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.

中文翻译：

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SHP-1 调节 CD8+ T 细胞效应器功能，但由于阶段特异性非冗余功能中继，在 T 细胞耗竭中与 SHP-2 一起发挥微妙作用


摘要 SHP-1（含Src同源区2结构域的磷酸酶1）是众所周知的T细胞负调节因子，而其密切同源物SHP-2是长期以来公认的PD-1抑制途径的主要信号传导介质。然而，最近的研究对 PD-1 信号传导中 SHP-2 的需求提出了质疑，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。在本研究中，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）感染期间负向调节CD8+ T细胞效应功能，但它对于慢性LCMV感染期间CD8+ T细胞耗竭却是可有可无的。此外，与慢性 LCMV 感染后 PD-1 敲除小鼠的死亡率相反，CD8+ T 细胞中 SHP-1 和 SHP-2 双缺陷的小鼠在没有免疫病理学的情况下存活下来。重要的是，缺乏两种磷酸酶的 CD8+ T 细胞仍会分化为衰竭细胞并对 PD-1 阻断做出反应。最后，我们发现在慢性 LCMV 感染过程中，SHP-1 和 SHP-2 分别在早期和晚期抑制效应 CD8+ T 细胞的扩增。