浙江大学鲁林荣课题组与清华刘万里课题组合作发文阐明TCR信号调控新机制

       2017年6月9日，国际学术权威刊物自然出版集团旗下子刊《Nature Communications》杂志上在线发表了浙江大学医学院鲁林荣教授课题组和清华大学生命科学学院刘万里教授研究组合作的一篇研究论文。论文题为“Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors”，研究阐明了T 细胞发育相关蛋白Tesap1调控TCR下游钙信号传导的调控机制。本文的第一作者为博士生梁静静和吕俊，本文的通讯作者为鲁林荣教授和清华大学刘万里教授。

       T细胞是一类在胸腺中发育成熟的关键免疫细胞。胸腺T细胞发育的后期依赖其表面抗原受体(TCR)的信号。TCR信号的调节对T细胞的成熟至关重要，不仅能决定T细胞对抗原的特异性反应，还帮助建立其对机体自身的耐受。因此胸腺T细胞发育过程中TCR信号的调节机制一直是T细胞免疫学的研究重点。

       鲁林荣教授课题组于2012年在《Nature Immunology》发表了题为“Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling.”的论文，发现并命名一个参与T 细胞发育调控的新分子Tespa1。本研究在原有的研究基础上进一步阐明了Tespa1的作用 分子机制：当TCR接受信号后，Tespa1通过与TCR信号复合体中磷脂酶PLCg1的结合参与TCR信号复合体的组装;与此同时，Tespa1能通过其PFF基序特异性结合内质网上钙离子通道IP3R，从而将IP3R招募至TCR复合体附近。IP3R在TCR信号复合物附近的重新定位，不但直接促进细胞膜上的激酶Fyn对IP3R的磷酸化，而且加速了其与配体IP3的结合，确保钙离子信号的快速高效启动。这一工作不仅阐明了Tespa1对TCR信号的调控机制， 而且揭示了钙离子通道的空间分布在TCR信号传导中的重要性。

Working Model：Tespa1 regulates TCR-induced calcium flux through the recruitment of IP3R to TCR signaling complex.

原文链接：

        Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR-induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, wher IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1-F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1.