Active Tonic mTORC1 Signals Shape Baseline Translation in Naive T Cells

Abstract

Summary: Naive CD4+ T cells are an example of dynamic cell homeostasis: T cells need to avoid autoreactivity while constantly seeing self-peptides, yet they must be primed to react to foreign antigens during infection. The instructive signals that balance this primed yet quiescent state are unknown. Interactions with self-peptides result in membrane-proximal, tonic signals in resting T cells. Here we reveal selective and robust tonic mTORC1 signals in CD4+ T cells that influence T cell fate decisions. We find that the Ras exchange factor Rasgrp1 is necessary to generate tonic mTORC1 signals. Genome-wide ribosome profiling of resting, primary CD4+ T cells uncovers a baseline translational landscape rich in mTOR targets linked to mitochondria, oxidative phosphorylation, and splicing. Aberrantly increased tonic mTORC1 signals from a Rasgrp1Anaef allele result in immunopathology with spontaneous appearance of T peripheral helper cells, follicular helper T cells, and anti-nuclear antibodies that are preceded by subtle alterations in the translational landscape. : Myers et al. evaluate a mouse model of autoimmunity, Rasgrp1Anaef. They find that T cells with the Rasgrp1Anaef allele exhibit altered signaling from Rasgrp1 to the mTORC1 pathway in the basal state. They show that increased basal Rasgrp1Anaef-mTORC1 signals lead to an altered translational landscape in T cells and immunopathology. Keywords: naive T cell, tonic signaling, mTOR, Rasgrp1, Anaef, CD44, CD5, mRNA translation, ribosome profiling, autoimmunity