AKT phosphorylation of hnRNPA1 and hnRNPL modulates T cell fate and function Regulatory T cells (Treg) play a significant role in maintaining self-tolerance and preventing autoimmune diseases. We and others have shown that low dose favors Treg and T helper (Th) 2 cell differentiation, while high Ag dose stimulation activates the PI3K/Akt/mTOR pathway, favoring inflammatory Th1 and Th17 cell differentiation (Teff). Differences in PI3K/Akt/mTOR signaling not only affect T cell fate but our research shows that Akt phosphorylation of the RNA-binding protein, (RBP) heterogeneous nuclear ribonucleoprotein (hnRNP) A1, is dependent on TCR signal strength. RBPs such as hnRNPA1 are emerging as regulators of RNA processing and stability in immune cells, and the effect of RBP on T cell differentiation is a growing subject of interest. We have shown hnRNPA1 is required for optimal Treg differentiation by performing knockdown experiments, and that it is phosphorylated by Akt following low dose stimulation. Our present research is focused on identifying a role for Akt phosphorylation in hnRNPA1 function. HnRNPA1 is known to have a single Akt phosphorylation site at S199 and our lab has generated a new mutant mouse model, hnRNPA1-S199A (mA1). This mutation affects the ability of Akt to phosphorylate hnRNPA1 in all immune cells. Preliminary data suggest that Treg differentiation induced by low TCR stimulation is impaired in the T cells from the mutant mouse. Based on these preliminary findings we hypothesize that Akt-mediated phosphorylation of hnRNPL and/or hnRNPA1 upon low TCR stimulation controls the processing of RNA transcripts involved in Treg differentiation. The following specific aims are proposed; 1) To determine how the hnRNPA1-S199A mutation affects T cell fate and function. 2) To determine the impact hnRNPA1 has on RNA splicing and stability. 3) To identify the AKT phosphorylation site on hnRNPL. 4)To determine how hnRNPL effects T cell fate and function.