: applications in autoimmunity and vaccine development. Immunol Today 1994; 15: 155–160.CrossRefGoogle Scholar
  16. 16.
    Monaco JJ. A molecular model of MHC class-I-restricted antigen processing. Immunol Today 1992; 13: 173–179.CrossRefGoogle Scholar
  17. 17.
    Townsend A, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Ann Rev Immunol 1989; 7: 601–624.CrossRefGoogle Scholar
  18. 18.
    Tsomides TJ, Eisen HN. Identification of naturally occurring peptides associated with MHC molecules. In: Sette A, ed. Chemical Immunology. Basel: Karger, 1993: 166–196.Google Scholar
  19. 19.
    Buus S, Sette A, Colón SM et al. Autologous peptides constitutively occupy the antigen binding site on Ia. Science 1988; 242: 1045–1047.CrossRefGoogle Scholar
  20. 20.
    Rötzschke O, Falk K, Wallny H-J et al. Characterization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science 1990; 249: 283–287.CrossRefGoogle Scholar
  21. 21.
    van Bleek GM, Nathenson SG. Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule. Nature 1990; 348: 213–216.CrossRefGoogle Scholar
  22. 22.
    Rötzschke O, Falk K, Deres K et al. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 1990; 348: 252–254.CrossRefGoogle Scholar
  23. 23.
    Jardetzky TS, Lane WS, Robinson RA et al. Identification of self peptides bound to purified HLA-B27. Nature 1991; 353: 326–329.CrossRefGoogle Scholar
  24. 24.
    Hunt DF, Henderson RA, Shabanowitz J et al. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992; 255: 1261–1263.CrossRefGoogle Scholar
  25. 25.
    Rudensky AY, Preston-Hurlburt P, Hong S-C et al. Sequence analysis of peptides bound to MHC class II molecules. Nature 1991; 353: 622–627.CrossRefGoogle Scholar
  26. 26.
    Chicz RM, Urban RG, Lane WS et al. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature 1992; 358: 764–768.CrossRefGoogle Scholar
  27. 27.
    Riberdy JM, Newcomb JR, Surman MJ et al. HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides. Nature 1992; 360: 474–477.CrossRefGoogle Scholar
  28. 28.
    Falk K, Rötzschke O, Stevanovic S et al. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 1991; 351: 290–296.CrossRefGoogle Scholar
  29. 29.
    Matsumura M, Fremont DH, Peterson PA et al. Emerging principles for the recognition of peptide antigens by MHC class I molecules. Science 1992; 257: 927–934.CrossRefGoogle Scholar
  30. 30.
    Madden DR, Gorga JC, Strominger JL et al. The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell 1992; 70: 1035–1048.CrossRefGoogle Scholar
  31. 31.
    Young ACM, Zhang W, Sacchettini JC et al. The three-dimensional structure of H-2Db at 2.4 A resolution: Implications for antigen-determinant selection. Cell 1994; 76: 39–50.CrossRefGoogle Scholar
  32. 32.
    Pamer EG, Harty JT, Bevan MJ. Precise prediction of a dominant class I MHC-restricted epitope of Listeria monocytogenes. Nature 1991; 353: 852–855.CrossRefGoogle Scholar
  33. 33.
    Udaka K, Tsomides TJ, Eisen HN. A naturally occurring peptide recognized by alloreactive CD8* cytotoxic T lymphocytes in association with a class I MHC protein. Cell 1992; 69: 989–998.CrossRefGoogle Scholar
  34. 34.
    Udaka K, Tsomides TJ, Walden P et al. A ubiquitous protein is the source of naturally occurring peptides that are recognized by a CD8* T-cell clone. Proc Natl Acad Sci USA 1993; 90: 11272–11276.CrossRefGoogle Scholar
  35. 35.
    Mandelboim O, Berke G, Fridkin M et al. CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma. Nature 1994; 369: 67–71.CrossRefGoogle Scholar
  36. 36.
    Henderson RA, Cox AL, Sakaguchi K et al. Direct identification of an endogenous peptide recognized by multiple HLA-A2.1 specific cytotoxic T cells. Proc Natl Acad Sci USA 1993; 90: 10275–10279.CrossRefGoogle Scholar
  37. 37.
    Cox AL, Skipper J, Chen Y et al. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 1994; 264: 716–719.CrossRefGoogle Scholar
  38. 38.
    Storkus WJ, Zeh HJ III, Maeurer MJ et al. Identification of human melanoma peptides recognized by class I restricted tumor infiltrating T lymphocytes. J Immunol 1993; 151: 3719–3727.Google Scholar
  39. 39.
    Castelli C, Storkus WJ, Maeurer MJ et al. Mass spectrometric identification of a naturally processed melanoma peptide recognized by CD8* cytotoxic T lymphocytes. J Exp Med 1995; 181: 363–368.CrossRefGoogle Scholar
  40. 40.
    Kageyama S, Tsomides TJ, Sykulev Y et al. Variations in the number of peptide-MHC class I complexes required to activate cytotoxic T cell responses. J Immunol 1995; 154: 567–576.Google Scholar
  41. 41.
    Tsomides TJ, Aldovini A, Johnson RP et al. Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J Exp Med 1994; 180: 1283–1293.CrossRefGoogle Scholar
  42. 42.
    De Plaen E, Lurquin C, Van Pel A et al. Immunogenic (turn-) variants of mouse tumor P815: Cloning of the gene of tum-antigen P91A and identification of the turn-mutation. Proc Natl Acad Sci USA 1988; 85: 2274–2278.CrossRefGoogle Scholar
  43. 43.
    Boon T, Cerottini J-C, Van den Eynde B et al. Tumor antigens recognized by T lymphocytes. Ann Rev Immunol 1994; 12: 337–365.CrossRefGoogle Scholar
  44. 44.
    van der Bruggen P, Traversari C, Chomez P et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254: 1643–1647.CrossRefGoogle Scholar
  45. 45.
    Traversari C, van der Bruggen P, Luescher IF et al. A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J Exp Med 1992; 176: 1453–1457.CrossRefGoogle Scholar
  46. 46.
    Brichard V, Van Pel A, Wölfel T et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1993; 178: 489–495.CrossRefGoogle Scholar
  47. 47.
    Kawakami Y, Eliyahu S, Delgado CH et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 1994; 91: 3515–3519.CrossRefGoogle Scholar
  48. 48.
    Coulie PG, Brichard V, Van Pel A et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1994; 180: 35–42.CrossRefGoogle Scholar
  49. 49.
    Wallny H-J, Deres K, Faath S et al. Identification and quantification of a naturally presented peptide as recognized by cytotoxic T lymphocytes specific for an immunogenic tumor variant. Internat Immunol 1992; 4: 1085–1090.CrossRefGoogle Scholar
  50. 50.
    Tsomides TJ, Walker BD, Eisen HN. An optimal viral peptide recognized by CD8’ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein. Proc Natl Acad Sci USA 1991; 88: 11276–11280.CrossRefGoogle Scholar
  51. 51.
    Falk K, Rötzschke O, Deres K et al. Identification of naturally processed viral nonapeptides allows their quantification in infected cells and suggests an allele-specific T cell epitope forecast. J Exp Med 1991; 174: 425–434.CrossRefGoogle Scholar
  52. 52.
    McMichael AJ, Gotch FM, Noble GR et al. Cytotoxic T-cell immunity to influenza. New Engl J Med 1983; 309: 13–17.CrossRefGoogle Scholar
  53. 53.
    Doherty PC, Allan W, Eichelberger M. Roles of all and yS T cell subsets in viral immunity. Ann Rev Immunol 1992; 10: 123–151.CrossRefGoogle Scholar
  54. 54.
    Nixon DF, Broliden K, Ogg G et al. Cellular and humoral antigenic epitopes in HIV and SIV. Immunology 1992; 76: 515–534.Google Scholar
  55. 55.
    Venet A, Walker BD. Cytotoxic T-cell epitopes in HIV/SIV infection. AIDS 1993; 7 (suppl 1): 5117 - S126.Google Scholar
  56. 56.
    Topalian SL, Solomon D, Rosenberg SA. Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol 1989; 142: 3714–3725.Google Scholar
  57. 56.
    Topalian SL, Solomon D, Rosenberg SA. Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol 1989; 142: 3714–3725.Google Scholar
  58. 58.
    Foote J, Eisen HN. Kinetic and affinity limits on antibodies produced during immune responses. Proc Natl Acad Sci USA 1995; 92: 1254–1256.CrossRefGoogle Scholar
  59. 59.
    Matsui K, Boniface JJ, Steffner P et al. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci USA 1994; 91: 12862–12866.CrossRefGoogle Scholar
  60. 60.
    Sykulev Y, Brunmark A, Tsomides TJ et al. High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins. Proc Natl Acad Sci USA 1994; 91: 11487–11491.CrossRefGoogle Scholar
  61. 61.
    Alexander MA, Damico CA, Wieties KM et al. Correlation between CD8 dependency and determinant density using peptide-induced, Ld-restricted cytotoxic T lymphocytes. J Exp Med 1991; 173: 849–858.CrossRefGoogle Scholar
  62. 62.
    Harding CV, Unanue ER. Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation. Nature 1990; 346: 574–576.CrossRefGoogle Scholar
  63. 63.
    Demotz S, Grey HM, Sette A. The minimal number of class II MHCantigen complexes needed for T cell activation. Science 1990; 249: 1028–1030.CrossRefGoogle Scholar
  64. 64.
    Christinck ER, Luscher MA, Barber BH et al. Peptide binding to class I MHC on living cells and quantitation of complexes required for CTL lysis. Nature 1991; 352: 67–70.CrossRefGoogle Scholar
  65. 65.
    Karush F. Affinity and the immune response. Annals NY Acad Sci 1970; 169: 56–64.CrossRefGoogle Scholar
  66. 66.
    Tsomides TJ, Eisen HN. Stoichiometric labeling of peptides by iodination on tyrosyl or histidyl residues. Analyt Biochem 1993; 210: 129–135.CrossRefGoogle Scholar
  67. 67.
    Schumacher TNM, Tsomides TJ. In vitro radiolabeling of peptides and proteins. In: Coligan JE, Dunn BM, Ploegh HL, Speicher DW, Wingfield PT, eds. Current Protocols in Protein Science. New York: John Wiley & Sons, Inc 1995:3.3.1–3. 3. 19.Google Scholar
  68. 68.
    Milligan GN, Morrison LA, Gorka J et al. The recognition of a viral antigenic moiety by class I MHC-restricted cytolytic T lymphocytes is limited by the availability of the endogenously processed antigen. J Immunol 1990; 145: 3188–3193.Google Scholar
  69. 69.
    Speiser DE, Kyburz D, Stübi U et al. Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection. J Immunol 1992; 149: 972–980.Google Scholar
  70. 70.
    Rötzschke O, Falk K, Stevanovic S et al. Exact prediction of a natural T cell epitope. Eur J Immunol 1991; 21: 2891–2894.CrossRefGoogle Scholar
  71. 71.
    del Val M, Schlicht H-J, Ruppert T et al. Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. Cell 1991; 66: 1145–1153.CrossRefGoogle Scholar
  72. 72.
    Dutz JP, Tsomides TJ, Kageyama S et al. A cytotoxic T lymphocyte clone can recognize the same naturally occurring self peptide in association with a self and a nonself class I MHC protein. Molec Immunol 1994; 31: 967–975.CrossRefGoogle Scholar
  73. 73.
    van der Bruggen P, Bastin J, Gajewski T et al. A peptide encoded by human gene MAGE-3 and presented by HLA-A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE-3. Eur J Immunol 1994; 24: 3038–3043.CrossRefGoogle Scholar
  74. 74.
    Gaugler B, Van den Eynde B, van der Bruggen P et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 1994; 179: 921–930.CrossRefGoogle Scholar
  75. 75.
    van der Bruggen P, Szikora J-P, Boël P et al. Autologous cytolytic T lymphocytes recognize a MAGE-1 nonapeptide on melanomas expressing HLA-Cw*1601. Eur J Immunol 1994; 24: 2134–2140.CrossRefGoogle Scholar
  76. 76.
    Wölfel T, Van Pel A, Brichard V et al. Two tyrosinase nonapeptides recognized on HLA-A2 melanomas by autologous cytolytic T lymphocytes. Eur J Immunol 1994; 24: 759–764.CrossRefGoogle Scholar
  77. 77.
    Kawakami Y, Eliyahu S, Sakaguchi K et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med 1994; 180: 347–352.CrossRefGoogle Scholar
  78. 78.
    Bakker ABH, Schreurs MWJ, de Boer AJ et al. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med 1994; 179: 1005–1009.CrossRefGoogle Scholar
  79. 79.
    Kawakami Y, Eliyahu S, Delgado CH et al. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci USA 1994; 91: 6458–6462.CrossRefGoogle Scholar
  80. 80.
    Buus S, Sette A, Colón SM et al. Isolation and characterization of antigen-Ia complexes involved in T cell recognition. Cell 1986; 47: 1071–1077.CrossRefGoogle Scholar
  81. 81.
    Sadegh-Nasseri S, McConnell HM. A kinetic intermediate in the reaction of an antigenic peptide and I-Ek. Nature 1989; 337: 274–276.CrossRefGoogle Scholar
  82. 82.
    Nelson CA, Petzold SJ, Unanue ER. Peptides determine the lifespan of MHC class II molecules in the antigen-presenting cell. Nature 1994; 371: 250–252.CrossRefGoogle Scholar
  83. 83.
    Fairchild PJ, Wildgoose R, Atherton E et al. An autoantigenic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction. Internat Immunol 1993; 5: 1151–1158.CrossRefGoogle Scholar
  84. 84.
    Mason K, McConnell HM. Short-lived complexes between myelin basic protein peptides and IAk. Proc Natl Acad Sci USA 1994; 91: 12463–12466.CrossRefGoogle Scholar
  85. 85.
    Cerundolo V, Elliott T, Elvin J et al. The binding affinity and dissociation rates of peptides for class I major histocompatibility complex molecules. Eur J Immunol 1991; 21: 2069–2075.CrossRefGoogle Scholar
  86. 86.
    Olsen AC, Pedersen LO, Hansen AS et al. A quantitative assay to measure the interaction between immunogenic peptides and purified class I major histocompatibility complex molecules. Eur J Immunol 1994; 24: 385–392.CrossRefGoogle Scholar
  87. 87.
    Pamer EG. Direct sequence identification and kinetic analysis of an MHC class I-restricted Listeria monocytogenes CTL epitope. J Immunol 1994; 152: 686–694.Google Scholar

Copyright information

© R.G. Landes Company 1996

Authors and Affiliations

  • Theodore J. Tsomides

There are no affiliations available

Personalised recommendations