Abstract
Using cytotoxic T lymphocyte (CTL) responses to the class I histocompatibility antigen Qa1 and to the minor histocompatibility antigen H-Y, we show that the immune system maintains a peripheral screening process that is able to tolerize a wide variety of potentially autoimmune CTL. The critical factor is the presence or absence of specific T helper cells. If T help is available, CTL precursors that recognize antigen are activated. In the absence of help, they are tolerized. Thus, T helper cells are guardians of peripheral tolerance in CTL.
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- Adams T. E., Alpert S., Hanahan D. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature. 1987 Jan 15;325(6101):223–228. doi: 10.1038/325223a0. [DOI] [PubMed] [Google Scholar]
- Agus D. B., Surh C. D., Sprent J. Reentry of T cells to the adult thymus is restricted to activated T cells. J Exp Med. 1991 May 1;173(5):1039–1046. doi: 10.1084/jem.173.5.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aldrich C. J., Rodgers J. R., Rich R. R. Regulation of Qa-1 expression and determinant modification by an H-2D-linked gene, Qdm. Immunogenetics. 1988;28(5):334–344. doi: 10.1007/BF00364232. [DOI] [PubMed] [Google Scholar]
- Augustin A. A., Sim G. K. T-cell receptors generated via mutations are specific for various major histocompatibility antigens. Cell. 1984 Nov;39(1):5–12. doi: 10.1016/0092-8674(84)90186-7. [DOI] [PubMed] [Google Scholar]
- Azuma E., Kaplan J. Role of lymphokine-activated killer cells as mediators of veto and natural suppression. J Immunol. 1988 Oct 15;141(8):2601–2606. [PubMed] [Google Scholar]
- Bailey D. W., Hoste J. A gene governing the female immune response to the male antigen in mice. Transplantation. 1971 Apr;11(4):404–407. doi: 10.1097/00007890-197104000-00008. [DOI] [PubMed] [Google Scholar]
- Bal V., McIndoe A., Denton G., Hudson D., Lombardi G., Lamb J., Lechler R. Antigen presentation by keratinocytes induces tolerance in human T cells. Eur J Immunol. 1990 Sep;20(9):1893–1897. doi: 10.1002/eji.1830200904. [DOI] [PubMed] [Google Scholar]
- Beller D. I., Kiely J. M., Unanue E. R. Regulation of macrophage populations. I. Preferential induction of Ia-rich peritoneal exudates by immunologic stimuli. J Immunol. 1980 Mar;124(3):1426–1432. [PubMed] [Google Scholar]
- Bendelac A., Matzinger P., Seder R. A., Paul W. E., Schwartz R. H. Activation events during thymic selection. J Exp Med. 1992 Mar 1;175(3):731–742. doi: 10.1084/jem.175.3.731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bendelac A., Matzinger P., Seder R. A., Paul W. E., Schwartz R. H. Activation events during thymic selection. J Exp Med. 1992 Mar 1;175(3):731–742. doi: 10.1084/jem.175.3.731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benjamin R. J., Waldmann H. Induction of tolerance by monoclonal antibody therapy. Nature. 1986 Apr 3;320(6061):449–451. doi: 10.1038/320449a0. [DOI] [PubMed] [Google Scholar]
- Bhardwaj N., Lau L. L., Friedman S. M., Crow M. K., Steinman R. M. Interleukin 1 production during accessory cell-dependent mitogenesis of T lymphocytes. J Exp Med. 1989 Mar 1;169(3):1121–1136. doi: 10.1084/jem.169.3.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bowen K. M., Prowse S. J., Lafferty K. J. Reversal diabetes by islet transplantation: vulnerability of the established allograft. Science. 1981 Sep 11;213(4513):1261–1262. doi: 10.1126/science.6791285. [DOI] [PubMed] [Google Scholar]
- Bretscher P., Cohn M. A theory of self-nonself discrimination. Science. 1970 Sep 11;169(3950):1042–1049. doi: 10.1126/science.169.3950.1042. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Cassell D., Forman J. Two roles for CD4 cells in the control of the generation of cytotoxic T lymphocytes. J Immunol. 1991 Jan 1;146(1):3–10. [PubMed] [Google Scholar]
- Cobbold S. P., Martin G., Waldmann H. The induction of skin graft tolerance in major histocompatibility complex-mismatched or primed recipients: primed T cells can be tolerized in the periphery with anti-CD4 and anti-CD8 antibodies. Eur J Immunol. 1990 Dec;20(12):2747–2755. doi: 10.1002/eji.1830201232. [DOI] [PubMed] [Google Scholar]
- Evavold B. D., Allen P. M. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science. 1991 May 31;252(5010):1308–1310. doi: 10.1126/science.1833816. [DOI] [PubMed] [Google Scholar]
- Eynon E. E., Parker D. C. Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med. 1992 Jan 1;175(1):131–138. doi: 10.1084/jem.175.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Fry A. M., Jones L. A., Kruisbeek A. M., Matis L. A. Thymic requirement for clonal deletion during T cell development. Science. 1989 Nov 24;246(4933):1044–1046. doi: 10.1126/science.2511630. [DOI] [PubMed] [Google Scholar]
- Gilbert K. M., Hoang K. D., Weigle W. O. Th1 and Th2 clones differ in their response to a tolerogenic signal. J Immunol. 1990 Mar 15;144(6):2063–2071. [PubMed] [Google Scholar]
- Groves E. S., Singer A. Role of the H-2 complex in the induction of T cell tolerance to self minor histocompatibility antigens. J Exp Med. 1983 Nov 1;158(5):1483–1497. doi: 10.1084/jem.158.5.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guerder S., Matzinger P. Activation versus tolerance: a decision made by T helper cells. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 2):799–805. doi: 10.1101/sqb.1989.054.01.093. [DOI] [PubMed] [Google Scholar]
- Gutstein N. L., Seaman W. E., Scott J. H., Wofsy D. Induction of immune tolerance by administration of monoclonal antibody to L3T4. J Immunol. 1986 Aug 15;137(4):1127–1132. [PubMed] [Google Scholar]
- Hodes R. J., Sharrow S. O., Solomon A. Failure of T cell receptor V beta negative selection in an athymic environment. Science. 1989 Nov 24;246(4933):1041–1044. doi: 10.1126/science.2587987. [DOI] [PubMed] [Google Scholar]
- Ikuta K., Ogura T., Shimizu A., Honjo T. Low frequency of somatic mutation in beta-chain variable region genes of human T-cell receptors. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7701–7705. doi: 10.1073/pnas.82.22.7701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Inaba K., Young J. W., Steinman R. M. Direct activation of CD8+ cytotoxic T lymphocytes by dendritic cells. J Exp Med. 1987 Jul 1;166(1):182–194. doi: 10.1084/jem.166.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jenkins M. K., Ashwell J. D., Schwartz R. H. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol. 1988 May 15;140(10):3324–3330. [PubMed] [Google Scholar]
- 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]
- Jenkins R. N., Aldrich C. J., Landolfi N. F., Rich R. R. Correlation of Qa-1 determinants defined by antisera and by cytotoxic T lymphocytes. Immunogenetics. 1985;21(3):215–225. doi: 10.1007/BF00375374. [DOI] [PubMed] [Google Scholar]
- 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]
- Kastner D. L., Rich R. R. H-2-nonrestricted cytotoxic responses to an antigen encoded telomeric to H-2D. J Immunol. 1979 Jan;122(1):196–201. [PubMed] [Google Scholar]
- Keene J. A., Forman J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J Exp Med. 1982 Mar 1;155(3):768–782. doi: 10.1084/jem.155.3.768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
- Lafferty K. J., Cunningham A. J. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975 Feb;53(1):27–42. doi: 10.1038/icb.1975.3. [DOI] [PubMed] [Google Scholar]
- Lassila O., Vainio O., Matzinger P. Can B cells turn on virgin T cells? Nature. 1988 Jul 21;334(6179):253–255. doi: 10.1038/334253a0. [DOI] [PubMed] [Google Scholar]
- Lin R. H., Stockinger B. T cell immunity or tolerance as a consequence of self antigen presentation. Eur J Immunol. 1989 Jan;19(1):105–110. doi: 10.1002/eji.1830190117. [DOI] [PubMed] [Google Scholar]
- Lorenz R. G., Allen P. M. Thymic cortical epithelial cells can present self-antigens in vivo. Nature. 1989 Feb 9;337(6207):560–562. doi: 10.1038/337560a0. [DOI] [PubMed] [Google Scholar]
- Matzinger P., Zamoyska R., Waldmann H. Self tolerance is H-2-restricted. Nature. 1984 Apr 19;308(5961):738–741. doi: 10.1038/308738a0. [DOI] [PubMed] [Google Scholar]
- Michie S. A., Kirkpatrick E. A., Rouse R. V. Rare peripheral T cells migrate to and persist in normal mouse thymus. J Exp Med. 1988 Nov 1;168(5):1929–1934. doi: 10.1084/jem.168.5.1929. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller R. G. An immunological suppressor cell inactivating cytotoxic T-lymphocyte precursor cells recognizing it. Nature. 1980 Oct 9;287(5782):544–546. doi: 10.1038/287544a0. [DOI] [PubMed] [Google Scholar]
- Mintz B., Baker W. W. Normal mammalian muscle differentiation and gene control of isocitrate dehydrogenase synthesis. Proc Natl Acad Sci U S A. 1967 Aug;58(2):592–598. doi: 10.1073/pnas.58.2.592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Newell M. K., Haughn L. J., Maroun C. R., Julius M. H. Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature. 1990 Sep 20;347(6290):286–289. doi: 10.1038/347286a0. [DOI] [PubMed] [Google Scholar]
- Ohki H., Martin C., Corbel C., Coltey M., Le Douarin N. M. Tolerance induced by thymic epithelial grafts in birds. Science. 1987 Aug 28;237(4818):1032–1035. doi: 10.1126/science.3616623. [DOI] [PubMed] [Google Scholar]
- Palacios R. Monoclonal antibodies against human Ia antigens stimulate monocytes to secrete interleukin 1. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6652–6656. doi: 10.1073/pnas.82.19.6652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parish C. R., Müllbacher A. Automated colorimetric assay for T cell cytotoxicity. J Immunol Methods. 1983 Mar 11;58(1-2):225–237. doi: 10.1016/0022-1759(83)90277-6. [DOI] [PubMed] [Google Scholar]
- 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]
- Rammensee H. G., Fink P. J., Bevan M. J. Functional clonal deletion of class I-specific cytotoxic T lymphocytes by veto cells that express antigen. J Immunol. 1984 Nov;133(5):2390–2396. [PubMed] [Google Scholar]
- Rammensee H. G., Hügin D. Masking of veto function in vivo by activated CD4+ T lymphocytes. Eur J Immunol. 1989 Apr;19(4):643–648. doi: 10.1002/eji.1830190411. [DOI] [PubMed] [Google Scholar]
- Rammensee H. G., Nagy Z. A., Klein J. Suppression of cell-mediated lymphocytotoxicity against minor histocompatibility antigens mediated by Lyt-1+Lyt-2+ T cells of stimulator-strain origin. Eur J Immunol. 1982 Nov;12(11):930–934. doi: 10.1002/eji.1830121107. [DOI] [PubMed] [Google Scholar]
- 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]
- Rees M. A., Rosenberg A. S., Munitz T. I., Singer A. In vivo induction of antigen-specific transplantation tolerance to Qa1a by exposure to alloantigen in the absence of T-cell help. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2765–2769. doi: 10.1073/pnas.87.7.2765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Stanton T. H., Hood L. Biochemical identification of the Qa-1 alloantigen. Immunogenetics. 1980;11(3):309–314. doi: 10.1007/BF01567797. [DOI] [PubMed] [Google Scholar]
- Stephenson S. P., Morley R. C., Butcher G. W. Genetics of the rat CT system: its apparent complexity is a consequence of cross-reactivity between the distinct MHC class I antigens RT1.C and RT1.A. J Immunogenet. 1985 Apr;12(2):101–114. doi: 10.1111/j.1744-313x.1985.tb00836.x. [DOI] [PubMed] [Google Scholar]
- Sunshine G. H., Cyrus M., Winchester G. In vitro responses to the liver antigen F. Immunology. 1982 Feb;45(2):357–363. [PMC free article] [PubMed] [Google Scholar]
- Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
- Vidović D., Roglić M., McKune K., Guerder S., MacKay C., Dembić Z. Qa-1 restricted recognition of foreign antigen by a gamma delta T-cell hybridoma. Nature. 1989 Aug 24;340(6235):646–650. doi: 10.1038/340646a0. [DOI] [PubMed] [Google Scholar]
- Walker E. B., Lanier L. L., Warner N. L. Concomitant induction of the cell surface expression of Ia determinants and accessory cell function by a murine macrophage tumor cell line. J Exp Med. 1982 Feb 1;155(2):629–634. doi: 10.1084/jem.155.2.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- von Boehmer H., Haas W., Jerne N. K. Major histocompatibility complex-linked immune-responsiveness is acquired by lymphocytes of low-responder mice differentiating in thymus of high-responder mice. Proc Natl Acad Sci U S A. 1978 May;75(5):2439–2442. doi: 10.1073/pnas.75.5.2439. [DOI] [PMC free article] [PubMed] [Google Scholar]