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. 1993 Feb 1;177(2):367–378. doi: 10.1084/jem.177.2.367

Tolerance of CD8+ T cells developing in parent-->F1 chimeras prepared with supralethal irradiation: step-wise induction of tolerance in the intrathymic and extrathymic environments

PMCID: PMC2190890  PMID: 8426108

Abstract

Tolerance of CD8+ cells was examined in parent-->F1 bone marrow chimeras (BMC) prepared with supralethal irradiation; host class I expression in the chimeras was limited to non-BM-derived cells. In terms of helper-independent proliferative responses in vitro and induction of graft-vs.-host disease on adoptive transfer, CD8+ cells from long-term chimeras showed profound tolerance to host antigens irrespective of whether the cells were prepared from the thymus or from spleen or lymph nodes. By limiting dilution analysis, cytotoxic T lymphocyte (CTL) precursors specific for host antigens were rare in the extrathymic lymphoid tissues. In the thymus, by contrast, host-specific CTL precursors were only slightly less frequent than in normal parental strain mice. These host-specific CD8+ cells survived when BMC thymocytes were transferred intravenously to a neutral environment, i.e., to donor strain mice. When transferred to further BMC hosts, however, most of the host-reactive cells disappeared. Collectively, the data suggest that tolerance of CD8+ cells in BMC hosts occurs in both the intrathymic and extrathymic environments. In the thymus, contact with host antigens on thymic epithelial cells deletes CD8+ cells controlling helper-independent proliferative responses and in vivo effector functions but spares typical helper-dependent CTL precursors. After export from the thymus, most of the CTL precursors are eliminated after contacting host antigens on stromal cells in the extrathymic environment.

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Selected References

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  1. Bradley S. M., Kruisbeek A. M., Singer A. Cytotoxic T lymphocyte responses in allogeneic radiation bone marrow chimeras. The chimeric host strictly dictates the self-repertoire of Ia-restricted T cells but not H-2K/D-restricted T cells. J Exp Med. 1982 Dec 1;156(6):1650–1664. doi: 10.1084/jem.156.6.1650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  3. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  4. Fink P. J., Bevan M. J., Weissman I. L. Thymic cytotoxic T lymphocytes are primed in vivo to minor histocompatibility antigens. J Exp Med. 1984 Feb 1;159(2):436–451. doi: 10.1084/jem.159.2.436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Flajnik M. F., Du Pasquier L., Cohen N. Immune responses of thymus/lymphocyte embryonic chimeras: studies on tolerance and major histocompatibility complex restriction in Xenopus. Eur J Immunol. 1985 Jun;15(6):540–547. doi: 10.1002/eji.1830150603. [DOI] [PubMed] [Google Scholar]
  6. Gao E. K., Kosaka H., Surh C. D., Sprent J. T cell contact with Ia antigens on nonhemopoietic cells in vivo can lead to immunity rather than tolerance. J Exp Med. 1991 Aug 1;174(2):435–446. doi: 10.1084/jem.174.2.435. [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. Heeg K., Reimann J., Heit H., Heit W., Wagner H. Host-reactive cytotoxic T lymphocyte precursors in long-lived fully allogeneic mouse bone marrow chimeras. Scand J Immunol. 1986 Feb;23(2):201–209. doi: 10.1111/j.1365-3083.1986.tb01959.x. [DOI] [PubMed] [Google Scholar]
  9. Hoffmann M. W., Allison J., Miller J. F. Tolerance induction by thymic medullary epithelium. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2526–2530. doi: 10.1073/pnas.89.7.2526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Houssaint E., Flajnik M. The role of thymic epithelium in the acquisition of tolerance. Immunol Today. 1990 Oct;11(10):357–360. doi: 10.1016/0167-5699(90)90141-u. [DOI] [PubMed] [Google Scholar]
  11. Houssaint E., Torano A., Ivanyi J. Split tolerance induced by chick embryo thymic epithelium allografted to embryonic recipients. J Immunol. 1986 May 1;136(9):3155–3159. [PubMed] [Google Scholar]
  12. Jenkinson E. J., Jhittay P., Kingston R., Owen J. J. Studies of the role of the thymic environment in the induction of tolerance to MHC antigens. Transplantation. 1985 Mar;39(3):331–333. doi: 10.1097/00007890-198503000-00030. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Koo G. C., Dumont F. J., Tutt M., Hackett J., Jr, Kumar V. The NK-1.1(-) mouse: a model to study differentiation of murine NK cells. J Immunol. 1986 Dec 15;137(12):3742–3747. [PubMed] [Google Scholar]
  15. Kosaka H., Surh C. D., Sprent J. Stimulation of mature unprimed CD8+ T cells by semiprofessional antigen-presenting cells in vivo. J Exp Med. 1992 Nov 1;176(5):1291–1302. doi: 10.1084/jem.176.5.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  17. Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ramsdell F., Fowlkes B. J. Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science. 1990 Jun 15;248(4961):1342–1348. doi: 10.1126/science.1972593. [DOI] [PubMed] [Google Scholar]
  19. Roberts J. L., Sharrow S. O., Singer A. Clonal deletion and clonal anergy in the thymus induced by cellular elements with different radiation sensitivities. J Exp Med. 1990 Mar 1;171(3):935–940. doi: 10.1084/jem.171.3.935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Salaün J., Bandeira A., Khazaal I., Calman F., Coltey M., Coutinho A., Le Douarin N. M. Thymic epithelium tolerizes for histocompatibility antigens. Science. 1990 Mar 23;247(4949 Pt 1):1471–1474. doi: 10.1126/science.247.4949.1471. [DOI] [PubMed] [Google Scholar]
  21. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  22. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  23. Sprent J., Boehmer H. V., Nabholz M. Association of immunity and tolerance to host H-2 determinants in irradiated F1 hybrid mice reconstituted with bone marrow cells from one parental strain. J Exp Med. 1975 Aug 1;142(2):321–331. doi: 10.1084/jem.142.2.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Sprent J., Gao E. K., Webb S. R. T cell reactivity to MHC molecules: immunity versus tolerance. Science. 1990 Jun 15;248(4961):1357–1363. doi: 10.1126/science.1694041. [DOI] [PubMed] [Google Scholar]
  26. Sprent J., Lo D., Gao E. K., Ron Y. T cell selection in the thymus. Immunol Rev. 1988 Jan;101:173–190. doi: 10.1111/j.1600-065x.1988.tb00737.x. [DOI] [PubMed] [Google Scholar]
  27. Sprent J. Role of H-2 gene products in the function of T helper cells from normal and chimeric mice in vivo. Immunol Rev. 1978;42:108–137. doi: 10.1111/j.1600-065x.1978.tb00260.x. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Surh C. D., Gao E. K., Kosaka H., Lo D., Ahn C., Murphy D. B., Karlsson L., Peterson P., Sprent J. Two subsets of epithelial cells in the thymic medulla. J Exp Med. 1992 Aug 1;176(2):495–505. doi: 10.1084/jem.176.2.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Von Boehmer H., Schubiger K. Thymocytes appear to ignore class I major histocompatibility complex antigens expressed on thymus epithelial cells. Eur J Immunol. 1984 Nov;14(11):1048–1052. doi: 10.1002/eji.1830141116. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. von Boehmer H., Hafen K. Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature. 1986 Apr 17;320(6063):626–628. doi: 10.1038/320626a0. [DOI] [PubMed] [Google Scholar]

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