Liu Xia, Mo Wei, Ye Jian, Li Lingyun, Zhang Yanping, Hsueh Eddy C, Hoft Daniel F, Peng Guangyong
Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA.
Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, St Louis, MO, 63110, USA.
Nat Commun. 2018 Jan 16;9(1):249. doi: 10.1038/s41467-017-02689-5.
Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence. Human Treg-induced T-cell senescence can be prevented via inhibition of the DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify molecular mechanisms of human Treg cell suppression and indicate that targeting Treg-induced T-cell senescence is a checkpoint for immunotherapy against cancer and other diseases associated with Treg cells.
明确调节性T（Treg）细胞所使用的抑制机制对于制定治疗肿瘤和慢性感染的有效策略至关重要。Treg细胞抑制的反应性T细胞中发生的分子过程尚不清楚。在这里，我们表明，人类Treg细胞在相互作用过程中通过代谢竞争在效应T细胞中引发DNA损伤，导致衰老和功能变化，这些变化在分子上与无反应性和耗竭不同。ERK1/2和p38信号通路与STAT1和STAT3协同作用，以控制Treg诱导的效应T细胞衰老。在T细胞过继转移小鼠模型中，通过抑制DNA损伤反应和/或STAT信号通路，可以预防人类Treg诱导的T细胞衰老。这些研究确定了人类Treg细胞抑制的分子机制，并表明靶向Treg诱导的T细胞衰老是针对癌症和其他与Treg细胞相关疾病的免疫治疗的一个检查点。
