作者
Yuying Liu,Nannan Zhou,Li Zhou,Jing Wang,Yabo Zhou,Tianzhen Zhang,Yi Fang,Jinwei Deng,Yahui Gao,Xiaoyu Liang,Jiadi Lv,Zhenfeng Wang,Jing Xie,Yuanbo Xue,Huafeng Zhang,Jingwei Ma,Ke Tang,Yiliang Fang,Feiran Cheng,Chengjuan Zhang,Bing Dong,Yuzhou Zhao,Peng Yuan,Quanli Gao,Haizeng Zhang,F. Xiao-Feng Qin,Bo Huang
摘要
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. IL-2 is a classic T cell growth factor. Huang and colleagues demonstrate, however, that chronic IL-2 stimulation leads to a new exhaustion pathway that impairs antitumor immune responses.