Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling.
Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling.
复制标题
作者：
T 细胞受体 (TCR) 信号传导由 Src 家族激酶 (SFK) 启动。为了了解 SFK 的负调节因子 C 末端 Src 激酶 (Csk) 如何控制基础状态和 TCR 信号传导的启动，我们培育了表达 PP1 类似物抑制剂敏感 Csk 变体 (CskAS) 的小鼠。在没有 TCR 参与的情况下，抑制胸腺细胞中的 CskAS 可诱导有效的 SFK 激活和近端 TCR 信号传导至磷脂酶 C-γ1 (PLC-γ1)。令人惊讶的是，磷酸肌醇 (InsP)、细胞内钙和 Erk 磷酸化的增加受到损害。通过药理学改变肌动蛋白细胞骨架或提供 CD28 共刺激可以挽救这些缺陷。因此，Csk 在阻止 TCR 信号传导方面发挥着关键作用。然而，我们的研究还揭示了完整 TCR 信号传导需要由共刺激引发的肌动蛋白重塑。
T cell receptor (TCR) signaling is initiated by Src-family kinases (SFKs). To understand how C-terminal Src kinase (Csk), the negative regulator of SFKs, controls the basal state and the initiation of TCR signaling, we generated mice expressing a PP1-analog inhibitor-sensitive Csk variant (CskAS). Inhibition of CskAS in thymocytes, without TCR engagement, induced potent SFK activation and proximal TCR signaling up to phospholipase C-γ1 (PLC-γ1). Surprisingly, increases in inositol phosphates (InsP), intracellular calcium and Erk phosphorylation were impaired. Altering the actin cytoskeleton pharmacologically or providing CD28 costimulation rescued these defects. Thus, Csk plays a critical role in preventing TCR signaling. However, our studies also revealed a requirement for actin remodeling, initiated by costimulation, for full TCR signaling.