T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR

TLDR

Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. The study aims to delineate signaling events that control de novo Foxp3 expression in naive peripheral CD4 T cells and thymocytes. The authors investigate how TCR signaling pathways regulate Foxp3 induction. Premature TCR signaling termination and inhibition of PI3K p110α/p110δ, Akt, or mTOR induced Foxp3 expression and Treg‑like gene profiles, whereas sustained TCR signaling and constitutive PI3K/Akt/mTOR activity suppressed Foxp3 induction; chromatin marks H3K4me2/3 at the Foxp3 TSS and 5′ UTR preceded active expression and were lost with continued TCR stimulation, demonstrating that PI3K/Akt/mTOR signaling regulates Foxp3 expression.

Abstract

Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphatidyl inositol 3-kinase (PI3K) p110alpha, p110delta, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treg-like gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di- and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5' untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/Akt/mTOR signaling network regulates Foxp3 expression.