SHP-1 调控 CD8+ T 细胞效应器功能,但由于阶段特异性非冗余功能中继,它与 SHP-2 在 T 细胞衰竭中发挥着微妙的作用

Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu
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摘要

SHP-1 (Src同源区2结构域磷酸酶1)是一个众所周知的T细胞负调控因子,而它的同源物SHP-2是长期以来公认的PD-1抑制途径的主要信号介质。然而,最近的研究质疑了PD-1信号传导对SHP-2的要求,后续研究进一步质疑了SHP-1可能在缺乏SHP-2的情况下取代SHP-2的另一种观点。在这项研究中,我们系统地研究了SHP-1单独或与SHP-2联合在一系列基因敲除小鼠的CD8+ T细胞中的作用。我们发现,尽管SHP-1在急性淋巴细胞性脉络丛脑膜炎病毒(LCMV)感染期间负调控CD8+ T细胞效应功能,但在慢性LCMV感染期间,它对CD8+ T细胞耗竭是必不可少的。此外,与PD-1敲除小鼠在慢性LCMV感染后的死亡率相反,CD8+ T细胞中SHP-1和SHP-2双重缺陷的小鼠存活而无免疫病理。重要的是,缺乏这两种磷酸酶的CD8+ T细胞仍然分化为衰竭细胞并对PD-1阻断作出反应。最后,我们发现SHP-1和SHP-2分别在慢性LCMV感染的早期和晚期抑制效应CD8+ T细胞的扩增。
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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
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.
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