Nutrient mTORC1 signaling underpins regulatory T cell control of immune tolerance. Academic Article uri icon

Overview

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.

authors

  • Do, Mytrang Hoang
  • Wang, Xinxin
  • Zhang, Xian
  • Chou, Chun
  • Nixon, Briana G
  • Capistrano, Kristelle J
  • Peng, Min
  • Efeyan, Alejo
  • Sabatini, David M
  • Li, Ming O

publication date

  • January 6, 2020

Research

keywords

  • Immune Tolerance
  • Mechanistic Target of Rapamycin Complex 1
  • Nutrients
  • Signal Transduction
  • T-Lymphocytes, Regulatory

Identity

PubMed Central ID

  • PMC7037250

Scopus Document Identifier

  • 85076387863

Digital Object Identifier (DOI)

  • 10.1038/nri1806

PubMed ID

  • 31649036

Additional Document Info

volume

  • 217

issue

  • 1