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T cell responses in calcineurin A alpha-deficient mice.

1996; Rockefeller University Press; Volume: 183; Issue: 2 Linguagem: Inglês

10.1084/jem.183.2.413

1540-9538

B W Zhang, Geraldine Zimmer‐Bensch, Jue Chen, Daniel Ladd, Erguang Li, Frederick W. Alt, Greg Wiederrecht, John G. Cryan, Edward A. O’Neill, Christine E. Seidman, Abul K. Abbas, J G Seidman,

RNA Interference and Gene Delivery

We have created embryonic stem (ES) cells and mice lacking the predominant isoform (alpha) of the calcineurin A subunit (CNA alpha) to study the role of this serine/threonine phosphatase in the immune system. T and B cell maturation appeared to be normal in CNA alpha -/- mice. CNA alpha -/- T cells responded normally to mitogenic stimulation (i.e., PMA plus ionomycin, concanavalin A, and anti-CD3 epsilon antibody). However, CNA alpha -/- mice generated defective antigen-specific T cell responses in vivo. Mice produced from CNA alpha -/- ES cells injected into RAG-2-deficient blastocysts had a similar defective T cell response, indicating that CNA alpha is required for T cell function per se, rather than for an activity of other cell types involved in the immune response. CNA alpha -/- T cells remained sensitive to both cyclosporin A and FK506, suggesting that CNA beta or another CNA-like molecule can mediate the action of these immunosuppressive drugs. CNA alpha -/- mice provide an animal model for dissecting the physiologic functions of calcineurin as well as the effects of FK506 and CsA.