Zhang B W, Zimmer G, Chen J, Ladd D, Li E, Alt F W, Wiederrecht G, Cryan J, O'Neill E A, Seidman C E, Abbas A K, Seidman J G
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Exp Med. 1996 Feb 1;183(2):413-20. doi: 10.1084/jem.183.2.413.
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.
我们创建了缺乏钙调神经磷酸酶A亚基（CNAα）主要同工型（α）的胚胎干细胞（ES）和小鼠，以研究这种丝氨酸/苏氨酸磷酸酶在免疫系统中的作用。CNAα-/-小鼠的T和B细胞成熟似乎正常。CNAα-/-T细胞对有丝分裂原刺激（即佛波酯加离子霉素、刀豆球蛋白A和抗CD3ε抗体）反应正常。然而，CNAα-/-小鼠在体内产生有缺陷的抗原特异性T细胞反应。将CNAα-/-ES细胞注射到RAG-2缺陷囊胚中产生的小鼠有类似的缺陷T细胞反应，这表明CNAα本身是T细胞功能所必需的，而不是免疫反应中其他细胞类型的活性所必需的。CNAα-/-T细胞对环孢素A和FK506均保持敏感，这表明CNAβ或另一种类似CNA的分子可以介导这些免疫抑制药物的作用。CNAα-/-小鼠为剖析钙调神经磷酸酶的生理功能以及FK506和环孢素A的作用提供了一个动物模型。
