IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor

作者：Liu, Yuying; Zhou, Nannan; Zhou, Li; Wang, Jing; Zhou, Yabo; Zhang, Tianzhen; Fang, Yi; Deng, Jinwei; Gao, Yunfeng; Liang, Xiaoyu; Lv, Jiadi; Wang, Zhenfeng; Xie, Jing; Xue, Yuanbo; Zhang, Huafeng; Ma, Jingwei; Tang, Ke; Fang, Yiliang; Cheng, Feiran; Zhang, Chengjuan; Dong, Bing; Zhao, Yuzhou; Yuan, Peng; Gao, Quanli; Zhang, Haizeng; Xiao-Feng Qin, F.; Huang, Bo^*

来源：Nature Immunology, 2021, 22(3): 358-+.

DOI：10.1038/s41590-020-00850-9

• PD-1 EXPRESSION
• INTERLEUKIN-2
• DIFFERENTIATION
• PROLIFERATION
• HOMEOSTASIS
• INDUCTION
• TOLERANCE
• EFFECTOR
• LIMITS
• TIM-3

CD8(+) T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8(+) T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8(+) T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8(+) T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.

• 单位
  郑州大学; 南方医科大学; 华中科技大学; 中国医学科学院