Britton Graham J, Ambler Rachel, Clark Danielle J, Hill Elaine V, Tunbridge Helen M, McNally Kerrie E, Burton Bronwen R, Butterweck Philomena, Sabatos-Peyton Catherine, Hampton-O'Neil Lea A, Verkade Paul, Wülfing Christoph, Wraith David Cameron
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
School of Biochemistry, University of Bristol, Bristol, United Kingdom.
Elife. 2017 Jan 31;6:e20003. doi: 10.7554/eLife.20003.
Notch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The protein kinase PKCθ is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKCθ selectively inactivates the negative regulator of F-actin generation, Coronin 1A, at the center of the T cell interface with the antigen presenting cell (APC). This allows for effective generation of the large actin-based lamellum required for recruitment of the Notch-processing membrane metalloproteinase ADAM10. Such enhancement of Notch activation is critical for efficient T cell proliferation and Th17 differentiation. We reveal a novel mechanism that, through modulation of the cytoskeleton, controls Notch activation at the T cell:APC interface thereby linking T cell receptor and Notch signaling pathways.
Notch是T细胞分化的关键调节因子，通过蛋白水解切割响应配体结合而被激活。利用小鼠髓鞘反应性CD4 T细胞，我们证明近端T细胞信号传导通过时空受限机制调节Notch激活。蛋白激酶PKCθ是T细胞抗原受体和主要共刺激受体CD28信号传导的关键介质。PKCθ在T细胞与抗原呈递细胞（APC）界面的中心选择性地使F-肌动蛋白生成的负调节因子Coronin 1A失活。这允许有效生成募集Notch加工膜金属蛋白酶ADAM10所需的基于肌动蛋白的大薄片。这种Notch激活的增强对于有效的T细胞增殖和Th17分化至关重要。我们揭示了一种新机制，该机制通过调节细胞骨架，在T细胞：APC界面控制Notch激活，从而连接T细胞受体和Notch信号通路。
