期刊
NATURE IMMUNOLOGY
卷 22, 期 3, 页码 358-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-020-00850-9
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资金
- National Natural Science Foundation of China [81788101, 81773062, 91942314]
- Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS-I2M) [2016-I2M-1-007]
IL-2 acts as an environmental cue to induce CD8(+) T cell exhaustion within tumor microenvironments by activating STAT5, inducing tryptophan hydroxylase 1, and subsequently causing T cell dysfunction.
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.
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