Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
Department of Chemistry, University of Southern California, California, USA.
Nat Immunol. 2014 Feb;15(2):186-94. doi: 10.1038/ni.2772. Epub 2013 Dec 8.
Signaling via the T cell antigen receptor (TCR) is initiated by Src-family kinases (SFKs). To understand how the kinase Csk, a negative regulator of SFKs, controls the basal state and the initiation of TCR signaling, we generated mice that express a Csk variant sensitive to an analog of the common kinase inhibitor PP1 (Csk(AS)). Inhibition of Csk(AS) in thymocytes, without engagement of the TCR, induced potent activation of SFKs and proximal TCR signaling up to phospholipase C-γ1 (PLC-γ1). Unexpectedly, increases in inositol phosphates, intracellular calcium and phosphorylation of the kinase Erk were impaired. Altering the actin cytoskeleton pharmacologically or providing costimulation via CD28 'rescued' those defects. Thus, Csk has a critical role in preventing TCR signaling. However, our studies also revealed a requirement for actin remodeling, initiated by costimulation, for full TCR signaling.
通过 T 细胞抗原受体 (TCR) 的信号转导是由 Src 家族激酶 (SFKs) 启动的。为了了解激酶 Csk（SFKs 的负调控因子）如何控制 TCR 信号转导的基础状态和启动，我们生成了表达对常见激酶抑制剂 PP1 的类似物敏感的 Csk 变体的小鼠（Csk(AS)）。在不结合 TCR 的情况下，Csk(AS) 的抑制在胸腺细胞中诱导了 SFKs 和近端 TCR 信号的强烈激活，直至磷脂酶 C-γ1 (PLC-γ1)。出乎意料的是，肌醇磷酸盐、细胞内钙和激酶 Erk 的磷酸化增加受到损害。通过药理学改变肌动球蛋白细胞骨架或通过 CD28 提供共刺激“挽救”了这些缺陷。因此，Csk 在防止 TCR 信号转导中具有关键作用。然而，我们的研究还揭示了肌动球蛋白重塑的需求，该重塑由共刺激启动，以实现完全的 TCR 信号转导。
