Theoretical Article

Immunology and Cell Biology (1996) 74, 278–285; doi:10.1038/icb.1996.49

Signal minus 1: A key factor in immunological tolerance to tissue-specific self antigens?

Christopher R Parish1

1Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University Canberra, ACT, Australia

Correspondence: Christopher R Parish, Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.

Received 31 January 1996; Accepted 6 February 1996.

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Abstract

Recent data suggest that many autoreactive T cells, particularly to tissue-specific self antigens, can escape thymic deletion. The current dogma is that these autoreactive T cells are silenced by the failure of most tissues to provide co-stimulation (signal 2), antigen alone (signal 1) inducing T cell unresponsiveness. However, I propose that activation of autoreactive T cells frequently occurs but autodestruction by effector T cells is tightly regulated. This phenomenon is most evident with lymph node metastasizing tumour cells where the regional lymph node can mount a vigorous response to the invading tumour cells but tumour growth is unimpaired. I suggest that autodestruction is prevented by inhibitory receptors on T cells which recognize class I MHC structures on target cells. These receptors, which I propose deliver 'signal minus T to T cells, were recently described on NK cells and a subpopulation of peripheral T cells. They are also strikingly similar to a family of anti-self receptors that my laboratory described on murine T and B cells 15 years ago. In the 'signal minus 1'model, antigen-activated T cells acquire the inhibitory receptors when they become co-stimulation independent and gain the ability to exit lymphoid organs and enter non-lymphoid tissues. Thus, if autoreactive effector T cells encounter autoantigen in tissues they are functionally silenced by inhibitory receptor engagement and signal minus 1 delivery. In contrast, I propose that in response to intracellular infections, cells down-regulate expression of their ligands for inhibitory receptors. Such a model allows infected cells to be selectively eliminated by effector T cells. If correct, the model predicts that effector T cells, whether foreign antigen- or autoantigen-specific, can selectively respond to infected cells. This apparent'usefulness'of autoreactive T cells may explain their observed persistence even after an encounter with autoantigen. It is also suggested that signal minus 1 may silence autoreactive B cells specific for tissue-specific cell surface antigens and lack of signal minus 1 may partially explain the vigorous T cell response to allogeneic MHC. Finally, it is hypothesized that, in evolutionary'terms, inhibition of autodestruction by the recognition of a 'self marker'and delivery of signal minus 1 is an ancient process which probably emerged in early metazoans.

Keywords:

alloreactivity, autoimmunity, inhibitory receptors, peripheral T cell tolerance, signal minus 1

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References

  1. Fowlkes BJ, Ramsdell F. T cell tolerance. Curr. Opin. Immunol. 1993; 5: 873–79. | Article | PubMed | ISI | ChemPort |
  2. Arnold B, Schönrich G, Hämmerling GJ. Multiple levels of peripheral tolerance. Immunol. Today. 1993; 14: 12–14. | Article | PubMed | ISI | ChemPort |
  3. Matzinger P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 1994; 12: 991–1045. | Article | PubMed | ISI | ChemPort |
  4. Boon T, Cerottini J-C, van den Eynde B, van der Bruggen P, Van Pel A. Tumor antigens recognized by T lymphocytes. Annu. Rev. Immunol. 1994; 12: 337–65. | Article | PubMed | ISI | ChemPort |
  5. Hellström KE, Hellström I, Chen L. Can co-stimulated tumor immunity be therapeutically efficacious? Immunol. Rev. 1995; 145: 123–45. | PubMed | ISI | ChemPort |
  6. Warren HS, Lafferty KJ. A high frequency of cytotoxic precursor cells for a syngeneic tumour. Scand. J. Immunol. 1979; 10: 349–52. | Article |
  7. Mackay CR. Homing of naive, memory and effector lymphocytes. Curr. Opin. Immunol. 1993; 5: 423–7. | Article | PubMed | ISI | ChemPort |
  8. Hart IR. The spread of tumours. In: Franks LM, Teich N (eds) Introduction to the Cellular and Molecular Biology of Cancer. Oxford: Oxford University Press, 1987; 27–39.
  9. Tachibana T, Yoshida K. Role of the regional lymph node in cancer metastasis. Cancer Metast. Rev. 1986; 5: 55–66. | Article |
  10. Yokoyama WM. Right-side-up and up-side-down NK-cell receptors. Curr. Biol. 1995; 5: 982–5. | Article |
  11. Raulet DH, Held W. Natural killer cell receptors: The offs and ons of NK cell recognition. Cell 1995; 82: 697–700. | PubMed |
  12. Lanier LL, Phillips JH. Molecular and cell biology of inhibitory MHC class I receptors on NK cells and T cells. Immunol. Today 1996; 17: 86–91. | Article | PubMed | ISI | ChemPort |
  13. Bottino C, Vitale M, Pende D, Biassoni R, Moretta A. Receptors for HLA class I molecules in human NK cells. Semin. Immunol. 1995; 7: 67–74. | Article |
  14. Liebson PJ. MHC recognizing receptors: They're not just for T cells anymore. Immunity. 1995; 3: 5–8. | Article |
  15. Gumperz JE, Parnham P. The enigma of the natural killer cell. Nature 1995; 378: 245–8. | Article | PubMed | ISI | ChemPort |
  16. Moretta A, Vitale M, Sivori S et al. Human natural killer cell receptors for HLA–class I molecules. Evidence that the Kp43 (CD94) molecule functions as a receptor for HLA–B alleles. J. Exp. Med. 1994; 180: 545–55. | Article | PubMed | ISI | ChemPort |
  17. Daniels BF, Nakamura MC, Rosen SD, Yokoyama WM, Seaman WE. Ly-49A, a receptor for H-2Dd, has a functional carbohydrate recognition domain. Immunity 1994; 1: 785–92. | Article | PubMed | ISI | ChemPort |
  18. Brennan J, Takei F, Wong S, Mager DL. Carbohydrate recognition by a natural killer cell receptor, Ly 49C. J. Biol. Chem. 1995; 270: 9691–94. | Article | PubMed | ISI | ChemPort |
  19. Gumperz JE, Litwin V, Phillips JH, Lanier LL, Parnham P. The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor. J. Exp. Med. 1995; 181: 1133–44. | Article | PubMed | ISI | ChemPort |
  20. Phillips JH, Gumperz JE, Pamham P, Lanier LL. MHC class I receptors on T lymphocytes inhibit superantigen dependent cell–mediated cytotoxicity. Science 1995; 268, 403–5. | Article | PubMed | ISI | ChemPort |
  21. Sia DY, Parish CR. Anti-self receptors. I. Direct detection of H-2L region-restricted receptors on murine thymocytes. J. Exp. Med. 1980; 151: 553–65. | Article |
  22. Sia DY, Parish CR. Anti-self receptors. II. Demonstration of H-2L region-restricted receptors on subpopulations of peripheral T and B lymphocytes. J. Immunol. 1980; 124: 2366–71.
  23. Primi D, Lewis GK, Triglia R, Goodman JW. Rosette formation between murine lymphocytes and erythrocytes. A new locus in the H-2 region. J. Exp. Med. 1979; 149: 1349–59. | Article |
  24. Charreire J, Carnaud C, Bach JF. Studies on mouse auto-reactive cells. I. Role of H-2 antigens in mouse autologous rosette formation. Cell Immunol. 1980; 49: 372–8. | Article |
  25. Sia DY, Parish CR. Anti-self receptors. IV H-2 restricted receptors on thymocytes recognize carbohydrate structures on target cells. Immunogenetics 1981; 12: 587–99. | Article |
  26. Kolb H. A ganglioside receptor on lymphocytes mediates recognition of self. Biochem. Biophys. Res. Comm. 1982; 85: 678–83. | Article |
  27. Parish CR, Rylatt DB, Snowden JM. Demonstration of lymphocyte surface lectins that recognize sulphated polysaccharides. J. Cell Sci. 1984; 67: 145–58. | PubMed | ChemPort |
  28. Sia DY, Parish CR. Anti-self receptors. III. Lack of allelic exclusion and thymic epithelium dependence of H-2L region-restricted receptors on lymphocytes. Scand. J. Immunol. 1981; 13: 535–40. | Article |
  29. Rylatt DB, Sia DY, Mundy JP, Parish CR. Autorosette inhibition factor; isolation and properties of the human plasma protein. Eur. J. Biochem. 1981; 119: 641–6. | Article | PubMed | ISI | ChemPort |
  30. Shatsky M, Saigo K, Burdach S, Leung LLK, Levitt LJ. Histidine-rich glycoprotein blocks T cell rosette formation and modulates both T cell activation and immunoregulation. J. Biol. Chem. 1989; 264: 8254–9. | PubMed | ChemPort |
  31. Malnati MS, Peruzzi M, Parker KC et al. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science 1995; 267: 1016–18. | PubMed | ChemPort |
  32. Parish CR. The paradox of carbohydrate histocompatibility antigens. In: Hoffmann GW, Levy JG, Nepom GT (eds) Paradoxes in Immunology, Boca Raton. CRC Press, 1986; 187–98.
  33. Kesson AM, Blanden RV, Müllbacher A. The secondary in vitro murine cytotoxic T cell response to the flavivirus. West Nile. Immunol. Cell Biol. 1988; 66: 23–32. | PubMed |
  34. Alferink J, Schittek B, Schönrich G, Hämmerling G, Arnold B. Long life span of tolerant T cells and the role of antigen in maintenance of peripheral tolerance. Int. Immunol. 1995; 7: 331–6. | PubMed | ISI | ChemPort |
  35. Coutinho A, Bandeira A. Tolerize one, tolerize them all: tolerance is self assertion. Immunol. Today 1989; 10: 264–6. | Article |
  36. McCullagh P. The significance of immune suppression in normal self tolerance. Immunol. Rev.. 1996; (in press).
  37. Macdonald HR, Cerottini J-C, Ryser J-E et al. Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol. Rev. 1980; 51: 93–120. | Article |
  38. Goodnow CC. B-cell tolerance. Curr. Opin. Immunol. 1992; 4: 703–10. | Article | PubMed | ISI | ChemPort |
  39. Geldhof AB, Raes G, Bakkus M, Devos S, Thielemans K, Debaetselier P. Expression of B7-1 by highly metastatic mouse T lymphomas induces optimal natural killer cell-mediated cytotoxicity. Cancer Res. 1995; 55: 2730–3. | PubMed | ISI | ChemPort |
  40. Hildemann WH. Specific immunorecognition by histocompatibility markers: The original polymorphic system of immunoreactivity characteristic of all multicellular animals. Immunogenetics 1977; 5: 193–202. | Article |
  41. Kolb H. On the phylogenetic origin of the immune system-a hypothesis. Dev. Comp. Immunol. 1977; 1: 193–206. | Article |
  42. Langman RE. Cell-mediated immunity and the major histo-compatibility complex. Rev. Physiol. Biochem. Pharmacol. 1978; 81: 1–37.
  43. Cohn M. The T-cell receptor mediating restrictive recognition of antigen. Cell 1983; 33: 657–69. | Article | PubMed | ISI | ChemPort |
  44. Coombe DR, Ey PL, Jenkin CR. Self/non–self recognition in invertebrates. Q. Rev. Biol. 1984; 59: 231–55. | Article |
  45. Coombe DR, Parish CR. Sulfated polysaccharide-mediated sponge cell aggregation: The clue to invertebrate self/nonself-recognition? In: Grosberg RK, Hedgecock D, Nelson K (eds) Invertebrate Historecognition. New York, Plenum Publishing Corp., 1988; 31–54.
  46. Parish CR. A simple model for self non–self discrimination in invertebrates. Nature 1977; 267: 711–12. | Article |
  47. Rothenberg BE. The self recognition concept: an active function for the molecules of the major histocompatibility complex based on the complementary interaction of protein and carbohydrate. Dev. Comp. Immunol. 1978; 2: 23–38. | Article |
  48. Scofield VL, Schlumpberger JM, Weissman IL. Colony specificity in the colonial tunicate Botryllus and the origins of vertebrate immunity. Am. Zool. 1982; 22: 783–94.
  49. Theodor JL. Histo-incompatibility in a natural population of gorgonians. Zool J. Linn. Soc. 1976; 58: 173–6.
  50. Reynolds BD. Interactions of protoplasmic masses in relation to the study of heredity and environment in Arcella polypora. Biol. Bull. 1924; 46: 106–40. | Article |

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