Regulation of apoptosis in thymocytes.
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.
Cairns
J S
JS
Pittsburgh Cancer Institute, Pa.
Mainwaring
M S
MS
Cacchione
R N
RN
Walker
J A
JA
McCarthy
S A
SA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology*
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D000001:Calcimycin; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate