Molecular and cellular aspects of immunologic tolerance

  • Gustav J. V. Nossal
Part of the EJB Reviews 1991 book series (EJB REVIEWS, volume 1991)


This review seeks to explain the most exciting recent data concerning the Nature of self/non-self discrimination by the immune system in a manner accessible to a biochemical readership. The Natureof recognition in the two great lymphocyte families, B cells and T cells, is described with special emphasis on the Nature of the ligands recognized by each. The history of the field of immunologic tolerance is surveyed, as are the key experiments on conventional mice which provided a conceptual framework. This suggested that tolerance was essentially due to ‘holes’ in the recognition repertoires of both the T and B cell populations so that lymphocytes competent to react to self antigens were not part of the immunologic dictionary. There were essentially two ways to achieve this situation. On the one hand, self antigens might ‘catch’ developing lymphocytes early in their ontogeny and delete the cell, a process of clonal abortion. On the other hand, self antigens might signal lymphocytes (particularly immature cells) in a negative manner, reducing or abolishing their capacity for later responses, without causing death. This process is referred to as clonal anergy. Evidence for both processes exists.


Major Histocompatibility Complex Human Serum Albumin Major Histocompatibility Complex Molecule Foreign Antigen Tolerance Induction 
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.



T cell receptor


major histocompatibility complex


antigen-presenting cell


hen egg lysozyme


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  1. 1.
    Ehrlich, P. (1900) Proc. Roy. Soc. Lond. B. 66, 424–448.Google Scholar
  2. 2.
    Burnet, F. M. & Fenner, F. (1949) The production of antibodies, 2nd edn, p 142, Macmillan, London.Google Scholar
  3. 3.
    Billingham, R. E., Brent, L. & Medawar, P. B. (1953) Nature 172, 603–606.PubMedCrossRefGoogle Scholar
  4. 4.
    Talmage, D. W. (1957) Annu. Rev. Med. 8, 239–256.PubMedCrossRefGoogle Scholar
  5. 5.
    Burnet, F. M. (1957) Austr. J. Sci. 20, 67–69.Google Scholar
  6. 6.
    Nossal, G. J. V. & Lederberg, J. (1958) Nature 181, 1419–1420.PubMedCrossRefGoogle Scholar
  7. 7.
    Nossal, G. J. V. & Pike, B. L. (1976) Immunology 30, 189–202.PubMedGoogle Scholar
  8. 8.
    Skinner, M. A. & Marbrook, J. (1976) J. Exp. Med. 143, 1562–1567.PubMedCrossRefGoogle Scholar
  9. 9.
    Quintans, J. & Lefkovits, I. (1973) Eur. J. Immunol. 3, 392–397.PubMedCrossRefGoogle Scholar
  10. 10.
    Nossal, G. J. V. & Pike, B. L. (1981) Proc. Natl. Acad. Sci. USA 75, 3844–3847.CrossRefGoogle Scholar
  11. 11.
    Metcalf, E. S. & Klinman, N. R. (1976) J. Exp. Med. 143, 1327–1340.PubMedCrossRefGoogle Scholar
  12. 12.
    Nossal, G. J. V. & Pike, B. L. (1975) J. Exp. Med. 141, 904–917.PubMedGoogle Scholar
  13. 13.
    Lederberg, J. (1959) Science 129, 1649–1653.PubMedCrossRefGoogle Scholar
  14. 14.
    Nossal, G. J. V. & Pike, B. L. (1978) J. Exp. Med. 148, 1101–1170.CrossRefGoogle Scholar
  15. 15.
    Nossal, G. J. V. & Pike, B. L. (1980) Proc. Natl Acad Sci. USA 77, 1602–1606.PubMedCrossRefGoogle Scholar
  16. 16.
    Haas, W. & Layton, J. E. (1975) J. Exp. Med. 141, 1004–1014.PubMedCrossRefGoogle Scholar
  17. 17.
    Pike, B. L., Boyd, A. W. & Nossal, G. J. V. (1982) Proc. Nati Acad. Sci. USA 79, 2013–2017.CrossRefGoogle Scholar
  18. 18.
    Lamb, J. R., Skidmore, B. J., Green, N., Chiller, J. M. & Feldmann, M. (1983) J. Exp. Med. 157, 1434–1447.PubMedCrossRefGoogle Scholar
  19. 19.
    Jenkins, M. K. & Schwartz, R. H. (1987) J. Exp. Med. 165, 302–319.PubMedCrossRefGoogle Scholar
  20. 20.
    Nossal, G. J. V. (1983) Annu. Rev. Immunol. 1, 33–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Nossal, G. J. V. (1989) Immunologie tolerance in Fundamental immunology, 2nd edn (W. E. Paul, ed.) pp. 571–586, Raven Press, New York.Google Scholar
  22. 22.
    Björkman, P. J., Saper, M. A., Samraoui, B., Bennett, W. S., Strominger, J. L. & Wiley, D. C. (1987) Nature 329, 512–518.PubMedCrossRefGoogle Scholar
  23. 23.
    Brown, J. H., Jardetzky, T., Saper, M. A., Samraoui, B., Björkman, P. J. & Wiley, D. C. (1988) Nature 332, 845–850.PubMedCrossRefGoogle Scholar
  24. 24.
    Zinkernagel, R. M. & Doherty, P. C. (1974) Nature 248, 701–702.PubMedCrossRefGoogle Scholar
  25. 25.
    Kisielow, P., Blüthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. (1988) Nature 333, 742–746.PubMedCrossRefGoogle Scholar
  26. 26.
    Kappler, J. M., Roehm, N. & Marrack, P. (1987) Cell 49, 273–280.PubMedCrossRefGoogle Scholar
  27. 27.
    MacDonald, H. R., Schneider, R., Lees, R. K., Howe, R. C., Acha-Orbea, H., Festenstein, H., Zinkernagel, R. M. & Hengartner, H. (1988) Nature 332, 40–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Pircher, H., Bürki, K., Lang, R., Hengartner, H. & Zinkernagel, R. M. (1989) Nature 342, 559–561.PubMedCrossRefGoogle Scholar
  29. 29.
    Dent, A. L., Matis, L. A., Hooshmand, F., Widacki, S. M., Bluestone, J. A. & Hedrick, S. M. (1990) Nature 343, 714–719.PubMedCrossRefGoogle Scholar
  30. 30.
    Murphy, K. M., Heimberger, A. B. & Loh, D. Y. (1990) Science 250, 1720–1722.PubMedCrossRefGoogle Scholar
  31. 31.
    Ferrick, D. A., Ohashi, P. S., Wallace, V. A., Schilham, M. & Mak, T. W. (1990) Immunol. Rev. 118, 257–283.PubMedCrossRefGoogle Scholar
  32. 32.
    Adelstein, S., Pritchard-Briscoe, H., Anderson, T. A., Crosbie, J., Gammon, G., Loblay, R. H., Basten, A. & Goodnow, C. C. (1991) Science 251, 1223–1225.PubMedCrossRefGoogle Scholar
  33. 33.
    Adams, T. E., Alpert, S. & Hanahan, D. (1987) Nature 325, 223–228.PubMedCrossRefGoogle Scholar
  34. 34.
    Allison, J., Campbell, I. L., Morahan, G., Mandel, T. E., Harrison, L. C. & Miller, J. F. A. P. (1988) Nature 333, 529–533.PubMedCrossRefGoogle Scholar
  35. 35.
    Morahan, G., Brennan, F. E., Bhathal, P. S., Allison, J., Cox, K. O. & Miller, J. F. A. P. (1989) Proc. Natl Acad. Sci. USA 86, 3782–3786.PubMedCrossRefGoogle Scholar
  36. 36.
    Lo, D., Burkly, L. C., Flavell, R. A., Palmiter, R. D. & Brinster, R. L. (1989) J. Exp. Med. 170, 87–104.PubMedCrossRefGoogle Scholar
  37. 37.
    Miller, J. F. A. P., Morahan, G., Allison, J., Bhathal, P. S., Cox, K. O. & Brennan, F. E. (1989) Immunol. Rev. 107, 109–123.PubMedCrossRefGoogle Scholar
  38. 38.
    Miller, J. F. A. P., Morahan, G., Slattery, R. & Allison, J. (1990) Immunol. Rev. 118, 21–35.PubMedCrossRefGoogle Scholar
  39. 39.
    Miller, J. F. A. P., Morahan, G., Allison, J. & Hoffmann, M. (1991) Immunol. Rev. 122, 103–116.PubMedCrossRefGoogle Scholar
  40. 40.
    Schönrich, G., Kalinke, U., Momburg, F., Malissen, M., Schmitt-Verhulst, A.-M., Malissen, B., Hämmerling, G. J. & Arnold, B. (1991) Cell 65, 293–304.PubMedCrossRefGoogle Scholar
  41. 41.
    Ohashi, P. S., Oehen, S., Buerki, K., Pircher, H., Ohashi, C. T., Odermatt, B., Malissen, B., Zinkernagel, R. M. & Hengartner, H. (1991) Cell 65, 305–317.PubMedCrossRefGoogle Scholar
  42. 42.
    Mueller, D. L., Jenkins, M. K., & Swartz, R. H. (1989) Annu. Rev. Immunol. 7, 445–480.PubMedCrossRefGoogle Scholar
  43. 43.
    Schwartz, R. H. (1989) Cell 57, 1073–1081.PubMedCrossRefGoogle Scholar
  44. 44.
    Gotch, F., Rothbard, J., Howland, K., Townsend, A. & McMichael, A. (1987) Nature 326, 881–882.PubMedCrossRefGoogle Scholar
  45. 45.
    Ohno, S. (1991) Proc. Natl. Acad. Sci. USA 88, 3065–3068.PubMedCrossRefGoogle Scholar
  46. 46.
    Herzenberg, L. A., Stall, A. M., Lalor, P. A., Sidman, C., Moore, W. A., Parks, D. R. & Herzenberg, L. A. (1986) Immunol. Rev. 93, 81–102.PubMedCrossRefGoogle Scholar
  47. 47.
    Nemazee, D. A. & Bürki, K. (1989) Nature 337, 562–566.PubMedCrossRefGoogle Scholar
  48. 48.
    Nemazee, D. A., Russell, D., Arnold, B., Hämmerling, G. J., Allison, J., Miller, J. F. A. P., Morahan, G. & Bürki, K. (1991) Immunol. Rev. 122, 117–132.PubMedCrossRefGoogle Scholar
  49. 49.
    Arnold, B., Dill, O., Küblbeck, G., Jatsch, L., Simon, M. M., Tucker, J. & Hämmerling, G. J. (1988) Proc. Natl Acad. Sci. USA 85, 2269–2273.PubMedCrossRefGoogle Scholar
  50. 50.
    Whiteley, P. J. & Kapp, J. A. (1989) in Progress in immunology VII (Melchers, F., Albert, E. D., von Boehmer, H., Dierich, M. P., Du Pasquier, L., Eichmann, K., Gemsa, D., Götze, O., Kalden, J. R., Kaufmann, S. H. E., Kirchner, H., Resch, K., Reithmüller, G., Schimpl, A., Sorg, C., Steinmetz, M., Wagner, H. & Zachau, H. G., eds) pp. 826–832, Springer-Verlag, Heidelberg.CrossRefGoogle Scholar
  51. 51.
    Goodnow, C. C., Crosbie, J., Adelstein, S., Lavoie, T. B., Smith-Gill, S., Brink, R. A., Pritchard-Briscoe, H., Wotherspoon, J. S., Loblay, R. H., Raphael, K., Trent, R. J. & Basten, A. (1988) Nature 334, 676–682.PubMedCrossRefGoogle Scholar
  52. 52.
    Goodnow, C. C., Crosbie, J., Jorgensen, H., Brink, R. A. & Basten, A. (1989) Nature 342, 385–391.PubMedCrossRefGoogle Scholar
  53. 53.
    Goodnow, C. C., Adelstein, S. & Basten, A. (1990) Science 248, 1373–1379.PubMedCrossRefGoogle Scholar
  54. 54.
    Adams, E., Basten, A. & Goodnow, C. C. (1990) Proc. Natl. Acad. Sci. USA 87, 5687–5691.PubMedCrossRefGoogle Scholar
  55. 55.
    Brink, R., Crosbie, J., Basten, A., Jorgensen, H., Adams, E., Hartley, S. & Goodnow, C. C. (1991) J. Cell. Biochem. Suppl. 15A, 260.Google Scholar
  56. 56.
    Theopold, U. & Köhler, G. (1990) Eur. J. Immunol. 20, 1311–1316.PubMedCrossRefGoogle Scholar
  57. 57.
    Erikson, J., Radie, M. Z., Camper, S. A., Hardy, R. R., Carmack, C., & Weigert, M. (1991) Nature 349, 331–334.PubMedCrossRefGoogle Scholar
  58. 58.
    Galelli, A. & Chariot, B. (1990) J. Immunol. 145, 2397–2405.PubMedGoogle Scholar
  59. 59.
    Seyfert, V. L., McMahon, S. B., Glenn, W. D., Yellen, A. J., Sukhatme, V. P., Cao, X. & Monroe, J. G. (1990) Science 250, 797–799.PubMedCrossRefGoogle Scholar
  60. 60.
    Weigert, M. G., Cesari, I. M., Yonkovich, S. J. & Cohn, M. (1970) Nature 228, 1045–1047.PubMedCrossRefGoogle Scholar
  61. 61.
    Rajewsky, K., Förster, I. & Cumano, A. (1987) Science 238, 1088–1094.PubMedCrossRefGoogle Scholar
  62. 62.
    Linton, P.-J., Decker, D. J. & Klinman, N. R. (1989) Cell 59, 1049–1059.CrossRefGoogle Scholar
  63. 63.
    Nossal, G. J. V. & Karvelas, M. (1990) Proc. Natl. Acad. Sci. USA 87, 1615–1619.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Gustav J. V. Nossal
    • 1
  1. 1.The Walter and Eliza Hall Institute of Medical ResearchP. O. Royal Melbourne HospitalAustralia

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