INTRACELLULAR CA2-A SYNERGISTICALLY INDUCE TGF-BETA-1-MEDIATED APOPTOSIS IN LYMPHOCYTES( ELEVATION AND CYCLOSPORINE)

Apoptosis plays an essential role in the development and homeostasis o f the immune system. During lymphocyte development, potentially autore active 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 eliminatin g activated lymphocytes. However, differences in susceptibility to sig nal-induced apoptosis between immature and mature lymphocytes are nume rous. One well-characterized example occurs in response to Ca2+ elevat ion: peripheral T lymphocytes are resistant, while immature thymocytes are highly susceptible, to Ca2+-mediated cell death (CMCD). In this s tudy, we show that the immunosuppressant cyclosporin A (CsA) primes sp lenic lymphocytes to undergo CMCD upon ionomycin stimulation. This CsA -induced CMCD affected both T and B lymphocytes. CsA-plug Ca2+-mediate d 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-be ta 1 and Ca2+ synergistically triggered T and B lymphocyte apoptosis. Together, our results suggest that lymphocyte apoptosis may play a rol e in CsA-induced immunosuppression via a TGF-beta-dependent mechanism.