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.

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We thank S. Yamamoto, S. Oonawa and Y. Doi for technical help; S. Kawamoto, T. Chaya, and T. Kozuka for the help with metabolome and brain dissection and preparations; S. Narumiya, T. Sato and K. Tanaka for discussions and suggestion; Y. Iwakura (Tokyo University of Science) and M. Kubo (IMS RIKEN) for Ifng−/− mice; B. Malissen (Centre d'Immunologie de Marseille-Luminy) for Cd3e−/− mice; and N. Lonberg (Bristol-Myers Squibb) for anti-PD-1. Supported by Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (14532135 to S.F.), Japan Agency for Medical Research and Development (145208 and 16770835 to T.H.) and the Cell Science Foundation (K.C).

Author information

Author notes

    • Michio Miyajima
    • , Baihao Zhang
    • , Yuki Sugiura
    •  & Kazuhiro Sonomura

    These authors contributed equally to this work.


  1. Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan.

    • Michio Miyajima
    • , Baihao Zhang
    • , Matteo M Guerrini
    • , Yumi Tsutsui
    • , Mikako Maruya
    • , Alexis Vogelzang
    • , Satomi Ito
    • , Keiichiro Suzuki
    •  & Sidonia Fagarasan
  2. Department of Immunology and Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Baihao Zhang
    • , Kenji Chamoto
    •  & Tasuku Honjo
  3. Department of Biochemistry and Integrative Biology, Keio University, Tokyo, Japan.

    • Yuki Sugiura
    • , Kurara Honda
    •  & Makoto Suematsu
  4. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • Kazuhiro Sonomura
    •  & Fumihiko Matsuda
  5. Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Takatoshi Hikida
  6. Department of Medical Genetics and Developmental Biology, 4th Military Medical University, Xi'an, China.

    • Hongyan Qin
  7. Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan.

    • Rikako Sanuki
    •  & Takahisa Furukawa
  8. Department of Molecular and Cellular Bioanalyses, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

    • Yasushi Ishihama


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M.Mi. performed most of the in vivo experiments; B.Z. performed all in vitro experiments and behavioral studies at Kyoto University facility; Y.S., K.So. and K.H. performed all metabolome analyses; M.M.G. performed quantitative PCR and 5-HT staining and collaborated in writing the manuscript; Y.T. and S.I. performed behavioral studies at the RIKEN IMS facility; M.Mi and M.Ma. performed all germ-free and gnotobiotic experiments; A.V. collaborated in the writing and revision of the manuscript; K.C. contributed to tumour and anti-PD-1 blockade experiments; T.Hi. contributed expertise in behavioral studies; H.Q. contributed initial observations of mouse behavior; R.S. performed brain-region dissection; K.Su. contributed to OT-I and OT-II in vivo experiments; T.F. Y.I., F.M., M.S. and T.Ho. contributed expertise in metabolome and behavioral studies and conceptual design; and S.F. conceived of the conceptual design, analyzed the results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sidonia Fagarasan.

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