Abstract
Brown-Norway (BN) rats injected with HgCl2 develop a systemic autoimmune disease associated with a polyclonal B cell activation, due to autoreactive T cells specific for self-class II molecules, while Lewis (LEW) rats injected with HgCl2 do not exhibit autoimmunity and develop a non-antigen-specific, CD8-mediated immunosuppression assessed by a depression of T cell functions, and a protection against experimental autoimmune encephalomyelitis (EAE). Resistance to HgCl2- induced autoimmunity is not due to these suppressor cells since treatment with an anti-CD8 monoclonal antibody (mAb) did not allow autoimmunity to appear. The absence of autoimmunity in this strain could result from the absence of autoreactive T cells, or from quantitative or qualitative differences of these cells between susceptible and resistant strains. In the present study, we show that CD4+ anti-class II T cells are present in HgCl2-injected LEW rats and are as frequent as in BN rats when assessed by limiting dilution analysis. LEW CD4+ autoreactive T cell lines were derived. They proliferated in the presence of normal class II-bearing cells, secreted interleukin 2, and did not induce B cells to produce immunoglobulins. Transfer of one of these lines, LEW Hg A, into normal LEW rats led to the appearance of CD8+ cells responsible for a non-antigen-specific immunosuppression that induced complete protection from EAE. Immunosuppression was abrogated after treatment with an anti-CD8 mAb. In vitro, CD8+ cells from rats injected with the LEW Hg A T cell line proliferated in the presence of activated T cells whatever their origin. We conclude that HgCl2 induces CD4+ autoreactive T cells that proliferate in the presence of class II+ cells in susceptible BN as well as in resistant LEW rats. But while these cells collaborate with B cells to produce autoantibodies in BN rats, they initiate in LEW rats a suppressor circuit involving antiergotypic CD8+ suppressor cells.
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- Barclay A. N. The localization of populations of lymphocytes defined by monoclonal antibodies in rat lymphoid tissues. Immunology. 1981 Apr;42(4):593–600. [PMC free article] [PubMed] [Google Scholar]
- 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]
- Brideau R. J., Carter P. B., McMaster W. R., Mason D. W., Williams A. F. Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur J Immunol. 1980 Aug;10(8):609–615. doi: 10.1002/eji.1830100807. [DOI] [PubMed] [Google Scholar]
- Cohen I. R. Regulation of autoimmune disease physiological and therapeutic. Immunol Rev. 1986 Dec;94:5–21. doi: 10.1111/j.1600-065x.1986.tb01161.x. [DOI] [PubMed] [Google Scholar]
- Del Prete G. F., De Carli M., Ricci M., Romagnani S. Helper activity for immunoglobulin synthesis of T helper type 1 (Th1) and Th2 human T cell clones: the help of Th1 clones is limited by their cytolytic capacity. J Exp Med. 1991 Oct 1;174(4):809–813. doi: 10.1084/jem.174.4.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Druet E., Sapin C., Günther E., Feingold N., Druet P. Mercuric chloride-induced anti-glomerular basement membrane antibodies in the rat: genetic control. Eur J Immunol. 1977 Jun;7(6):348–351. doi: 10.1002/eji.1830070605. [DOI] [PubMed] [Google Scholar]
- Dubey C., Bellon B., Druet P. TH1 and TH2 dependent cytokines in experimental autoimmunity and immune reactions induced by chemicals. Eur Cytokine Netw. 1991 May-Jun;2(3):147–152. [PubMed] [Google Scholar]
- Faherty D. A., Johnson D. R., Zauderer M. Origin and specificity of autoreactive T cells in antigen-induced populations. J Exp Med. 1985 Jun 1;161(6):1293–1301. doi: 10.1084/jem.161.6.1293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fukumoto T., McMaster W. R., Williams A. F. Mouse monoclonal antibodies against rat major histocompatibility antigens. Two Ia antigens and expression of Ia and class I antigens in rat thymus. Eur J Immunol. 1982 Mar;12(3):237–243. doi: 10.1002/eji.1830120313. [DOI] [PubMed] [Google Scholar]
- Hirsch F., Couderc J., Sapin C., Fournie G., Druet P. Polyclonal effect of HgCl2 in the rat, its possible role in an experimental autoimmune disease. Eur J Immunol. 1982 Jul;12(7):620–625. doi: 10.1002/eji.1830120716. [DOI] [PubMed] [Google Scholar]
- Hisatsune T., Enomoto A., Nishijima K., Minai Y., Asano Y., Tada T., Kaminogawa S. CD8+ suppressor T cell clone capable of inhibiting the antigen- and anti-T cell receptor-induced proliferation of Th clones without cytolytic activity. J Immunol. 1990 Oct 15;145(8):2421–2426. [PubMed] [Google Scholar]
- Janeway C. A. Autoimmune disease: immunotherapy by peptides? Nature. 1989 Oct 12;341(6242):482–483. doi: 10.1038/341482a0. [DOI] [PubMed] [Google Scholar]
- Karpus W. J., Swanborg R. H. CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta. J Immunol. 1991 Feb 15;146(4):1163–1168. [PubMed] [Google Scholar]
- Lider O., Karin N., Shinitzky M., Cohen I. R. Therapeutic vaccination against adjuvant arthritis using autoimmune T cells treated with hydrostatic pressure. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4577–4580. doi: 10.1073/pnas.84.13.4577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lider O., Reshef T., Beraud E., Ben-Nun A., Cohen I. R. Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science. 1988 Jan 8;239(4836):181–183. doi: 10.1126/science.2447648. [DOI] [PubMed] [Google Scholar]
- Lohse A. W., Mor E., Reshef T., Meyer zum Büschenfelde K. H., Cohen I. R. Inhibition of the mixed lymphocyte reaction by T cell vaccination. Eur J Immunol. 1990 Nov;20(11):2521–2524. doi: 10.1002/eji.1830201126. [DOI] [PubMed] [Google Scholar]
- Lohse A. W., Mor F., Karin N., Cohen I. R. Control of experimental autoimmune encephalomyelitis by T cells responding to activated T cells. Science. 1989 May 19;244(4906):820–822. doi: 10.1126/science.2471264. [DOI] [PubMed] [Google Scholar]
- McMaster W. R., Williams A. F. Identification of Ia glycoproteins in rat thymus and purification from rat spleen. Eur J Immunol. 1979 Jun;9(6):426–433. doi: 10.1002/eji.1830090603. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
- Nagarkatti P. S., Nagarkatti M., Mann L. W., Jones L. A., Kaplan A. M. Characterization of an endogenous Lyt2+ T-suppressor-cell population regulating autoreactive T cells in vitro and in vivo. Cell Immunol. 1988 Mar;112(1):64–77. doi: 10.1016/0008-8749(88)90276-6. [DOI] [PubMed] [Google Scholar]
- Nagarkatti P. S., Snow E. C., Kaplan A. M. Characterization and function of autoreactive T-lymphocyte clones isolated from normal, unprimed mice. Cell Immunol. 1985 Aug;94(1):32–48. doi: 10.1016/0008-8749(85)90083-8. [DOI] [PubMed] [Google Scholar]
- Ochel M., Vohr H. W., Pfeiffer C., Gleichmann E. IL-4 is required for the IgE and IgG1 increase and IgG1 autoantibody formation in mice treated with mercuric chloride. J Immunol. 1991 May 1;146(9):3006–3011. [PubMed] [Google Scholar]
- Paterson D. J., Jefferies W. A., Green J. R., Brandon M. R., Corthesy P., Puklavec M., Williams A. F. Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol. 1987 Dec;24(12):1281–1290. doi: 10.1016/0161-5890(87)90122-2. [DOI] [PubMed] [Google Scholar]
- Pelletier L., Galceran M., Pasquier R., Ronco P., Verroust P., Bariety J., Druet P. Down modulation of Heymann's nephritis by mercuric chloride. Kidney Int. 1987 Aug;32(2):227–232. doi: 10.1038/ki.1987.196. [DOI] [PubMed] [Google Scholar]
- Pelletier L., Pasquier R., Rossert J., Vial M. C., Mandet C., Druet P. Autoreactive T cells in mercury-induced autoimmunity. Ability to induce the autoimmune disease. J Immunol. 1988 Feb 1;140(3):750–754. [PubMed] [Google Scholar]
- Pelletier L., Rossert J., Pasquier R., Villarroya H., Belair M. F., Vial M. C., Oriol R., Druet P. Effect of HgCl2 on experimental allergic encephalomyelitis in Lewis rats. HgCl2-induced down-modulation of the disease. Eur J Immunol. 1988 Feb;18(2):243–247. doi: 10.1002/eji.1830180210. [DOI] [PubMed] [Google Scholar]
- Pelletier L., Rossert J., Pasquier R., Villarroya H., Belair M. F., Vial M. C., Oriol R., Druet P. Effect of HgCl2 on experimental allergic encephalomyelitis in Lewis rats. HgCl2-induced down-modulation of the disease. Eur J Immunol. 1988 Feb;18(2):243–247. doi: 10.1002/eji.1830180210. [DOI] [PubMed] [Google Scholar]
- Pelletier L., Rossert J., Pasquier R., Villarroya H., Oriol R., Druet P. HgCl2-induced perturbation of the T cell network in experimental allergic encephalomyelitis. II. In vivo demonstration of the role of T suppressor and contrasuppressor cells. Cell Immunol. 1991 Oct 15;137(2):379–388. doi: 10.1016/0008-8749(91)90087-r. [DOI] [PubMed] [Google Scholar]
- Romain P. L., Morimoto C., Daley J. F., Palley L. S., Reinherz E. L., Schlossman S. F. Reactivity of inducer cell subsets and T8-cell activation during the human autologous mixed lymphocyte reaction. Clin Immunol Immunopathol. 1984 Jan;30(1):117–128. doi: 10.1016/0090-1229(84)90012-6. [DOI] [PubMed] [Google Scholar]
- Rossert J., Pelletier L., Pasquier R., Druet P. Autoreactive T cells in mercury-induced autoimmunity. Demonstration by limiting dilution analysis. Eur J Immunol. 1988 Nov;18(11):1761–1766. doi: 10.1002/eji.1830181116. [DOI] [PubMed] [Google Scholar]
- Sano K., Fujisawa I., Abe R., Asano Y., Tada T. MHC-restricted minimal regulatory circuit initiated by a class II-autoreactive T cell clone. J Exp Med. 1987 May 1;165(5):1284–1295. doi: 10.1084/jem.165.5.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sapin C., Hirsch F., Delaporte J. P., Bazin H., Druet P. Polyclonal IgE increase after HgCl2 injections in BN and LEW rats: a genetic analysis. Immunogenetics. 1984;20(3):227–236. doi: 10.1007/BF00364205. [DOI] [PubMed] [Google Scholar]
- Spickett G. P., Brandon M. R., Mason D. W., Williams A. F., Woollett G. R. MRC OX-22, a monoclonal antibody that labels a new subset of T lymphocytes and reacts with the high molecular weight form of the leukocyte-common antigen. J Exp Med. 1983 Sep 1;158(3):795–810. doi: 10.1084/jem.158.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sun D., Ben-Nun A., Wekerle H. Regulatory circuits in autoimmunity: recruitment of counter-regulatory CD8+ T cells by encephalitogenic CD4+ T line cells. Eur J Immunol. 1988 Dec;18(12):1993–1999. doi: 10.1002/eji.1830181219. [DOI] [PubMed] [Google Scholar]
- Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
- Vandenbark A. A., Hashim G., Offner H. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature. 1989 Oct 12;341(6242):541–544. doi: 10.1038/341541a0. [DOI] [PubMed] [Google Scholar]
- Zhang J. W., Schreurs M., Medaer R., Raus J. C. Regulation of myelin basic protein-specific helper T cells in multiple sclerosis: generation of suppressor T cell lines. Cell Immunol. 1992 Jan;139(1):118–130. doi: 10.1016/0008-8749(92)90105-x. [DOI] [PubMed] [Google Scholar]