Intracellular Ca²⁺ Elevation and Cyclosporin A Synergistically Induce TGF-β1-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-β1 secretion by B cells; and then TGF-β1 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-β-dependent mechanism.