Experimental Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria.
J Autoimmun. 2011 Nov;37(3):198-208. doi: 10.1016/j.jaut.2011.05.018. Epub 2011 Jun 22.
Transforming growth factor β (TGFβ) plays a central role in maintaining immune homeostasis by regulating the initiation and termination of immune responses and thus preventing the development of autoimmune diseases. In this study, we describe an essential mechanism by which the actin regulatory protein Coronin 1A (Coro1A) ensures the proper response of Th17 CD4(+) T cells to TGFβ. Coro1A has been established as a key player in T cell survival, migration, activation, and Ca(2+) regulation in naive T cells. We show that mice lacking Coro1a developed less severe experimental autoimmune encephalomyelitis (EAE). Unexpectedly, upon the re-induction of EAE, Coro1a(-/-) mice exhibited enhanced EAE signs that correlated with increased numbers of IL-17 producing CD4(+) cells in the central nervous system (CNS) compared to wild-type mice. In vitro differentiated Coro1a(-/-) Th17 CD4(+) T cells consistently produced more IL-17 than wild-type cells and displayed a Th17/Th1-like phenotype in regard to the expression of the Th1 markers T-bet and IFNγ. Mechanistically, the Coro1a(-/-) Th17 cell phenotype correlated with a severe defect in TGFβR-mediated SMAD3 activation. Taken together, these data provide experimental evidence of a non-redundant role of Coro1A in the regulation of Th17 CD4(+) cell effector functions and, subsequently, in the development of autoimmunity.
转化生长因子 β（TGFβ）通过调节免疫反应的启动和终止，在维持免疫稳态方面发挥核心作用，从而防止自身免疫性疾病的发生。在本研究中，我们描述了肌动蛋白调节蛋白 Coronin 1A（Coro1A）确保 Th17 CD4（+）T 细胞对 TGFβ 产生适当反应的基本机制。Coro1A 已被确定为幼稚 T 细胞中 T 细胞存活、迁移、激活和 Ca（2+）调节的关键因子。我们发现缺乏 Coro1a 的小鼠发生实验性自身免疫性脑脊髓炎（EAE）的程度较轻。出乎意料的是，在重新诱导 EAE 后，与野生型小鼠相比，Coro1a（-/-）小鼠表现出增强的 EAE 迹象，这与中枢神经系统（CNS）中产生更多 IL-17 的 CD4（+）细胞数量增加相关。体外分化的 Coro1a（-/-）Th17 CD4（+）T 细胞始终比野生型细胞产生更多的 IL-17，并在 Th1 标志物 T-bet 和 IFNγ的表达方面表现出 Th17/Th1 样表型。从机制上讲，Coro1a（-/-）Th17 细胞表型与 TGFβR 介导的 SMAD3 激活的严重缺陷相关。综上所述，这些数据提供了实验证据，表明 Coro1A 在调节 Th17 CD4（+）细胞效应功能以及随后的自身免疫发展中具有非冗余作用。
