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

Yuying Liu # 1 2, Nannan Zhou # 1, Li Zhou # 1, Jing Wang # 3, Yabo Zhou 1, Tianzhen Zhang 1, Yi Fang 3, Jinwei Deng 4, Yunfeng Gao 1, Xiaoyu Liang 1, Jiadi Lv 1, Zhenfeng Wang 1, Jing Xie 1, Yuanbo Xue 5 6, Huafeng Zhang 7, Jingwei Ma 7, Ke Tang 7, Yiliang Fang 1, Feiran Cheng 1, Chengjuan Zhang 8 9, Bing Dong 10, Yuzhou Zhao 11, Peng Yuan 12, Quanli Gao 13, Haizeng Zhang 3, F Xiao-Feng Qin 14, Bo Huang 15 16 17

Nat Immunol. 2021 Mar;22(3):358-369. doi: 10.1038/s41590-020-00850-9. Epub 2021 Jan 11.

PMID: 33432230

Abstract

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.