Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk
Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk
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DOI：
10.1016/j.immuni.2004.07.005
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发表时间：
2004-08-01
期刊：
影响因子：
32.4
通讯作者：
Luban, J
中科院分区：
文献类型：
--
作者：
Colgan, J;Asmal, M;Luban, J
亲环蛋白 A (CypA/Ppia) 是一种肽基脯氨酰异构酶 (PPlase)，可结合免疫抑制药物环孢菌素。由此产生的复合物通过抑制钙依赖性磷酸酶钙调神经磷酸酶来阻断 T 细胞功能。为了鉴定长期以来被怀疑调节信号转导的 CypA 的天然功能，我们培育了缺乏 Ppia 基因的小鼠。这些动物会出现过敏性疾病，伴有 IgE 升高以及肥大细胞和嗜酸性粒细胞组织浸润，这是由 CD4(+) T 辅助细胞 II 型 (Th2) 细胞因子驱动的。 Ppia(-/-) Th2 细胞对 TCR 刺激高度敏感，这种表型与 Itk 活性增加一致，Itk 是一种对 Th2 反应至关重要的 Tec 家族酪氨酸激酶。 CypA 通过 PPLase 活性位点结合 Itk。 Itk SH2 结构域中构象异质脯氨酸的突变破坏了与 CypA 的相互作用，并特别增加了野生型 CD4+ T 细胞的 Th2 细胞因子产生。因此，在没有环孢菌素的情况下，CypA 通过 Itk 中的调节性脯氨酸残基抑制 CD4(+) T 细胞信号转导。
Cyclophilin A (CypA/Ppia) is a peptidyl-prolyl isomerase (PPlase) that binds the immunosuppressive drug cyclosporine. The resulting complex blocks T cell function by inhibiting the calcium-dependent phosphatase calcineurin. To identify the native function of CypA, long suspected of regulating signal transduction, we generated mice lacking the Ppia gene. These animals develop allergic disease, with elevated IgE and tissue infiltration by mast cells and eosinophils, that is driven by CD4(+) T helper type II (Th2) cytokines. Ppia(-/-) Th2 cells were hypersensitive to TCR stimulation, a phenotype consistent with increased activity of Itk, a Tec family tyrosine kinase crucial for Th2 responses. CypA bound Itk via the PPlase active site. Mutation of a conformationally heterogeneous proline in the SH2 domain of Itk disrupted interaction with CypA and specifically increased Th2 cytokine production from wild-type CD4(+) T cells. Thus, CypA inhibits CD4(+) T cell signal transduction in the absence of cyclosporine via a regulatory proline residue in Itk.