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. 1994 Jun 7;91(12):5627–5631. doi: 10.1073/pnas.91.12.5627

Specific T-cell tolerance may be preceded by a primary response.

L Vidard 1, L J Colarusso 1, B Benacerraf 1
PMCID: PMC44049  PMID: 8202538

Abstract

We have evaluated the ability of ovalbumin to induce T-cell-specific tolerance in SJL mice. A significant decrease of interleukin 2 in lymph-node culture supernatants from tolerant mice upon antigen stimulation was seen. Oral tolerization was less effective than i.p.- or s.c.-tolerization protocols. Transfer experiments of either splenic or lymph-node T cells from tolerant mice to naive mice definitely ruled out suppression as a mechanism involved in tolerant mice. Surprisingly, we found that, before the establishment of specific T-cell tolerance to ovalbumin, T cells from mice that will display tolerance were responsive and synthesized interleukin 2 upon antigen challenge in vitro. Thus, we concluded that anergy cannot account solely for the T-cell unresponsiveness in tolerant mice. Furthermore, although we cannot rule out the hypothesis that the T-cell unresponsiveness in tolerant mice can be explained by programmed cell death of ovalbumin-specific T cells, these data led us to speculate that T-cell "refractoriness" could explain the drop of interleukin 2 production in lymph-node T-cell culture supernatant from tolerant mice.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aichele P., Kyburz D., Ohashi P. S., Odermatt B., Zinkernagel R. M., Hengartner H., Pircher H. Peptide-induced T-cell tolerance to prevent autoimmune diabetes in a transgenic mouse model. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):444–448. doi: 10.1073/pnas.91.2.444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bloom B. R., Salgame P., Diamond B. Revisiting and revising suppressor T cells. Immunol Today. 1992 Apr;13(4):131–136. doi: 10.1016/0167-5699(92)90110-S. [DOI] [PubMed] [Google Scholar]
  3. Boussiotis V. A., Freeman G. J., Gribben J. G., Daley J., Gray G., Nadler L. M. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11059–11063. doi: 10.1073/pnas.90.23.11059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burstein H. J., Abbas A. K. In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen. J Exp Med. 1993 Feb 1;177(2):457–463. doi: 10.1084/jem.177.2.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dorf M. E., Benacerraf B. Suppressor cells and immunoregulation. Annu Rev Immunol. 1984;2:127–157. doi: 10.1146/annurev.iy.02.040184.001015. [DOI] [PubMed] [Google Scholar]
  6. Faria A. M., Garcia G., Rios M. J., Michalaros C. L., Vaz N. M. Decrease in susceptibility to oral tolerance induction and occurrence of oral immunization to ovalbumin in 20-38-week-old mice. The effect of interval between oral exposures and rate of antigen intake in the oral immunization. Immunology. 1993 Jan;78(1):147–151. [PMC free article] [PubMed] [Google Scholar]
  7. Freeman G. J., Borriello F., Hodes R. J., Reiser H., Hathcock K. S., Laszlo G., McKnight A. J., Kim J., Du L., Lombard D. B. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science. 1993 Nov 5;262(5135):907–909. doi: 10.1126/science.7694362. [DOI] [PubMed] [Google Scholar]
  8. Freeman G. J., Gribben J. G., Boussiotis V. A., Ng J. W., Restivo V. A., Jr, Lombard L. A., Gray G. S., Nadler L. M. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993 Nov 5;262(5135):909–911. doi: 10.1126/science.7694363. [DOI] [PubMed] [Google Scholar]
  9. Gammon G., Sercarz E. Does the presence of self-reactive T cells indicate the breakdown of tolerance? Clin Immunol Immunopathol. 1990 Sep;56(3):287–297. doi: 10.1016/0090-1229(90)90150-o. [DOI] [PubMed] [Google Scholar]
  10. Gammon G., Sercarz E. How some T cells escape tolerance induction. Nature. 1989 Nov 9;342(6246):183–185. doi: 10.1038/342183a0. [DOI] [PubMed] [Google Scholar]
  11. Hanson D. G., Vaz N. M., Rawlings L. A., Lynch J. M. Inhibition of specific immune responses by feeding protein antigens. II. Effects of prior passive and active immunization. J Immunol. 1979 Jun;122(6):2261–2266. [PubMed] [Google Scholar]
  12. Hathcock K. S., Laszlo G., Dickler H. B., Bradshaw J., Linsley P., Hodes R. J. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993 Nov 5;262(5135):905–907. doi: 10.1126/science.7694361. [DOI] [PubMed] [Google Scholar]
  13. Hoyne G. F., O'Hehir R. E., Wraith D. C., Thomas W. R., Lamb J. R. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice. J Exp Med. 1993 Nov 1;178(5):1783–1788. doi: 10.1084/jem.178.5.1783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  15. Kawabe Y., Ochi A. Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med. 1990 Oct 1;172(4):1065–1070. doi: 10.1084/jem.172.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Khoury S. J., Hancock W. W., Weiner H. L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med. 1992 Nov 1;176(5):1355–1364. doi: 10.1084/jem.176.5.1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. King L. B., Ashwell J. D. Signaling for death of lymphoid cells. Curr Opin Immunol. 1993 Jun;5(3):368–373. doi: 10.1016/0952-7915(93)90055-w. [DOI] [PubMed] [Google Scholar]
  18. Liu L. M., MacPherson G. G. Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo. J Exp Med. 1993 May 1;177(5):1299–1307. doi: 10.1084/jem.177.5.1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Markmann J., Lo D., Naji A., Palmiter R. D., Brinster R. L., Heber-Katz E. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature. 1988 Dec 1;336(6198):476–479. doi: 10.1038/336476a0. [DOI] [PubMed] [Google Scholar]
  20. Melamed D., Friedman A. Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin. Eur J Immunol. 1993 Apr;23(4):935–942. doi: 10.1002/eji.1830230426. [DOI] [PubMed] [Google Scholar]
  21. Miller A., Lider O., Roberts A. B., Sporn M. B., Weiner H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):421–425. doi: 10.1073/pnas.89.1.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mohapatra S., Chen Y., Takata M., Mohapatra S. S., Sehon A. H. Analysis of T-cell receptor alpha beta chains of CD8+ suppressor T cells induced by tolerogenic conjugates of antigen and monomethoxypolyethylene glycol. Involvement of TCR alpha-CDR3 domain in immunosuppression. J Immunol. 1993 Jul 15;151(2):688–698. [PubMed] [Google Scholar]
  23. Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
  24. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  25. Pierre P., Denis O., Bazin H., Mbongolo Mbella E., Vaerman J. P. Modulation of oral tolerance to ovalbumin by cholera toxin and its B subunit. Eur J Immunol. 1992 Dec;22(12):3179–3182. doi: 10.1002/eji.1830221223. [DOI] [PubMed] [Google Scholar]
  26. Ramsdell F., Lantz T., Fowlkes B. J. A nondeletional mechanism of thymic self tolerance. Science. 1989 Nov 24;246(4933):1038–1041. doi: 10.1126/science.2511629. [DOI] [PubMed] [Google Scholar]
  27. Richman L. K., Chiller J. M., Brown W. R., Hanson D. G., Vaz N. M. Enterically induced immunologic tolerance. I. Induction of suppressor T lymphoyctes by intragastric administration of soluble proteins. J Immunol. 1978 Dec;121(6):2429–2434. [PubMed] [Google Scholar]
  28. Rocha B., Tanchot C., Von Boehmer H. Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen. J Exp Med. 1993 May 1;177(5):1517–1521. doi: 10.1084/jem.177.5.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rock K. L. The role of Ia molecules in the activation of T lymphocytes. I. The activation of an IL 1-dependent IL 2-producing T cell hybridoma by Con A requires an interaction, which is not H-2-restricted, with an Ia-bearing accessory cell. J Immunol. 1982 Oct;129(4):1360–1366. [PubMed] [Google Scholar]
  30. Romball C. G., Weigle W. O. In vivo induction of tolerance in murine CD4+ cell subsets. J Exp Med. 1993 Nov 1;178(5):1637–1644. doi: 10.1084/jem.178.5.1637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schwartz R. H. Acquisition of immunologic self-tolerance. Cell. 1989 Jun 30;57(7):1073–1081. doi: 10.1016/0092-8674(89)90044-5. [DOI] [PubMed] [Google Scholar]
  32. Shi Y., Glynn J. M., Guilbert L. J., Cotter T. G., Bissonnette R. P., Green D. R. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 1992 Jul 10;257(5067):212–214. doi: 10.1126/science.1378649. [DOI] [PubMed] [Google Scholar]
  33. Spaner D., Migita K., Ochi A., Shannon J., Miller R. G., Pereira P., Tonegawa S., Phillips R. A. Gamma delta T cells differentiate into a functional but nonproliferative state during a normal immune response. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8415–8419. doi: 10.1073/pnas.90.18.8415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tisch R., McDevitt H. O. Antigen-specific immunotherapy: is it a real possibility to combat T-cell-mediated autoimmunity? Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):437–438. doi: 10.1073/pnas.91.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
  36. da-Silva A. C., Massa S., Sant'Anna O. A. Preliminary results corroborating the polygenic control of immunological tolerance. Braz J Med Biol Res. 1990;23(6-7):581–584. [PubMed] [Google Scholar]

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