Opposing effects of rapamycin and cyclosporin A on activation-induced Ca2+release

Insofar as Ca2+ plays a major role in T cell activation, we investigated th e effect of the immunosuppressants cyclosporin A and rapamycin on T cell pr oliferation and on the activation-induced increase in [Ca2+](i). Both cyclo sporin A and rapamycin inhibited mitogen (concanavalin A and phytohemagglut inin) and ionomycin + phorbol myristate acetate (PMA)-driven T cell prolife ration (Ca2+-dependent). However, only rapamycin suppressed T cell prolifer ation stimulated by anti-CD28 antibody (Ab) + PMA, and recombinant interleu kin-6-stimulated proliferation of the interleukin-6 dependent B9 cells (Ca2 +-independent). These differences were associated with a different effect o f both drugs on Ca2+ release, as cyclosporin A attenuated while rapamycin a ugmented the mitogen-induced elevation in [Ca2+](i). Collectively, this sup ports the notion that Ca2+ is required in early stages of T cell activation , and that cyclosporin A blocked only Ca2+-dependent while rapamycin blocke d both Ca2+-dependent and -independent events of T cell activation. (C) 199 9 Elsevier Science B.V. All rights reserved.