Opposing effects of rapamycin and cyclosporin A on activation-induced Ca(2+) release.

Insofar as Ca(2+) plays a major role in T cell activation, we investigated the effect of the immunosuppressants cyclosporin A and rapamycin on T cell proliferation and on the activation-induced increase in [Ca(2+)](i). Both cyclosporin A and rapamycin inhibited mitogen (concanavalin A and phytohemagglutinin) and ionomycin+phorbol myristate acetate (PMA)-driven T cell proliferation (Ca(2+)-dependent). However, only rapamycin suppressed T cell proliferation stimulated by anti-CD28 antibody (Ab)+PMA, and recombinant interleukin-6-stimulated proliferation of the interleukin-6 dependent B9 cells (Ca(2+)-independent). These differences were associated with a different effect of both drugs on Ca(2+) release, as cyclosporin A attenuated while rapamycin augmented the mitogen-induced elevation in [Ca(2+)](i). Collectively, this supports the notion that Ca(2+) is required in early stages of T cell activation, and that cyclosporin A blocked only Ca(2+)-dependent while rapamycin blocked both Ca(2+)-dependent and -independent events of T cell activation.