Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation

The second messenger calcium plays an essential role in mediating the T-cell receptor (TCR) signaling pathway leading to cytokine production and T-cell clonal expansion. The immunosuppressive drugs cyclosporine A and FK506 have served both as therapeutic agents and as molecular probes for unraveling the protein phosphatase calcineurin as a rate-limiting enzyme involved in the transmission of calcium signal from the cytosol into the nucleus to reprogram gene expression. The use of mouse knockout models has helped to verify and further elucidate the functions of different isoforms of calcineurin in both helper T-cell activation and thymocyte development. In addition to calcineurin, three other classes of calmodulin-binding proteins have also been shown to play important roles in calcium signaling in T cells. Thus, Cabin1 and class II histone deacetylases have been found to constitute a novel calcium-signaling module in conjunction with the transcription factor myocyte enhance factor family and the transcriptional coactivator p300 to suppress and activate cytokine gene transcription in a calcium-dependent manner. The calmodulin-dependent protein kinases II and IV were also shown to play negative and positive regulatory functions, respectively, in TCR-mediated cytokine production. The crosstalks among these and other signal transducers in T cells form an extensive nonlinear signaling network that dictates the final outcome of the TCR signaling pathway.