Abstract
We have developed a model of peripheral in vivo T cell tolerance that is induced by administration of the protein superantigen staphylococcal enterotoxin B (SEB). Rather than activating V beta 8+ T cells, in vivo administration of SEB induced in them a profound state of anergy. This was shown by their failure to proliferate to subsequent in vitro restimulation with SEB or to anti-V beta 8 antibodies. This unresponsiveness was V beta 8 specific since T cells from SEB-immunized mice responded normally to other antigens. 8 d after SEB administration, there was no reduction in the number of V beta 8+ T cells or in the intensity of V beta 8 T cell receptor (TCR) expression. Although a portion of the V beta 8+ T cells from SEB-primed mice were able to express interleukin 2 receptors (IL-2Rs), they failed to proliferate in response to exogenous IL-2, indicating they were defective in their IL-2 responsiveness. 2-4 wk after SEB administration, there was a reduction of approximately 50% in the number of V beta 8+ cells in immunized compared with control animals. There was, however, no reduction in the level of TCR expression on the remaining V beta 8+ cells. These data demonstrate that proteins that activate T cells in vitro in a V beta-specific manner can induce a state of anergy in peripheral T cells in vivo and may possibly further mediate clonal deletion in a portion of the tolerized cells.
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- Abe R., Vacchio M. S., Fox B., Hodes R. J. Preferential expression of the T-cell receptor V beta 3 gene by Mlsc reactive T cells. Nature. 1988 Oct 27;335(6193):827–830. doi: 10.1038/335827a0. [DOI] [PubMed] [Google Scholar]
- Acha-Orbea H., Mitchell D. J., Timmermann L., Wraith D. C., Tausch G. S., Waldor M. K., Zamvil S. S., McDevitt H. O., Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. doi: 10.1016/0092-8674(88)90558-2. [DOI] [PubMed] [Google Scholar]
- Battisto J. R., Bloom B. R. Dual immunological unresponsiveness induced by cell membrane coupled hapten or antigen. Nature. 1966 Oct 8;212(5058):156–157. doi: 10.1038/212156a0. [DOI] [PubMed] [Google Scholar]
- Burkly L. C., Lo D., Kanagawa O., Brinster R. L., Flavell R. A. T-cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC class II I-E. Nature. 1989 Nov 30;342(6249):564–566. doi: 10.1038/342564a0. [DOI] [PubMed] [Google Scholar]
- Cleveland R. P., Claman H. N. T cell signals: tolerance to DNFB is converted to sensitization by a separate nonspecific second signal. J Immunol. 1980 Jan;124(1):474–480. [PubMed] [Google Scholar]
- Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
- Fleischer B., Schrezenmeier H., Conradt P. T lymphocyte activation by staphylococcal enterotoxins: role of class II molecules and T cell surface structures. Cell Immunol. 1989 Apr 15;120(1):92–101. doi: 10.1016/0008-8749(89)90177-9. [DOI] [PubMed] [Google Scholar]
- Fraser J. D. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989 May 18;339(6221):221–223. doi: 10.1038/339221a0. [DOI] [PubMed] [Google Scholar]
- Gahring L. C., Weigle W. O. The induction of peripheral T cell unresponsiveness in adult mice by monomeric human gamma-globulin. J Immunol. 1989 Oct 1;143(7):2094–2100. [PubMed] [Google Scholar]
- Gao E. K., Lo D., Cheney R., Kanagawa O., Sprent J. Abnormal differentiation of thymocytes in mice treated with cyclosporin A. Nature. 1988 Nov 10;336(6195):176–179. doi: 10.1038/336176a0. [DOI] [PubMed] [Google Scholar]
- Goodnow C. C., Crosbie J., Jorgensen H., Brink R. A., Basten A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature. 1989 Nov 23;342(6248):385–391. doi: 10.1038/342385a0. [DOI] [PubMed] [Google Scholar]
- Hathcock K. S., Segal D. M., Hodes R. J. Activation of Lyt-2+ (CD8+) and L3T4+ (CD4+) T cell subsets by anti-receptor antibody. J Immunol. 1989 Apr 1;142(7):2181–2186. [PubMed] [Google Scholar]
- Howard J. G., Mitchison N. A. Immunological tolerance. Prog Allergy. 1975;18:43–96. doi: 10.1159/000395256. [DOI] [PubMed] [Google Scholar]
- Janeway C. A., Jr, Yagi J., Conrad P. J., Katz M. E., Jones B., Vroegop S., Buxser S. T-cell responses to Mls and to bacterial proteins that mimic its behavior. Immunol Rev. 1989 Feb;107:61–88. doi: 10.1111/j.1600-065x.1989.tb00003.x. [DOI] [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., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [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 M. K., Schwartz R. H., Pardoll D. M. Effects of cyclosporine A on T cell development and clonal deletion. Science. 1988 Sep 23;241(4873):1655–1658. doi: 10.1126/science.241.4873.1655. [DOI] [PubMed] [Google Scholar]
- Kanagawa O., Palmer E., Bill J. The T cell receptor V beta 6 domain imparts reactivity to the Mls-1a antigen. Cell Immunol. 1989 Apr 1;119(2):412–426. doi: 10.1016/0008-8749(89)90255-4. [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]
- 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]
- Krieger J. I., Grammer S. F., Grey H. M., Chesnut R. W. Antigen presentation by splenic B cells: resting B cells are ineffective, whereas activated B cells are effective accessory cells for T cell responses. J Immunol. 1985 Nov;135(5):2937–2945. [PubMed] [Google Scholar]
- Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
- Lamb J. R., Skidmore B. J., Green N., Chiller J. M., Feldmann M. Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med. 1983 May 1;157(5):1434–1447. doi: 10.1084/jem.157.5.1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacDonald H. R., Pedrazzini T., Schneider R., Louis J. A., Zinkernagel R. M., Hengartner H. Intrathymic elimination of Mlsa-reactive (V beta 6+) cells during neonatal tolerance induction to Mlsa-encoded antigens. J Exp Med. 1988 Jun 1;167(6):2005–2010. doi: 10.1084/jem.167.6.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Marrack P., Blackman M., Kushnir E., Kappler J. The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells. J Exp Med. 1990 Feb 1;171(2):455–464. doi: 10.1084/jem.171.2.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
- Minami M., Shreffler D. C., Cowing C. Characterization of the stimulator cells in the murine primary mixed leukocyte response. J Immunol. 1980 Mar;124(3):1314–1321. [PubMed] [Google Scholar]
- Mollick J. A., Cook R. G., Rich R. R. Class II MHC molecules are specific receptors for staphylococcus enterotoxin A. Science. 1989 May 19;244(4906):817–820. doi: 10.1126/science.2658055. [DOI] [PubMed] [Google Scholar]
- Ortega G., Robb R. J., Shevach E. M., Malek T. R. The murine IL 2 receptor. I. Monoclonal antibodies that define distinct functional epitopes on activated T cells and react with activated B cells. J Immunol. 1984 Oct;133(4):1970–1975. [PubMed] [Google Scholar]
- Pinto M., Torten M., Birnbaum S. C. Suppression of the in vivo humoral and cellular immune response by staphylococcal enterotoxin B (SEB). Transplantation. 1978 Jun;25(6):320–323. doi: 10.1097/00007890-197806000-00008. [DOI] [PubMed] [Google Scholar]
- Platsoucas C. D., Oleszak E. L., Good R. A. Immunomodulation of human leukocytes by staphylococcal enterotoxin A: augmentation of natural killer cells and induction of suppressor cells. Cell Immunol. 1986 Feb;97(2):371–385. doi: 10.1016/0008-8749(86)90407-7. [DOI] [PubMed] [Google Scholar]
- Pullen A. M., Marrack P., Kappler J. W. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature. 1988 Oct 27;335(6193):796–801. doi: 10.1038/335796a0. [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]
- Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
- Rajewsky K., Brenig C. Paralysis to serum albumins in T and B lymphocytes in mice. Dose dependence, specificity and kinetics of escape. Eur J Immunol. 1974 Feb;4(2):120–125. doi: 10.1002/eji.1830040211. [DOI] [PubMed] [Google Scholar]
- Rammensee H. G., Kroschewski R., Frangoulis B. Clonal anergy induced in mature V beta 6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells. Nature. 1989 Jun 15;339(6225):541–544. doi: 10.1038/339541a0. [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]
- Reich E. P., Sherwin R. S., Kanagawa O., Janeway C. A., Jr An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Nature. 1989 Sep 28;341(6240):326–328. doi: 10.1038/341326a0. [DOI] [PubMed] [Google Scholar]
- Ria F., Chan B. M., Scherer M. T., Smith J. A., Gefter M. L. Immunological activity of covalently linked T-cell epitopes. Nature. 1990 Jan 25;343(6256):381–383. doi: 10.1038/343381a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Scholl P. R., Diez A., Geha R. S. Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 bind to distinct sites on HLA-DR and HLA-DQ molecules. J Immunol. 1989 Oct 15;143(8):2583–2588. [PubMed] [Google Scholar]
- Shi Y. F., Sahai B. M., Green D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. doi: 10.1038/339625a0. [DOI] [PubMed] [Google Scholar]
- Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
- Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
- Ucker D. S., Ashwell J. D., Nickas G. Activation-driven T cell death. I. Requirements for de novo transcription and translation and association with genome fragmentation. J Immunol. 1989 Dec 1;143(11):3461–3469. [PubMed] [Google Scholar]
- Urban J. L., Kumar V., Kono D. H., Gomez C., Horvath S. J., Clayton J., Ando D. G., Sercarz E. E., Hood L. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell. 1988 Aug 12;54(4):577–592. doi: 10.1016/0092-8674(88)90079-7. [DOI] [PubMed] [Google Scholar]
- White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
- Wraith D. C., Smilek D. E., Mitchell D. J., Steinman L., McDevitt H. O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell. 1989 Oct 20;59(2):247–255. doi: 10.1016/0092-8674(89)90287-0. [DOI] [PubMed] [Google Scholar]