PD-1阻断增加了干细胞样CD8 T细胞的自我更新能力，以弥补它们加速分化为效应细胞的缺陷。
PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.
发表日期：2023 Aug 04
作者：
Amanda L Gill, Peter H Wang, Judong Lee, William H Hudson, Satomi Ando, Koichi Araki, Yinghong Hu, Andreas Wieland, Sejin Im, Autumn Gavora, Christopher B Medina, Gordon J Freeman, Masao Hashimoto, Steven L Reiner, Rafi Ahmed
来源：
Cell Death & Disease
摘要：
PD-1+TCF-1+干细胞样CD8 T细胞在维持慢性病毒感染和癌症中发挥着关键的资源细胞作用。此外，在程序性死亡蛋白1（PD-1）免疫疗法后，它们为效应T细胞提供了增殖突发。然而，目前不清楚免疫检查点阻断是否会随着效应细胞分化增加而减少这些干细胞样前体细胞的数量。为了研究这一点，我们使用小鼠慢性淋巴细胞性脑膜炎病毒（LCMV）感染模型。将慢性感染小鼠治疗于αPD-1或αPD-L1抗体，不仅增加了从病毒特异性干细胞样CD8 T细胞中的效应细胞分化，还增加了它们的增殖，因此它们的数量得到了维持。LCMV特异性干细胞样CD8 T细胞的增加自我更新依赖于mTOR。我们使用显微镜来了解这些前体细胞的分裂情况，发现在PD-1阻断后，一个分裂的细胞能够产生一个分化的TCF-1-细胞和一个自我更新的TCF-1+兄弟细胞。这种不对称分裂有助于保持干细胞样细胞的数量。此外，我们发现PD-1+TCF-1+干细胞样CD8 T细胞保留了它们的转录程序和它们对病毒感染和重复PD-1阻断的体内功能。总之，我们的研究结果表明，尽管增加了效应细胞分化，PD-1阻断并不会耗尽干细胞样人群的数量。这些发现对于PD-1免疫疗法在人类中具有重要意义。
PD-1+TCF-1+ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)-directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1- daughter cell alongside a self-renewing TCF-1+ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1+TCF-1+ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1-directed immunotherapy in humans.