Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Kayo Ikeda; Makoto Kinoshita; Hisako Kayama; Shushi Nagamori; Pornparn Kongpracha; Eiji Umemoto; Ryu Okumura; Takashi Kurakawa; Mari Murakami; Norihisa Mikami; Yasunori Shintani; Satoko Ueno; Ayatoshi Andou; Morihiro Ito; Hideki Tsumura; Koji Yasutomo; Keiichi Ozono; Seiji Takashima; Shimon Sakaguchi; Yoshikatsu Kanai; Kiyoshi Takeda

Cell Reports (Nov 2017)

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Kayo Ikeda,
Makoto Kinoshita,
Hisako Kayama,
Shushi Nagamori,
Pornparn Kongpracha,
Eiji Umemoto,
Ryu Okumura,
Takashi Kurakawa,
Mari Murakami,
Norihisa Mikami,
Yasunori Shintani,
Satoko Ueno,
Ayatoshi Andou,
Morihiro Ito,
Hideki Tsumura,
Koji Yasutomo,
Keiichi Ozono,
Seiji Takashima,
Shimon Sakaguchi,
Yoshikatsu Kanai,
Kiyoshi Takeda

Affiliations

Kayo Ikeda: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Makoto Kinoshita: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan
Hisako Kayama: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan
Shushi Nagamori: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan; Laboratory of Biomolecular Dynamics, Department of Collaborative Research, Nara Medical University, Nara, Japan
Pornparn Kongpracha: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan; Laboratory of Biomolecular Dynamics, Department of Collaborative Research, Nara Medical University, Nara, Japan
Eiji Umemoto: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan
Ryu Okumura: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan
Takashi Kurakawa: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan
Mari Murakami: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Norihisa Mikami: Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
Yasunori Shintani: Department of Medical Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Satoko Ueno: Fundamental Technology Laboratory, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Japan
Ayatoshi Andou: Innovation Promotion Department, Research Institute, EA Pharma Co., Ltd., Kawasaki, Japan
Morihiro Ito: Department of Microbiology, College of Life and Health Science, Chubu University, Aichi, Japan
Hideki Tsumura: Division of Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan
Koji Yasutomo: Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan
Keiichi Ozono: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Seiji Takashima: Department of Medical Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Shimon Sakaguchi: Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
Yoshikatsu Kanai: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan
Kiyoshi Takeda: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan; Corresponding author

Journal volume & issue: Vol. 21, no. 7
pp. 1824 – 1838

Abstract

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Summary: Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation. : Treg cells regulate excess immune responses and are highly proliferative in vivo. Ikeda et al. find that branched-chain amino acids (BCAAs) are essentially required to maintain expansion and the suppressive capacity of Treg cells via Slc3a2 and mTORC1. Keywords: Treg cells, amino acids, immunometabolism, immune regulation, transporter

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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