PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions
PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions
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DOI：
10.1016/j.jaut.2019.06.007
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发表时间：
2019-12-01
影响因子：
12.8
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Okamura, Hikari;Okazaki, Il-mi;Okazaki, Taku
抗PD-1治疗可以诱导人类和模型动物的肿瘤根除和免疫相关不良事件（irAE）。然而，抗PD-1治疗如何改变CD 8（+）T细胞的细胞表型以破坏肿瘤和损伤自身组织仍有待澄清。在此，我们对靶组织中PD-1抑制下或超过PD-1抑制的自身反应性CD 8（+）T细胞进行了单细胞mRNA表达谱分析，并重建了它们的激活轨迹。自身反应性CD 8（+）T细胞经历了四个活化阶段，PD-1强烈减弱了从第二阶段到第三阶段的过渡，在第三阶段获得了效应功能。自身反应性CD 8（+）T细胞簇组成的变化明显反映了自身免疫的严重程度。此外，在抗PD-1治疗中，沿着自身免疫中的激活轨迹沿着上调的基因在黑素瘤患者的应答者中高度表达，这表明肿瘤特异性T细胞需要以类似的轨迹被激活以在PD-1阻断后破坏人类患者中的肿瘤。这些发现表明，PD-1阻断促进了CD 8（+）T细胞的激活轨迹，以增强其效应功能。有针对性地操纵轨迹可能会带来新的治疗机会。
Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8(+) T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8(+) T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8(+) T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8(+) T cells markedly reflected the severity of autoimmunity. In addition, genes upregulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8(+) T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.