Immunological Tolerance by Antigen-Induced Apoptosis of Mature T Lymphocytes
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Although the immune system has evolved to mount defensive lymphocyte activation responses to pathogens, it has long been known that antigen can specifically abrogate an immune response.1 This form of acquired immunological tolerance can occur in adult animals and in certain circumstances has been shown to involve T lymphocytes. We have found conditions under which antigen causes the programmed death of mature T lymphocytes. We first determined that susceptibility of T lymphocytes to programmed death results from the exposure to growth lymphokines such as interleukin-2 (IL-2) followed by cell cycle progression. Susceptible T lymphocytes can then be triggered to die by T cell receptor (TCR) engagement. We have found that this mechanism leads to T cell death when T cells are exposed to large concentrations of antigen under fully activating conditions. Our results suggest that the induction of death by antigen is a feedback regulatory process that controls the intensity of immune responses involving T lymphocytes. We have called this mechanism “propriocidal regulation” and propose that it represents one means by which antigen-induces tolerance. We have recently shown that autoreactive T lymphocytes are susceptible to death by the propriocidal mechanism. This allowed us to use antigen to delete pathogenic T lymphocytes resulting in clinical and pathological amelioration of experimental allergic encephalomyelitis in mice. In this review we shall describe the results mentioned above, which are contained in several recent publications,1,3,4,6,12 that support the concept that antigen-induced apoptosis of mature T lymphocytes is a potent form of immunological tolerance.
KeywordsMyelin Basic Protein Cell Cycling Experimental Allergic Encephalomyelitis Immunological Tolerance Clonal Anergy
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- 1.J.M. Critchfield, S.A. Boehme, and M.J. Lenardo, Regulation of antigen-induced mature T lymphocyte apoptosis, in: “Apoptosis and the Immune Response,” C. Gregory, ed., Wiley and Sons, New York (1972).Google Scholar
- 4.S.A. Boehme, L. Zheng, and M.J. Lenardo, Distinct antigen receptor signal requirements for programmed cell death compared to lymphokine expression in mature T lymphocytes, Manuscript submitted.Google Scholar
- 12.J.M. Critchfield, M.K. Racke, J.C. Zuniga-Pflucker, B. Cannella, C.S. Raine, J. Goverman, and M.J. Lenardo, T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis, Science in press (1994).Google Scholar