Nutrient mTORC1 signaling underpins regulatory T cell control of immune tolerance.

J Exp Med
Authors
Abstract

Foxp3+ regulatory T (T reg) cells are pivotal regulators of immune tolerance, with T cell receptor (TCR)-driven activated T reg (aT reg) cells playing a central role; yet how TCR signaling propagates to control aT reg cell responses remains poorly understood. Here we show that TCR signaling induces expression of amino acid transporters, and renders amino acid-induced activation of mTORC1 in aT reg cells. T reg cell-specific ablation of the Rag family small GTPases RagA and RagB impairs amino acid-induced mTORC1 signaling, causing defective amino acid anabolism, reduced T reg cell proliferation, and a rampant autoimmune disorder similar in severity to that triggered by T reg cell-specific TCR deficiency. Notably, T reg cells in peripheral tissues, including tumors, are more sensitive to Rag GTPase-dependent nutrient sensing. Ablation of RagA alone impairs T reg cell accumulation in the tumor, resulting in enhanced antitumor immunity. Thus, nutrient mTORC1 signaling is an essential component of TCR-initiated T reg cell reprogramming, and Rag GTPase activities may be titrated to break tumor immune tolerance.

Year of Publication
2020
Journal
J Exp Med
Volume
217
Issue
1
Date Published
2020 Jan 06
ISSN
1540-9538
DOI
10.1084/jem.20190848
PubMed ID
31649036
PubMed Central ID
PMC7037250
Links
Grant list
F30 AI129273 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 AI102888 / AI / NIAID NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States