Abstract
The present study demonstrates in MRl-lpr/lpr autoimmune mice an age- dependent loss of MHC-self-restricted function by L3T4+ Th. This defect is not present in age-matched, congenic MRL-+/+ spleen cells and appears to be due to the presence of suppressor cells that are selective for L3T4+ Th and not for Lyt-2+ Th. Surprisingly, the suppressor cells are also L3T4+ T cells and can suppress the IL-2 production of congenic MRL/+ L3T4+ Th to MHC-self-restricted antigens. These data support the idea of functional specialization within the L3T4+ population of T cells. Because L3T4+ suppressor cells are detected late in the course of autoimmunity, we interpret their presence not as a primary initiating event in the development of autoimmunity, but rather as a compensatory mechanism. Additionally, similar suppression of L3T4+ Th function has also been reported in a murine graft-vs.-host model of autoimmunity, suggesting that the suppressor cells represent an immunoregulatory mechanism that is a common feature of autoimmunity. Since excessive class II-restricted Th activity for B cells has been reported for both models of autoimmunity, L3T4+ suppressor cells may represent an attempt to down regulate such excessive Th activity. These findings may be relevant to human autoimmune diseases, such as systemic lupus erythematosus, in which B cell hyperactivity is also associated with reduced IL-2 production by Th.
Full Text
The Full Text of this article is available as a PDF (1.0 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Altman A., Theofilopoulos A. N., Weiner R., Katz D. H., Dixon F. J. Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2. J Exp Med. 1981 Sep 1;154(3):791–808. doi: 10.1084/jem.154.3.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andrews B. S., Eisenberg R. A., Theofilopoulos A. N., Izui S., Wilson C. B., McConahey P. J., Murphy E. D., Roths J. B., Dixon F. J. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978 Nov 1;148(5):1198–1215. doi: 10.1084/jem.148.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Asano Y., Hodes R. J. T cell regulation of b cell activation. Cloned Lyt-1+2-T suppressor cells inhibit the major histocompatibility complex-restricted interaction of T helper cells with B cells and/or accessory cells. J Exp Med. 1983 Oct 1;158(4):1178–1190. doi: 10.1084/jem.158.4.1178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bottomly K., Kaye J., Jones B., Jones F., 3rd, Janeway C. A., Jr A cloned, antigen-specific, Ia-restricted Lyt-1+,2- T cell with suppressive activity. J Mol Cell Immunol. 1983;1(1):42–49. [PubMed] [Google Scholar]
- Cantor H., Boyse E. A. Lymphocytes as models for the study of mammalian cellular differentiation. Immunol Rev. 1977 Jan;33:105–124. doi: 10.1111/j.1600-065x.1977.tb00364.x. [DOI] [PubMed] [Google Scholar]
- Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
- Dauphinée M. J., Kipper S. B., Wofsy D., Talal N. Interleukin 2 deficiency is a common feature of autoimmune mice. J Immunol. 1981 Dec;127(6):2483–2487. [PubMed] [Google Scholar]
- Davidson W. F., Dumont F. J., Bedigian H. G., Fowlkes B. J., Morse H. C., 3rd Phenotypic, functional, and molecular genetic comparisons of the abnormal lymphoid cells of C3H-lpr/lpr and C3H-gld/gld mice. J Immunol. 1986 Jun 1;136(11):4075–4084. [PubMed] [Google Scholar]
- 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]
- Fischbach M. Defective T cell response to presented antigen in autoimmune mice. J Immunol. 1984 Nov;133(5):2365–2368. [PubMed] [Google Scholar]
- Guimezanes A., Schmitt-Verhulst A. M. Inhibition of helper function with anti-Lyt-2 or anti-L3T4 monoclonal antibodies depending on stimulating antigens. Eur J Immunol. 1985 Dec;15(12):1187–1191. doi: 10.1002/eji.1830151209. [DOI] [PubMed] [Google Scholar]
- Hang L., Theofilopoulos A. N., Balderas R. S., Francis S. J., Dixon F. J. The effect of thymectomy on lupus-prone mice. J Immunol. 1984 Apr;132(4):1809–1813. [PubMed] [Google Scholar]
- Hodes R. J. Cloned Lyt-1+, 2- T suppressor cells--a commentary. J Mol Cell Immunol. 1985;2(1):14–16. [PubMed] [Google Scholar]
- Killar L., MacDonald G., West J., Woods A., Bottomly K. Cloned, Ia-restricted T cells that do not produce interleukin 4(IL 4)/B cell stimulatory factor 1(BSF-1) fail to help antigen-specific B cells. J Immunol. 1987 Mar 15;138(6):1674–1679. [PubMed] [Google Scholar]
- Levy R. B., Shearer G. M. Regulation of T-cell-mediated lympholysis by the murine major histocompatibility complex. I. Preferential in vitro responses to trinitrophenyl-modified self K- and D-coded gene products in parental and F1 hybrid mouse strains. J Exp Med. 1979 Jun 1;149(6):1379–1392. doi: 10.1084/jem.149.6.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liew F. Y. Specific suppression of responses to Leishmania tropica by a cloned T-cell line. Nature. 1983 Oct 13;305(5935):630–632. doi: 10.1038/305630a0. [DOI] [PubMed] [Google Scholar]
- Linker-Israeli M., Bakke A. C., Kitridou R. C., Gendler S., Gillis S., Horwitz D. A. Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J Immunol. 1983 Jun;130(6):2651–2655. [PubMed] [Google Scholar]
- Lu C. Y., Unanue E. R. Spontaneous T-cell lymphokine production and enhanced macrophage Ia expression and tumoricidal activity in MRL-lpr mice. Clin Immunol Immunopathol. 1982 Nov;25(2):213–222. doi: 10.1016/0090-1229(82)90184-2. [DOI] [PubMed] [Google Scholar]
- Malek T. R., Robb R. J., Shevach E. M. Identification and initial characterization of a rat monoclonal antibody reactive with the murine interleukin 2 receptor-ligand complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5694–5698. doi: 10.1073/pnas.80.18.5694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller R. A. IL 2 production by mitogen-stimulated T cell subsets: helper-precursors are predominantly Lyt-2-. J Immunol. 1983 Dec;131(6):2864–2867. [PubMed] [Google Scholar]
- Mizuochi T., Golding H., Rosenberg A. S., Glimcher L. H., Malek T. R., Singer A. Both L3T4+ and Lyt-2+ helper T cells initiate cytotoxic T lymphocyte responses against allogenic major histocompatibility antigens but not against trinitrophenyl-modified self. J Exp Med. 1985 Aug 1;162(2):427–443. doi: 10.1084/jem.162.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morse H. C., 3rd, Davidson W. F., Yetter R. A., Murphy E. D., Roths J. B., Coffman R. L. Abnormalities induced by the mutant gene Ipr: expansion of a unique lymphocyte subset. J Immunol. 1982 Dec;129(6):2612–2615. [PubMed] [Google Scholar]
- Moser M., Mizuochi T., Sharrow S. O., Singer A., Shearer G. M. Graft-vs-host reaction limited to a class II MHC difference results in a selective deficiency in L3T4+ but not in Lyt-2+ T helper cell function. J Immunol. 1987 Mar 1;138(5):1355–1362. [PubMed] [Google Scholar]
- Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
- Naides S. J. Suppression of antigen-specific interleukin 2 production in the MRL/MpJ-lpr/lpr mouse. J Immunol. 1986 Jun 1;136(11):4113–4121. [PubMed] [Google Scholar]
- Pfizenmaier K., Scheurich P., Däubener W., Krönke M., Röllinghoff M., Wagner H. Quantitative representation of all T cells committed to develop into cytotoxic effector cells and/or interleukin 2 activity-producing helper cells within murine T lymphocyte subsets. Eur J Immunol. 1984 Jan;14(1):33–39. doi: 10.1002/eji.1830140107. [DOI] [PubMed] [Google Scholar]
- Prud'Homme G. J., Park C. L., Fieser T. M., Kofler R., Dixon F. J., Theofilopoulos A. N. Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype. J Exp Med. 1983 Feb 1;157(2):730–742. doi: 10.1084/jem.157.2.730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Santoro T. J., Portanova J. P., Kotzin B. L. The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice. J Exp Med. 1988 May 1;167(5):1713–1718. doi: 10.1084/jem.167.5.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott C. F., Jr, Tsurufuji M., Lu C. Y., Finberg R., Sy M. S. Comparison of antigen-specific T cell responses in autoimmune MRL/Mp-lpr/lpr and MRL/Mp-+/+ mice. J Immunol. 1984 Feb;132(2):633–639. [PubMed] [Google Scholar]
- Singer A., Kruisbeek A. M., Andrysiak P. M. T cell-accessory cell interactions that initiate allospecific cytotoxic T lymphocyte responses: existence of both Ia-restricted and Ia-unrestricted cellular interaction pathways. J Immunol. 1984 May;132(5):2199–2209. [PubMed] [Google Scholar]
- Steinberg A. D., Roths J. B., Murphy E. D., Steinberg R. T., Raveche E. S. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J Immunol. 1980 Aug;125(2):871–873. [PubMed] [Google Scholar]
- Theofilopoulos A. N., Dixon F. J. Murine models of systemic lupus erythematosus. Adv Immunol. 1985;37:269–390. doi: 10.1016/s0065-2776(08)60342-9. [DOI] [PubMed] [Google Scholar]
- Theofilopoulos A. N., Shawler D. L., Eisenberg R. A., Dixon F. J. Splenic immunoglobulin-secreting cells and their regulation in autoimmune mice. J Exp Med. 1980 Feb 1;151(2):446–466. doi: 10.1084/jem.151.2.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Via C. S., Sharrow S. O., Shearer G. M. Role of cytotoxic T lymphocytes in the prevention of lupus-like disease occurring in a murine model of graft-vs-host disease. J Immunol. 1987 Sep 15;139(6):1840–1849. [PubMed] [Google Scholar]
- Via C. S., Shearer G. M. T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease. Immunol Today. 1988 Jul-Aug;9(7-8):207–213. doi: 10.1016/0167-5699(88)91215-7. [DOI] [PubMed] [Google Scholar]
- Wofsy D., Ledbetter J. A., Hendler P. L., Seaman W. E. Treatment of murine lupus with monoclonal anti-T cell antibody. J Immunol. 1985 Feb;134(2):852–857. [PubMed] [Google Scholar]
- Wofsy D., Murphy E. D., Roths J. B., Dauphinée M. J., Kipper S. B., Talal N. Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene. J Exp Med. 1981 Nov 1;154(5):1671–1680. doi: 10.1084/jem.154.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]