Regulation of apoptosis in thymocytes.

Abstract

Programmed cell death, or apoptosis, is tightly regulated during the development of T lymphocytes. Several studies have indicated that in normal mice, thymocyte are sensitive to apoptosis primarily during a brief period relatively late in the CD4+8+ maturation stage, when both positive and negative selection are thought to occur. One factor regulating sensitivity to apoptosis may be the expression and signalling capacity of the TcR/CD3 complex on developing thymocytes. In the present study, we report that sensitivity to apoptosis in immature thymocytes may also be regulated by a mechanism that can prevent induction of apoptosis in many thymocytes. This protective mechanism is induced by TcR/CD3 engagement and cross-linking, as well as by agents that mimic TcR/CD3-dependent phosphoinositol bisphosphate hydrolysis and activate Ca++ fluxes and Protein Kinase C. Cyclosporin A (CsA) inhibits the protective mechanism, permitting the induction of apoptosis by TcR/CD3 or TcR/CD3-mimicking stimuli in otherwise resistant thymocytes. In contrast, mature naive T cells do not undergo apoptosis following stimulation by these agents, even in the presence of CsA, suggesting that in mature naive T-cells the apoptotic machinery itself is normally no longer inducible. We discuss the possible implications of these results for regulation of T-cell development. In this study we also demonstrate that CsA can inhibit the ability of accessory cells to trigger thymocyte apoptosis in accessory cell-dependent assays, which may explain previous reports that CsA can inhibit the induction of thymic clonal deletion in vivo.