Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes.
Apoptosis plays an essential role in the development and homeostasis of the immune system. During lymphocyte development, potentially autoreactive cells are eliminated via the activation of a tightly regulated cell death program(s). Similar processes operate in mature lymphocytes, to control the magnitude of the normal immune response by eliminating activated lymphocytes. However, differences in susceptibility to signal-induced apoptosis between immature and mature lymphocytes are numerous. One well-characterized example occurs in response to Ca2+ elevation: peripheral T lymphocytes are resistant, while immature thymocytes are highly susceptible, to Ca2+-mediated cell death (CMCD). In this study, we show that the immunosuppressant cyclosporin A (CsA) primes splenic lymphocytes to undergo CMCD upon ionomycin stimulation. This CsA-induced CMCD affected both T and B lymphocytes. CsA-plug Ca2+-mediated apoptosis was dissected into a two-step process: first, CsA and Ca2+ synergized to induce TGF-beta 1 secretion by B cells; and then TGF-beta 1 and Ca2+ synergistically triggered T and B lymphocyte apoptosis. Together, our results suggest that lymphocyte apoptosis may play a role in CsA-induced immunosuppression via a TGF-beta-dependent mechanism.
Andjelíc
S
S
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, USA.
Khanna
A
A
Suthanthiran
M
M
Nikolić-Zugić
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D002118:Calcium