Immunological Tolerance by Antigen-Induced Apoptosis of Mature T Lymphocytes

Abstract

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.