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
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
