T cell responses in calcineurin A alpha-deficient mice.
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.
Zhang
B W
BW
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zimmer
G
G
Chen
J
J
Ladd
D
D
Li
E
E
Alt
F W
FW
Wiederrecht
G
G
Cryan
J
J
O'Neill
E A
EA
Seidman
C E
CE
Abbas
A K
AK
Seidman
J G
JG
D000818:Animals; D001483:Base Sequence; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002678:Chimera; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D010749:Phosphoprotein Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D013234:Stem Cells; D013601:T-Lymphocytes / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008934:Mitogens; D011506:Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C038600:trinitrophenyl-ovalbumin; D007371:Interferon-gamma; D016572:Cyclosporine; D010047:Ovalbumin; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D016559:Tacrolimus