Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes.

Overview

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.