4 years ago

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

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells
Satoko Ueno, Kayo Ikeda, Koji Yasutomo, Morihiro Ito, Makoto Kinoshita, Yoshikatsu Kanai, Pornparn Kongpracha, Keiichi Ozono, Ayatoshi Andou, Shimon Sakaguchi, Yasunori Shintani, Takashi Kurakawa, Shushi Nagamori, Kiyoshi Takeda, Mari Murakami, Hideki Tsumura, Eiji Umemoto, Hisako Kayama, Norihisa Mikami, Ryu Okumura, Seiji Takashima


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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31545-0

DOI: 10.1016/j.celrep.2017.10.082

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