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. 1991 Aug 1;174(2):435–446. doi: 10.1084/jem.174.2.435

T cell contact with Ia antigens on nonhemopoietic cells in vivo can lead to immunity rather than tolerance

PMCID: PMC2118920  PMID: 1677393

Abstract

Long-term H-2-heterozygous a----(a x b)F1 bone marrow (BM) chimeras prepared with supralethal irradiation (1,300 rad) are devoid of Ia+ host BM-derived antigen-presenting cells (APC), but show quite strong host Ia expression in germinal centers, probably on follicular dendritic cells (a class of nonhemopoietic stromal cells). To examine whether Ia expression on these non-BM-derived cells is capable of inducing post-thymic tolerance of T cells, thymectomized irradiated (a x b)F1 mice were reconstituted with parent alpha stem cells and then, 6 mo later, given parent alpha thymus grafts. As measured by primary mixed lymphocyte reactions and V beta expression, the CD4+ cells differentiating in the thymus-grafted mice showed no detectable tolerance to the H-2 (Ia) antigens of the host. To examine whether the thymus-grafted mice contained immunologically significant quantities of host Ia antigens, long-term alpha----(alpha x b)F1 chimeras were injected with normal strain alpha CD4+ cells; the donor cells were recovered from thoracic duct lymph of the chimeras and tested for host reactivity in vitro. The results showed that Ia expression in the chimeras was sufficient to cause selective trapping of a substantial proportion of host-Ia-reactive CD4+ cells soon after transfer and, at later stages, to induce strong priming. Tolerance was not seen. The data place constraints on the view that T cell recognition of antigen expressed on cells other than typical BM-derived APC leads to tolerance induction.

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Selected References

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  1. Atkins R. C., Ford W. L. Early cellular events in a systemic graft-vs.-host reaction. I. The migration of responding and nonresponding donor lymphocytes. J Exp Med. 1975 Mar 1;141(3):664–680. doi: 10.1084/jem.141.3.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradley S. M., Morrissey P. J., Sharrow S. O., Singer A. Tolerance of thymocytes to allogeneic I region determinants encountered prethymically. Evidence for expression of anti-Ia receptors by T cell precursors before their entry into the thymus. J Exp Med. 1982 Jun 1;155(6):1638–1652. doi: 10.1084/jem.155.6.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Böhme J., Haskins K., Stecha P., van Ewijk W., LeMeur M., Gerlinger P., Benoist C., Mathis D. Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant. Science. 1989 Jun 9;244(4909):1179–1183. doi: 10.1126/science.2499048. [DOI] [PubMed] [Google Scholar]
  4. Ford W. L., Atkins R. C. Specific unresponsiveness of recirculating lymphocytes ater exposure to histocompatibility antigen in F 1 hybrid rats. Nat New Biol. 1971 Dec 8;234(49):178–180. doi: 10.1038/newbio234178a0. [DOI] [PubMed] [Google Scholar]
  5. Ford W. L., Simmonds S. J., Atkins R. C. Early cellular events in a systemic graft-vs.-host reaction. II. Autoradiographic estimates of the frequency of donor lymphocytes which respond to each Ag-B-determined antigenic complex. J Exp Med. 1975 Mar 1;141(3):681–696. doi: 10.1084/jem.141.3.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gao E. K., Kanagawa O., Sprent J. Capacity of unprimed CD4+ and CD8+ T cells expressing V beta 11 receptors to respond to I-E alloantigens in vivo. J Exp Med. 1989 Dec 1;170(6):1947–1957. doi: 10.1084/jem.170.6.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gao E. K., Lo D., Sprent J. Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy. J Exp Med. 1990 Apr 1;171(4):1101–1121. doi: 10.1084/jem.171.4.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hayakawa K., Hardy R. R. Murine CD4+ T cell subsets defined. J Exp Med. 1988 Nov 1;168(5):1825–1838. doi: 10.1084/jem.168.5.1825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Humphrey J. H., Grennan D., Sundaram V. The origin of follicular dendritic cells in the mouse and the mechanism of trapping of immune complexes on them. Eur J Immunol. 1984 Sep;14(9):859–864. doi: 10.1002/eji.1830140916. [DOI] [PubMed] [Google Scholar]
  10. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Kosco M. H., Tew J. G., Szakal A. K. Antigenic phenotyping of isolated and in situ rodent follicular dendritic cells (FDC) with emphasis on the ultrastructural demonstration of Ia antigens. Anat Rec. 1986 Jul;215(3):201-13, 219-25. doi: 10.1002/ar.1092150303. [DOI] [PubMed] [Google Scholar]
  13. Lafferty K. J., Prowse S. J., Simeonovic C. J., Warren H. S. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol. 1983;1:143–173. doi: 10.1146/annurev.iy.01.040183.001043. [DOI] [PubMed] [Google Scholar]
  14. Lo D., Burkly L. C., Flavell R. A., Palmiter R. D., Brinster R. L. Tolerance in transgenic mice expressing class II major histocompatibility complex on pancreatic acinar cells. J Exp Med. 1989 Jul 1;170(1):87–104. doi: 10.1084/jem.170.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lo D., Burkly L. C., Widera G., Cowing C., Flavell R. A., Palmiter R. D., Brinster R. L. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell. 1988 Apr 8;53(1):159–168. doi: 10.1016/0092-8674(88)90497-7. [DOI] [PubMed] [Google Scholar]
  16. MILLER J. F. Studies on mouse leukaemia. The role of the thymus in leukaemogenesis by cell-free leukaemic filtrates. Br J Cancer. 1960 Mar;14:93–98. doi: 10.1038/bjc.1960.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Marrack P., Kappler J. The T cell receptor. Science. 1987 Nov 20;238(4830):1073–1079. doi: 10.1126/science.3317824. [DOI] [PubMed] [Google Scholar]
  18. Miller J., Daitch L., Rath S., Selsing E. Tissue-specific expression of allogeneic class II MHC molecules induces neither tissue rejection nor clonal inactivation of alloreactive T cells. J Immunol. 1990 Jan 1;144(1):334–341. [PubMed] [Google Scholar]
  19. Morahan G., Allison J., Miller J. F. Tolerance of class I histocompatibility antigens expressed extrathymically. Nature. 1989 Jun 22;339(6226):622–624. doi: 10.1038/339622a0. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Murphy K. M., Weaver C. T., Elish M., Allen P. M., Loh D. Y. Peripheral tolerance to allogeneic class II histocompatibility antigens expressed in transgenic mice: evidence against a clonal-deletion mechanism. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10034–10038. doi: 10.1073/pnas.86.24.10034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  23. Sprent J. Circulating T and B lymphocytes of the mouse. I. Migratory properties. Cell Immunol. 1973 Apr;7(1):10–39. doi: 10.1016/0008-8749(73)90180-9. [DOI] [PubMed] [Google Scholar]
  24. Sprent J., Miller J. F. Activation of thymus cells by histocompatibility antigens. Nat New Biol. 1971 Sep 15;234(50):195–198. doi: 10.1038/newbio234195a0. [DOI] [PubMed] [Google Scholar]
  25. Sprent J., Miller J. F. Effect of recent antigen priming on adoptive immune responses. III. Antigen-induced selective recruitment of subsets of recirculating lymphocytes reactive to H-2 determinants. J Exp Med. 1976 Mar 1;143(3):585–600. doi: 10.1084/jem.143.3.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sprent J., Schaefer M. Properties of purified T cell subsets. I. In vitro responses to class I vs. class II H-2 alloantigens. J Exp Med. 1985 Dec 1;162(6):2068–2088. doi: 10.1084/jem.162.6.2068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sprent J., Webb S. R. Function and specificity of T cell subsets in the mouse. Adv Immunol. 1987;41:39–133. doi: 10.1016/s0065-2776(08)60030-9. [DOI] [PubMed] [Google Scholar]
  28. Szakal A. K., Kosco M. H., Tew J. G. Microanatomy of lymphoid tissue during humoral immune responses: structure function relationships. Annu Rev Immunol. 1989;7:91–109. doi: 10.1146/annurev.iy.07.040189.000515. [DOI] [PubMed] [Google Scholar]
  29. Webb S. R., Sprent J. Tolerogenicity of thymic epithelium. Eur J Immunol. 1990 Nov;20(11):2525–2528. doi: 10.1002/eji.1830201127. [DOI] [PubMed] [Google Scholar]
  30. 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]

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