Recruitment of calcineurin to the T cell receptor positively regulates T cell activation

Abstract Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and its inhibition with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we show that calcineurin is recruited to the T cell receptor signaling complex where it reverses the inhibitory phosphorylation of Lck on Ser-59 (LckS59). Loss of calcineurin activity impaired phosphorylation of ZAP-70Y493 and some downstream pathways in a manner consistent with signaling in cells expressing LckS59A (non-phosphorylatable) or LckS59E (phosphomimetic). Importantly, CsA inhibited activation-induced LFA-1-dependent and NFAT-independent adhesion of T cells to ICAM-1, with little effect on cells expressing mutant Lck. These results provide a new understanding of how widely-used immunosuppressive drugs interfere with essential processes in the immune response.