Cell Reports
Volume 21, Issue 7, 14 November 2017, Pages 1824-1838
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Article
Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

https://doi.org/10.1016/j.celrep.2017.10.082Get rights and content
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Highlights

  • Branched-chain amino acids are required for the in vivo maintenance of Treg cells

  • Branched-chain amino acids activate the mTOR pathway via Slc3a2

  • Slc3a2 is required for branched-chain amino-acid-dependent maintenance of Treg cells

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.

Keywords

Treg cells
amino acids
immunometabolism
immune regulation
transporter

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