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

Abstract

Insofar as Ca2+ 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 [Ca2+]i. Both cyclosporin A and rapamycin inhibited mitogen (concanavalin A and phytohemagglutinin) and ionomycin+phorbol myristate acetate (PMA)-driven T cell proliferation (Ca2+-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 (Ca2+-independent). These differences were associated with a different effect of both drugs on Ca2+ release, as cyclosporin A attenuated while rapamycin augmented the mitogen-induced elevation in [Ca2+]i. Collectively, this supports the notion that Ca2+ is required in early stages of T cell activation, and that cyclosporin A blocked only Ca2+-dependent while rapamycin blocked both Ca2+-dependent and -independent events of T cell activation.