Akt phosphorylation of hnRNP A1 controls CD4+ T cell fate decisions

Abstract

Abstract The interaction between T-cell receptor (TCR) and a specific peptide-bound major histocompatibility complex (MHC) class II molecule on an antigen-presenting cell stimulates naive CD4+ T cells to differentiate into either effector T (Teff) or regulatory T cells (Treg). Previous studies have shown that CD4+ T cell fate decision is controlled by TCR signal strength. High dose of antigen promotes the differentiation into Teff cells, while low dose of antigen favors the Treg fate. We previously reported that the Akt/mTOR signaling pathway is involved in this process of alternate fate decision. High or low dose of antigen results in differential Akt phosphorylation and subsequent Akt substrate specificity. Upon high dose of antigen, dually phosphorylated Akt (T308 and S473) phosphorylates FoxO1, which excludes it from the nucleus; while under low dose of antigen, phosphorylated Akt (T308) activates RNA processing factors hnRNP L and hnRNP A1. Our lab has shown that both hnRNP L and A1 are necessary for the induction of Tregs in vitro. Other studies reported the identification of S199 as the phosphorylation site of hnRNP A1 by Akt. However, the relationship between Akt phosphorylation on S199 of hnRNP A1 and Treg induction is unclear. In order to investigate this, we are performing RIP-Seq on RNAs bound by hnRNP A1 under low or high stimulatory condition. We have generated a mutant mouse in which the hnRNP A1 S199 site has been mutated to Alanine. We are currently examining the impact of this mutation on the nature of RNAs bound by hnRNP A1 in T cells stimulated by low or high dose of antigen. In conclusion, our goal is to determine the mechanism by which Akt phosphorylation of hnRNP A1 is implicated in the CD4+ T cell differentiation programs.