ANTIGEN-INDUCED APOPTOSIS (PROPRIOCIDAL REGULATION) OF MATURE T LYMPHOCYTES

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We have found that stimulation of the antigen receptor of mature T cells following exposure of the cells to mitogenic lymphokines such as IL-2 leads to the induction of programmed cell death or apoptosis (propriocidal regulation). This process can lead to the deletion of specific antigen-reactive T cells without affecting bystander cells. We are interested in two aspects of this effect: 1) the molecular events that take place, and 2) the possibility of using this mechanism to pharmacologically induce the elimination of T cells involved in disease processes. Our results indicate that antigen-induced apoptosis can only occur at specific stages of the cell cycle. Moreover, we can demonstrate that appropriate immunization will lead to the suppression of immune responsiveness, most likely because the specifically reactive T cells have been eliminated. Several types of diseases that arise from the over-stimulation of the immune system including: allergies, autoimmune disorders such as multiple sclerosis and rheumatoid arthritis, and the rejection of tissue grafts. Activated T cells are the driving force behind the destructive immune response in these diseases. Current therapies involve drugs such as steroids and cyclosporin A that impair, in a general way, T lymphocyte function. Therefore, one serious side effect of these therapies is to increase susceptibility to infections. We have discovered that the cytokine IL-2 is able to cause the death of T cells that are specifically stimulated through their antigen receptor. This previously unknown property of IL-2 should allow the specific elimination of certain receptor-bearing T cells which could form the basis for new clinical applications of IL-2. It is conceivable that disease-causing T lymphocytes could be eliminated while sparing helpful T lymphocytes. Thus, the severe immunosuppression which is a side-effect of current therapies could be avoided. Conversly, because of the recent evidence that apoptosis may underly the loss of CD4+ T cells in AIDS, our in vitro model of T cell apoptosis may prove to be an important system to test for drugs that block apoptosis.