SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay
Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Cong Yu, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hongrui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu
Abstract
SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.