Active Tonic mTORC1 Signals Shape Baseline Translation in Naive T Cells

Abstract

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 Rasgrp1^Anaef 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.

Keywords: Anaef; CD44; CD5; Rasgrp1; autoimmunity; mRNA translation; mTOR; naive T cell; ribosome profiling; tonic signaling.