THE ROLE OF INTRACELLULAR SIGNALING PATHWAYS REGULATING THYMOCYTE ANDLEUKEMIC T-CELL APOPTOSIS

Apoptosis plays a critical role during T cell development, both in the generation of functionally competent T cells in the thymus and the re gulation of peripheral T cell populations. The fate of any T cell, whe ther it is developing in the thymus, or functioning in the peripheral immune system, is dependent on T cell receptor (TCR) specificity for a ntigens presented by MHC molecules and on the consequences of TCR-gene rated intracellular signalling pathways which lead to activation, aner gy or apoptosis. This review describes data that have elucidated the w ay in which these highly regulated TCR-derived signalling pathways lea d to such diverse final outcomes in thymocytes. Contributions to the i nduction of apoptosis in thymocytes by signalling pathways and recepto rs such as Fas, CD45 and CD28 are summarized, particularly with regard to the analysis of relevant transgenic mice. Developments concerning regulation of apoptosis by bcl-2 family members and the possible effec ters of apoptosis, proteases, are assessed. Finally, this information is contrasted with the relatively scarce data on signalling pathways i n thymic-derived T-ALL cells together with potential explanations of h ow transformation might occur by perturbation of apoptotic mechanisms. Precise understanding of these pathways may lead to the development o f novel therapeutic reagents.