In this essay, I make four points about the operation of the immune system. First, thanks to the innate immune system's regulation of the main costimulatory molecules CD80 and CD86, the immune system rarely mistakes a pathogen for a self-antigen. Second, the adaptive immune system consisting of T lymphocytes and B lymphocytes can mistake self for non-self because adaptive immunity is selected in single somatic cells. Third, the adaptive immune system of T lymphocytes and B lymphocytes is always referential to self, as it is selected on self-ligands; it persists in the periphery on self-ligands; and at least for T cells, it is dependent on self-ligands to be able to mount a response. Fourth, it is becoming clear that regulatory or suppressor T cells are our main defense against autoimmunity, as my first boss, Richard Gershon, had predicted. These cells recognize antigen as do all T cells, but they secrete the immunoregulatory cytokines IL-10 and TGFβ.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Padovan E, Mauri-Hellweg D, Pichler WJ, Weltzien HU. 1996. T cell recognition of penicillin G: structural features determining antigenic specificity.. Eur. J. Immunol. 26:42–48 [Google Scholar]
  2. Agrawal A, Eastman QM, Schatz DG. 1998. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system.. Nature 394:744–51 [Google Scholar]
  3. Liu Y, Janeway CA Jr. 1992. Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells.. Proc. Natl. Acad. Sci. USA 89:3845–49 [Google Scholar]
  4. Galvin F, Freeman GJ, Razi-Wolf Z, Hall W Jr, Benacerraf B, Nadler L, Reiser H. 1992. Murine B7 antigen provides a sufficient costimulatory signal for antigen-specific and MHC-restricted T cell activation.. J. Immunol. 149:3802–8 [Google Scholar]
  5. Liu Y, Janeway CA Jr. 1991. Microbial induction of co-stimulatory activity for CD4 T-cell growth.. Int. Immunol. 3:323–32 [Google Scholar]
  6. Janeway CA Jr. 1989. Approaching the asymptote? Evolution and revolution in immunology.. Cold Spring Harb. Symp. Quant. Biol. 54:1–13 [Google Scholar]
  7. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.. Nature 388:394–97 [Google Scholar]
  8. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults.. Cell 86:973–83 [Google Scholar]
  9. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S. 1999. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.. Immunity 11:443–51 [Google Scholar]
  10. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A. 2001. The innate immune response to bacterial flagellin is mediated by Toll- like receptor 5.. Nature 410:1099–103 [Google Scholar]
  11. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S. 2000. A Toll-like receptor recognizes bacterial DNA.. Nature 408:740–45 [Google Scholar]
  12. Medzhitov R, Janeway C Jr. 2000. Innate immunity.. N. Engl. J. Med. 343:338–44 [Google Scholar]
  13. Ayehunie S, Garcia-Zepeda EA, Hoxie JA, Horuk R, Kupper TS, Luster AD, Ruprecht RM. 1997. Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors.. Blood 90:1379–86 [Google Scholar]
  14. Burnet FM. 1959. The Clonal Selection Theory. London: Cambridge Univ. Press 209 pp. [Google Scholar]
  15. Gershon RK, Kondo K. 1971. Infectious immunological tolerance.. Immunology 21:903–14 [Google Scholar]
  16. von Boehmer H. 1994. Positive selection of lymphocytes.. Cell 76:219–28 [Google Scholar]
  17. Nossal GJ. 1994. Negative selection of lymphocytes.. Cell 76:229–39 [Google Scholar]
  18. Viret C, Wong FS, Janeway CA Jr. 1999. Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition.. Immunity 10:559–68 [Google Scholar]
  19. Brocker T. 1997. Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells.. J. Exp. Med. 186:1223–32 [Google Scholar]
  20. Tanchot C, Lemonnier FA, Perarnau B, Freitas AA, Rocha B. 1997. Differential requirements for survival and proliferation of CD8 naive or memory T cells.. Science 276:2057–62 [Google Scholar]
  21. Ignatowicz L, Kappler J, Marrack P. 1996. The repertoire of T cells shaped by a single MHC/peptide ligand.. Cell 84:521–29 [Google Scholar]
  22. Hunt DF, Michel H, Dickinson TA, Shabanowitz J, Cox AL, Sakaguchi K, Appella E, Grey HM, Sette A. 1992. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad.. Science 256:1817–20 [Google Scholar]
  23. Alam SM, Davies GM, Lin CM, Zal T, Nasholds W, Jameson SC, Hogquist KA, Gascoigne NR, Travers PJ. 1999. Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands.. Immunity 10:227–37 [Google Scholar]
  24. Viret C, He X, Janeway CA Jr. 2001. Paradoxical intrathymic selection in mice with only a covalently presented agonist peptide.. Proc. Natl. Acad. Sci. USA. 98:9243–48 [Google Scholar]
  25. Levine MH, Haberman AM, Sant'Angelo DB, Hannum LG, Cancro MP, Janeway CA Jr, Shlomchik MJ. 2000. A B-cell receptor-specific selection step governs immature to mature B cell differentiation.. Proc. Natl. Acad. Sci. USA 97:2743–48 [Google Scholar]
  26. Jerne NK. 1974. Towards a network theory of the immune system.. Ann. Immunol. (Paris 125C:373–89 [Google Scholar]
  27. Sakato N, Janeway CA Jr, Eisen HN. 1977. Immune responses of BALB/c mice to the idiotype of T15 and of other myeloma proteins of BALB/c origin: implications for an immune network and antibody multispecificity.. Cold Spring Harb. Symp. Quant. Biol. 41:719–24 [Google Scholar]
  28. Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S. 1994. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice.. Cell 78:399–408 [Google Scholar]
  29. Olivares-Villagomez D, Wang Y, Lafaille JJ. 1998. Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis.. J. Exp. Med. 188:1883–94 [Google Scholar]
  30. Van de Keere F, Tonegawa S. 1998. CD4(+) T cells prevent spontaneous experimental autoimmune encephalomyelitis in anti-myelin basic protein T cell receptor transgenic mice.. J. Exp. Med. 188:1875–82 [Google Scholar]
  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error