SummaryWe have created embryonic stem (ES) cells and mice lacking the predominant isoform (or) of the calcineurin A subunit (CNAc~) to study the role of this serine/threonine phosphatase in the immune system. T and B cell maturation appeared to be normal in CNAct -/-mice. CNAc~ -/-T cells responded normally to mitogenic stimulation (i.e., PMA plus ionomycin, concanavalin A, and anti-CD3e antibody). However, CNAot -/-mice generated defective antigen-specific T cell responses in vivo. Mice produced from CNAot -/-ES cells injected into RAG-2-deficient blastocysts had a similar defective T cell response, indicating that CNAot is required for T cell function per se, rather than for an activity of other cell types involved in the immune response. CNAoL -/-T cells remained sensitive to both cyclosporin A and FK506, suggesting that CNA[3 or another CNA-hke molecule can mediate the action of these immunosuppressive drugs. CNAc, -/-mice provide an animal model for dissecting the physiologic functions of calcineurin as well as the effects of FK506 and CsA.

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