Advertisement

Options for TCR Interactions: TCR Agonists, Antagonists and Partial Agonists

  • Stephen C. Jameson
  • Kristin A. Hogquist

Abstract

Over the last 25 years or so, immunologists have exerted considerable effort toward determining how antigens are perceived by T cells, resulting in a huge body of knowledge about this event. Pioneering work defined the requirement for MHC and subsequently showed that “antigen” was presented to T cells as a peptide complexed to a suitable MHC molecule (reviewed in ref. 1). As the rest of the chapters in this book vividly portray, we have come a long way with this type of analysis, such that we now know much about how peptides interact with the MHC, have clues to which residues in the TCR engage which regions of the MHC + peptide, and have detailed molecular structures for several MHC/peptide complexes, with a complete structure for the TCR tantalizingly near. On the other side of the membrane, much is now known about the signaling events following TCR engagement (reviewed in ref. 2). Although most of these studies involve stimulation of transformed T cells by anti-TCR antibodies, similar results are being found using antigen activated T cell clones. Until recently, these results have lead to a pleasingly simple model—the TCR needs only to find its ligand and it will engage, undergo cross-linking on the T cell surface, and then induce a “standard” cascade of activation events. However, as with most biological models, there were unexpected layers of complexity to be discovered.

Keywords

Partial Agonist Experimental Allergic Encephalomyelitis Full Agonist Altered Peptide Ligand Signaling Machinery 
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.

Referzences

  1. 1.
    Germain RN. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994; 76: 287.CrossRefGoogle Scholar
  2. 2.
    Chan AC, Desai DM, Weiss A. The role of protein tyrosine kinases and protein tyrosine phophatases in T cell antigen receptor signal transduction. Annu Rev Immunol 1994; 12: 555.CrossRefGoogle Scholar
  3. 3.
    Evavold BD, Sloan-Lancaster J, Allen PM. Tickling the TCR: selective T cell functions stimulated by altered peptide ligands. Immunol Today 1993; 14: 602.CrossRefGoogle Scholar
  4. 4.
    Sette A et al. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Annu Rev Immunol 1994; 12: 413.CrossRefGoogle Scholar
  5. 5.
    Jameson SC, Bevan MJ. T cell receptor antagonists and partial agonists. Immunity 1995; 2: 1.CrossRefGoogle Scholar
  6. 6.
    Kenakin T. Agonists, partial agonists, antagonists, inverse agonists and agonist/antagonists? Trends Pharmacol Sci 1987; 8: 423.CrossRefGoogle Scholar
  7. 7.
    Evavold BD, Allen PM. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science 1991; 252: 1308.CrossRefGoogle Scholar
  8. 8.
    De Magistris MT et al. Antigen analog-Major Histocompatibility Complexes act as antagonists of the T cell receptor. Cell 1992; 68: 625.CrossRefGoogle Scholar
  9. 9.
    Ruppert J et al. Effect of T cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T cell signaling events. Proc Natl Acad Sci USA 1993; 90: 2671Google Scholar
  10. 10.
    Jameson SC, Carbone FR, Bevan MJ. Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells. J Exp Med 1993; 177: 1541.CrossRefGoogle Scholar
  11. 11.
    Lo D, Ron Y, Sprent J. Induction of MHC-restricted specificity and tolerance in the thymus. Immunol Res 1986; 5: 221.CrossRefGoogle Scholar
  12. 12.
    Fowlkes BJ, Pardoll DM. Molecular and cellular events of T cell development. Adv Immunol 1989; 44: 207.CrossRefGoogle Scholar
  13. 13.
    Jameson SC, Hogquist KA, Bevan MJ. Positive selection of thymocytes. Annu Rev Immunol 1995; 13: 93.CrossRefGoogle Scholar
  14. 14.
    Hogquist K et al. T cell receptor antagonist peptides induce positive selection. Cell 1994; 76: 17.CrossRefGoogle Scholar
  15. 15.
    Jameson SC, Hogquist KA, Bevan MJ. Specificity and flexibility in thymic selection. Nature 1994; 369: 750.CrossRefGoogle Scholar
  16. 16.
    Spain L et al. A peptide antigen antagonist prevents the differentiation of T cell receptor transgenic thymocytes. J Immunol 1994; 152: 1709.Google Scholar
  17. 17.
    Page DM et al. Negative selection of CD4’ CD8’ thymocytes by T cell receptor peptide antagonists. Proc Natl Acad Sci USA 1994; 91: 4057.CrossRefGoogle Scholar
  18. 18.
    Pfeiffer C et al. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med 1995; 181: 1569.CrossRefGoogle Scholar
  19. 19.
    Windhagen A et al. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity 1995; 2: 373.CrossRefGoogle Scholar
  20. 20.
    Kuchroo VK et al. A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis by a diverse T cell repertoire. J Immunol 1994; 153: 3326.Google Scholar
  21. 21.
    Franco A et al. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur J Immunol 1994; 24: 940.CrossRefGoogle Scholar
  22. 22.
    Karin N et al. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J Exp Med 1994; 180: 2227.Google Scholar
  23. 23.
    Bertoletti A et al. Natural variants of cytotoxic epitopes are T cell receptor antagonists for antiviral cytotoxic T cells. Nature 1994; 369: 407.CrossRefGoogle Scholar
  24. 24.
    Klenerman P et al. Cytotoxic T cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature 1994; 369: 403.CrossRefGoogle Scholar
  25. 25.
    Mannie MD. A unified model for T cell antigen recognition and thymic selection of the T cell repertoire. J Theor Biol 1991; 151: 169.CrossRefGoogle Scholar
  26. 26.
    Janeway CA Jr. High fives or hand clasps? Curr Biol 1993; 2: 591.CrossRefGoogle Scholar
  27. 27.
    Rojo JM, Janeway CA Jr. The biologic activity of anti-T cell receptor V region monoclonal antibodies is determined by the epitope recognized. J Immunol 1988; 140: 1081.Google Scholar
  28. 28.
    Yoon ST et al. Both high and low avidity antibodies to the T cell receptor can have agonist and antagonist activity. Immunity 1994; 1: 563.CrossRefGoogle Scholar
  29. 29.
    Sloan Lancaster J et al. Partial T cell signaling: Altered phospho-z and lack of zap70 recruiment in APL-induced T cell anergy. Cell 1994; 79: 913.CrossRefGoogle Scholar
  30. 30.
    Medrenas J et al. Z phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 1995; 267: 515.CrossRefGoogle Scholar
  31. 31.
    Wegener A-M et al. The T cell receptor/ CD3 complex is composed of at least two autonomous signal transduction modules. Cell 1992; 68: 83.CrossRefGoogle Scholar
  32. 32.
    Shinkai Y et al. CD3e and CD3z cytoplasmic domains can independently generate signals for T cell development and function. Immunity 1995; 2: 401.CrossRefGoogle Scholar
  33. 33.
    Davis MM. T cell receptors: Serial engagement proposed. Nature 1995; 375: 104.Google Scholar
  34. 34.
    Valitutti S et al. Serial triggering of many T cell receptors by a few peptide-MHC complexes. Nature 1995; 375: 148.CrossRefGoogle Scholar
  35. 35.
    Valitutti S et al. Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. J Exp Med 1995; 181: 577.CrossRefGoogle Scholar

Copyright information

© R.G. Landes Company 1996

Authors and Affiliations

  • Stephen C. Jameson
  • Kristin A. Hogquist

There are no affiliations available

Personalised recommendations