磷酸酶SHP-1和SHP-2在T细胞耗竭中的作用

T细胞耗竭常发生于慢性病毒感染和肿瘤进展过程当中，最终导致病毒不能被清除或者肿瘤不能被抑制。T细胞耗竭主要是由抑制性分子 (如PD-1) 介导的负调节。近年来PD-1/PD-L1的阻断性抗体已被成功用来逆转T细胞耗竭治疗肿瘤，但在某些肿瘤患者中疗效仍不如人意。.磷酸酶SHP-1和SHP-2是公认的PD-1信号通路下游分子。然而，对它们的机制研究主要来源于体外实验，对它们在体内如何调控T细胞耗竭知之甚少。最近有报道T细胞中SHP-2缺失的小鼠在慢性病毒感染中没有发生死亡。我们的前期实验结果也表明在T细胞中SHP-1/SHP-2双重缺失的小鼠也没有发生死亡。我们的体外细胞水平实验也证明双重缺失SHP-1/SHP-2的T细胞仍可对PD-L1刺激产生响应。这些结果提示PD-1信号通路中尚存在着完全未知的其他机制， 需要深入的研究。揭示这些机制不仅是学术问题，而且还具有重要的临床意义和应用前景。

T cell exhaustion often occurs in the course of chronic viral infection and tumor progression, which can result in viral persistence or failure of tumor control. Mechanistically, T cell exhaustion is mainly mediated by the negative regulation of inhibitory molecules such as PD-1. In recent years, PD-1 / PD-L1 blocking antibodies have been successfully used to reverse T cell exhaustion and restore T cell function in the treatment of tumors, however the efficacy is not satisfactory in patients with certain tumor types. Phosphatases SHP-2, to a lesser extent, SHP-1 are putatively recognized downstream effector molecules of the PD-1 signaling pathway. However, our understanding of their role in T cell exhaustion mainly derived from in vitro experiments using cell lines, and little is known about how they regulate T cell exhaustion in vivo. Recently, it has been reported that mice lacking SHP-2 in T cells did not die in a chronic viral infection model. Our preliminary results also showed that mice lacking SHP-2 and SHP-1 in T cells did not die in such infection model. Moreover, our recent published results showed that T cells with double deletion of SHP-1 / SHP-2 can still respond to PD-L1 stimulation in vitro. Together, these results strongly suggest that the signaling pathway of PD-L1 / PD-1 is far from clear as originally thought, and there are other mechanisms that we do not know yet, and warrant further research. Revealing these mechanisms is not only an academic interest, but also has important clinical significance and prospects for translational applications.