Rigulation of T cell activation by intro-cellular phosphatase calcineurin

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We studied regulatory roles of intra-cellular phosphatase, calcineurin. Calcineurin is calcium-calmodulin-dependent phosphatase, and known to be a target of immunosuppressive drug, FK506 and Cyclosporin A.It consists of A and B chains.Here we generated a dominant-negative from of murine calcineurin, and established transgenic mice. We used lck-distal promoter for making transgenic mouse in order to direct high expression of transgenic mutant Lck molecules in T lymphocyte. We obtained three lines with different copy numbers. From analyzes with these mice, we found that 1) total cell number of thymocyte was decreased at 30-50%, 2) CD4/CD8 profiles were not significantly changed, 3) mature T cell response to produce cytokines against anti-TCR mAb was decreased, suggesting essential roles of calcineurin for T cell activation in mature T cells, and 3) calcium influx upon TCR ligation was not affected. From these results, calcineurin appeared to essntial for T cell activation upon antigen recognition by TCR.