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

被引：97

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

共 42 条

[1] Isoleucine and Leucine Independently Regulate mTOR Signaling and Protein Synthesis in MAC-T Cells and Bovine Mammary Tissue Slices
Appuhamy, J. A. D. Ranga Niroshan
Knoebel, Nicole A.
Nayananjalie, W. A. Deepthi
Escobar, Jeffery
Hanigan, Mark D.
[J]. JOURNAL OF NUTRITION, 2012, 142 (03) : 484 - 491
[2] Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells
Battaglia, M
Stabilini, A
Roncarolo, MG
[J]. BLOOD, 2005, 105 (12) : 4743 - 4748
[3] CD98hc regulates the development of experimental colitis by controlling effector and regulatory CD4+ T cells
Bhuyan, Zaied Ahmed
Arimochi, Hideki
Nishida, Jun
Kataoka, Keiko
Kurihara, Takeshi
Ishifune, Chieko
Tsumura, Hideki
Ito, Morihiro
Ito, Yasuhiko
Kitamura, Akiko
Yasutomo, Koji
[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2014, 444 (04) : 628 - 633
[4] Identification of LAT4, a novel amino acid transporter with system L activity
Bodoy, S
Martín, L
Zorzano, A
Palacín, M
Estévez, R
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (12) : 12002 - 12011
[5] Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder
Bröer, A
Klingel, K
Kowalczuk, S
Rasko, JEJ
Cavanaugh, J
Bröer, S
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (23) : 24467 - 24476
[6] BURNS CP, 1975, BLOOD, V45, P643
[7] Branched-chain amino acids and immunity
Calder, PC
[J]. JOURNAL OF NUTRITION, 2006, 136 (01) : 288S - 293S
[8] Loss of T Cell CD98 H Chain Specifically Ablates T Cell Clonal Expansion and Protects from Autoimmunity
Cantor, Joseph
Slepak, Marina
Ege, Nil
Chang, John T.
Ginsberg, Mark H.
[J]. JOURNAL OF IMMUNOLOGY, 2011, 187 (02) : 851 - 860
[9] Regulatory T cell proliferative potential is impaired in human autoimmune disease
Carbone, Fortunata
De Rosa, Veronica
Carrieri, Pietro B.
Montella, Silvana
Bruzzese, Dario
Porcellini, Antonio
Procaccini, Claudio
La Cava, Antonio
Matarese, Giuseppe
[J]. NATURE MEDICINE, 2014, 20 (01) : 69 - +
[10] Regulation and function of mTOR signalling in T cell fate decisions
Chi, Hongbo
[J]. NATURE REVIEWS IMMUNOLOGY, 2012, 12 (05) : 325 - 338

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