Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes
Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes
复制标题
DOI：
10.1038/s41586-022-05388-4
复制
发表时间：
2022-11-02
期刊：
影响因子：
64.8
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Wang, Teh-Wei;Johmura, Yoshikazu;Nakanishi, Makoto
衰老细胞的积累是与年龄相关的炎症的主要原因，并易患各种与年龄相关的疾病（1）。然而，人们对这种积累的分子基础及其作为改善衰老过程的目标的潜力知之甚少。在这里，我们表明衰老细胞不均匀表达免疫检查点蛋白程序性死亡配体1（PD-L1），并且PD-L1（+）衰老细胞在体内随着年龄的增长而积累。PD-L1（-）细胞对T细胞监视敏感，而PD-L1（+）细胞即使在存在衰老相关分泌表型（SASP）的情况下也具有抗性。体内p16（+）细胞的单细胞分析显示，PD-L1表达与较高水平的SASP相关。与此一致，向自然衰老小鼠或具有正常肝脏或诱导的非酒精性脂肪性肝炎的小鼠模型给予程序性细胞死亡蛋白1（PD-1）抗体，以活化的CD 8（+）T细胞依赖性方式减少体内p16（+）细胞总数以及PD-L1（+）群体，改善各种衰老相关表型。这些结果表明，PD-L1的异质性表达在衰老细胞的积累和与衰老相关的炎症中具有重要作用，通过免疫检查点阻断消除PD-L1（+）衰老细胞可能是抗衰老治疗的一种有前景的策略。
The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases(1). However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1(+) senescent cells accumulate with age in vivo. PD-L1(-) cells are sensitive to T cell surveillance, whereas PD-L1(+) cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16(+) cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16(+) cells in vivo as well as the PD-L1(+) population in an activated CD8(+) T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1(+) senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.