Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
Cell Rep. 2018 Apr 3;23(1):39-49. doi: 10.1016/j.celrep.2018.03.026.
In chronic infection and cancer, T cells acquire a dysfunctional state characterized by the expression of inhibitory receptors. In vitro studies implicated the phosphatase Shp-2 downstream of these receptors, including PD-1. However, whether Shp-2 is responsible in vivo for such dysfunctional responses remains elusive. To address this, we generated T cell-specific Shp-2-deficient mice. These mice did not show differences in controlling chronic viral infections. In this context, Shp-2-deleted CD8 T lymphocytes expanded moderately better but were less polyfunctional than control cells. Mice with Shp-2-deficient T cells also showed no significant improvement in controlling immunogenic tumors and responded similarly to controls to α-PD-1 treatment. We therefore showed that Shp-2 is dispensable in T cells for globally establishing exhaustion and for PD-1 signaling in vivo. These results reveal the existence of redundant mechanisms downstream of inhibitory receptors and represent the foundation for defining these relevant molecular events.
在慢性感染和癌症中，T 细胞获得一种功能失调的状态，其特征是表达抑制性受体。体外研究表明，这些受体（包括 PD-1）下游的磷酸酶 Shp-2 与之有关。然而，Shp-2 是否在体内负责这种功能失调的反应仍不清楚。为了解决这个问题，我们生成了 T 细胞特异性 Shp-2 缺陷型小鼠。这些小鼠在控制慢性病毒感染方面没有差异。在这种情况下，Shp-2 缺失的 CD8 T 淋巴细胞适度更好地扩增，但比对照细胞的多功能性差。缺乏 Shp-2 的 T 细胞的小鼠在控制免疫原性肿瘤方面也没有显著改善，并且对 α-PD-1 治疗的反应与对照小鼠相似。因此，我们表明 Shp-2 在 T 细胞中对于全面建立衰竭和体内的 PD-1 信号传导是可有可无的。这些结果揭示了抑制性受体下游存在冗余机制，并为定义这些相关分子事件奠定了基础。
