PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity
PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity
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DOI：
10.1038/s41590-019-0480-4
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发表时间：
2019-10-01
影响因子：
30.5
通讯作者：
Sharpe, Arlene H.
中科院分区：
文献类型：
--
作者：
LaFleur, Martin W.;Nguyen, Thao H.;Sharpe, Arlene H.
CD8+ T细胞耗竭是慢性病毒感染和癌症中获得的一种功能障碍状态，其特征是通过未知机制形成Slamf6+祖细胞耗竭和Tim-3(+)终末耗竭亚群。在这里，我们将磷酸酶 PTPN2 确立为终末衰竭亚群分化的新调节因子，其通过减弱 1 型干扰素信号传导发挥作用。在淋巴细胞性脉络丛脑膜炎病毒克隆13感染期间，CD8+T细胞中Ptpn2的缺失增加了Tim-3(+)细胞的生成、增殖能力和细胞毒性，而不改变Slamf6(+)数量。同样，CD8+T细胞中Ptpn2的缺失增强了Tim-3+抗肿瘤反应并改善了肿瘤控制。整个免疫系统中 Ptpn2 的缺失导致 MC38 肿瘤被清除，并改善了对 B16 肿瘤的程序性细胞死亡 1 检查点阻断反应。我们的结果表明，增加细胞毒性Tim-3(+)CD8(+) T细胞的数量可以促进有效的抗肿瘤免疫，并表明免疫细胞中的PTPN2是一个有吸引力的癌症免疫治疗靶点。
CD8(+) Tcell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3(+) terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8(+) Tcells increased the generation, proliferative capacity and cytotoxicity of Tim-3(+) cells without altering Slamf6(+) numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8(+) Tcells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3(+)CD8(+) Tcells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.