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.

中文翻译：

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调节性T细胞触发由代谢竞争引起的效应T细胞DNA损伤和衰老。

定义调节性T（Treg）细胞使用的抑制机制对于开发有效的治疗肿瘤和慢性感染的策略至关重要。目前尚不清楚在被Treg细胞抑制的应答性T细胞中发生的分子过程。在这里，我们显示人类Treg细胞在串扰期间由代谢竞争引起的效应T细胞中引发DNA损伤，从而导致衰老和功能变化，而这些变化在分子上与无能和力竭完全不同。ERK1 / 2和p38信号转导与STAT1和STAT3共同控制Treg诱导的效应T细胞衰老。可以通过抑制T细胞过继转移小鼠模型中的DNA损伤反应和/或STAT信号传导来防止人Treg诱导的T细胞衰老。