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

doi:10.1016/j.celrep.2017.10.082

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

Cell Rep. 2017 Nov 14;21(7):1824-1838. doi: 10.1016/j.celrep.2017.10.082.

Authors

Kayo Ikeda¹, Makoto Kinoshita², Hisako Kayama², Shushi Nagamori³, Pornparn Kongpracha³, Eiji Umemoto², Ryu Okumura², Takashi Kurakawa², Mari Murakami¹, Norihisa Mikami⁴, Yasunori Shintani⁵, Satoko Ueno⁶, Ayatoshi Andou⁷, Morihiro Ito⁸, Hideki Tsumura⁹, Koji Yasutomo¹⁰, Keiichi Ozono¹¹, Seiji Takashima⁵, Shimon Sakaguchi⁴, Yoshikatsu Kanai¹², Kiyoshi Takeda¹³

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁵ Department of Medical Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
⁶ Fundamental Technology Laboratory, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Japan.
⁷ Innovation Promotion Department, Research Institute, EA Pharma Co., Ltd., Kawasaki, Japan.
⁸ Department of Microbiology, College of Life and Health Science, Chubu University, Aichi, Japan.
⁹ Division of Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan.
¹⁰ Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
¹¹ Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
¹² Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.
¹³ 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. Electronic address: ktakeda@ongene.med.osaka-u.ac.jp.

PMID: 29141216
DOI: 10.1016/j.celrep.2017.10.082

Abstract

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.

Keywords: Treg cells; amino acids; immune regulation; immunometabolism; transporter.

MeSH terms

Amino Acids, Branched-Chain / metabolism*
Animals
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Fusion Regulatory Protein 1, Heavy Chain / genetics
Fusion Regulatory Protein 1, Heavy Chain / metabolism*
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
T-Lymphocytes, Regulatory / metabolism*

Substances

Amino Acids, Branched-Chain
Forkhead Transcription Factors
Foxp3 protein, mouse
Fusion Regulatory Protein 1, Heavy Chain
Slc3A2 protein, mouse
Mechanistic Target of Rapamycin Complex 1