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

被引：105

作者：

Ikeda, Kayo ^{[1
,2
,3
]}

Kinoshita, Makoto ^{[1
,2
]}

Kayama, Hisako ^{[1
,2
]}

Nagamori, Shushi ^{[4
,5
]}

Kongpracha, Pornparn ^{[4
,5
]}

Umemoto, Eiji ^{[1
,2
]}

Okumura, Ryu ^{[1
,2
]}

Kurakawa, Takashi ^{[1
,2
]}

Murakami, Mari ^{[1
,2
,3
]}

Mikami, Norihisa ^{[6
]}

Shintani, Yasunori ^{[7
]}

Ueno, Satoko ^{[8
]}

Andou, Ayatoshi ^{[9
]}

Ito, Morihiro ^{[10
]}

Tsumura, Hideki ^{[11
]}

Yasutomo, Koji ^{[12
]}

Ozono, Keiichi ^{[3
]}

Takashima, Seiji ^{[7
]}

Sakaguchi, Shimon ^{[6
]}

Kanai, Yoshikatsu ^{[4
]}

Takeda, Kiyoshi ^{[1
,2
]}

机构：

[1] Osaka Univ, WPI Immunol Frontier Res Ctr, Grad Sch Med, Lab Immune Regulat,Dept Microbiol & Immunol, Suita, Osaka, Japan

[2] Japan Agcy Med Res & Dev, Core Res Evolut Sci & Technol, Tokyo, Japan

[3] Osaka Univ, Grad Sch Med, Dept Pediat, Suita, Osaka, Japan

[4] Osaka Univ, Grad Sch Med, Dept Biosyst Pharmacol, Suita, Osaka, Japan

[5] Nara Med Univ, Dept Collaborat Res, Lab Biomol Dynam, Nara, Japan

[6] Osaka Univ, WPI Immunol Frontier Res Ctr, Dept Expt Immunol, Suita, Osaka, Japan

[7] Osaka Univ, Grad Sch Med, Dept Med Biochem, Suita, Osaka, Japan

[8] Ajinomoto Co Inc, Inst Innovat, Fundamental Technol Lab, Kawasaki, Kanagawa, Japan

[9] EA Pharma Co Ltd, Res Inst, Innovat Promot Dept, Kawasaki, Kanagawa, Japan

[10] Chubu Univ, Coll Life & Hlth Sci, Dept Microbiol, Kasugai, Aichi, Japan

[11] Natl Res Inst Child Hlth & Dev, Div Anim Resources, Tokyo, Japan

[12] Tokushima Univ, Grad Sch Med, Dept Immunol & Parasitol, Tokushima, Japan

来源：

CELL REPORTS | 2017年 / 21卷 / 07期

基金：

日本科学技术振兴机构;

关键词：

SELF-TOLERANCE; MTOR KINASE; HEAVY-CHAIN; CD98; TRANSPORTER; ACTIVATION; EFFECTOR; DIFFERENTIATION; AUTOIMMUNITY; INFLAMMATION;

D O I：

10.1016/j.celrep.2017.10.082

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 Foxp(3+) Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp(3+) 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.

引用

页码：1824 / 1838

页数：15

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