Cyclosponne A (CsA)is an immunosuppressive drug that is widely used in transplantation medicine. Many of its suppressive effects appear to be related to inhibition of T lymphocyte function at the level of T cell receptor (TCR)-mediated activation events. Paradoxically, in certain situations CsA is responsible for the induction of a T cell-mediated autoimmunity. A potential explanation for this was obtained from our recent results which revealed two major effects of CsA on T cell development in the thymus: a) CsA inhibits the development of mature single positive (CD4+8- or CD4-8+) thymocytes without discernibly affecting the development of CD4-8- or CD4+8+ precursors or T cells expressing TCR-gamma delta, b) CsA interferes with the deletion of cells bearing autoreactive TCRs in the population of single positive thymocytes that do develop. The experiments proposed here seek to exploit these unexpected properties of CsA to gain new information on T cell development and autoimmunity. Specifically, the peripheral lymphoid tissues of CsA-treated mice will be tested for evidence of autoimmunity by examining in vitro T cell responses and by flow cytometric analysis of autoreactive TCR expression. The effects of CsA on positive selection, the process by which the developing T cell population is enriched for T cells capable of recognizing foreign antigens in association with self major histocompatibility complex (MHC)-encoded molecules, will also be tested. The cellular basis for CsA's effects will be explored with emphasis on the role of decreased intrathymic expression of MHC antigens, and on the involvement of suppressor cells and gamma delta-T cells. Successful completion of these experiments should increase our knowledge of the cellular mechanisms underlying autoimmunity. In addition, new information may be gained on the mode of action of CsA, an important, but poorly understood immunomodulatory drug.
