A ligand-independent fast function of RARα promotes exit from metabolic quiescence upon T cell activation and controls T cell differentiation.

Abstract

Vitamin A metabolites play important roles in T cell activation and differentiation. A conventional model of RARα function relies upon retinoic acid (RA)-liganded RARα binding to specific DNA motifs to regulate gene expression in the nucleus. However, this genomic function fails to explain many of the biological responses of the RA-RARα axis on T cells. We generated a mouse line where RARα is over-expressed in T cells to probe RARα function with unprecedented sensitivity. Using this model together with mice specifically lacking RARα in T cells, we found that RARα is required for prompt exit from metabolic quiescence in resting T cells upon T cell activation. The positive effect of RARα on metabolism is mediated through PI3K and subsequent activation of the Akt and mTOR signaling pathway. This largely non-genomic function of RARα is surprisingly ligand-independent and controls the differentiation of effector and regulatory T cell subsets.