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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5-Hydroxytryptophan / metabolism
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Animals
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Antibodies, Neutralizing / pharmacology
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Antineoplastic Agents / pharmacology
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Basic Helix-Loop-Helix Transcription Factors / deficiency
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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CD8-Positive T-Lymphocytes / drug effects*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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HEK293 Cells
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Humans
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / genetics
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Interleukin-2 / metabolism*
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Jurkat Cells
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Lymphocytes, Tumor-Infiltrating / drug effects*
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / metabolism
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MCF-7 Cells
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / immunology
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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NIH 3T3 Cells
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Neoplasms / drug therapy
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Neoplasms / immunology
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Neoplasms / metabolism*
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Neoplasms / pathology
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Receptors, Aryl Hydrocarbon / deficiency
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Receptors, Aryl Hydrocarbon / genetics
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Receptors, Aryl Hydrocarbon / metabolism*
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Signal Transduction
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Tryptophan Hydroxylase / metabolism
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Tumor Microenvironment*
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Xenograft Model Antitumor Assays
Substances
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AHR protein, human
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Ahr protein, mouse
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Antibodies, Neutralizing
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Antineoplastic Agents
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Basic Helix-Loop-Helix Transcription Factors
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IL2 protein, human
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Interleukin-2
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Receptors, Aryl Hydrocarbon
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5-Hydroxytryptophan
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TPH1 protein, human
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Tph1 protein, mouse
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Tryptophan Hydroxylase