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Nat Immunol. 2017 Dec;18(12):1342-1352. doi: 10.1038/ni.3867. Epub 2017 Oct 23.

Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior.

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Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan.
Department of Immunology and Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Biochemistry and Integrative Biology, Keio University, Tokyo, Japan.
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Medical Genetics and Developmental Biology, 4th Military Medical University, Xi'an, China.
Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan.
Department of Molecular and Cellular Bioanalyses, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.


T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1-/- mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1-/- T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.

[Indexed for MEDLINE]

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