Understanding how AKT phosphorylation of hnRNPA1 modulates T cell fate and function

Abstract

T regulatory 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 (Tconv). Differences in PI3K/Akt/mTOR signaling not only affects 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 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. Using Cytek’s Aurora flow cytometer we characterized the immune cell populations of mA1 at steady state. Preliminary data do not indicate any major changes in innate immune and B cells populations at steady state. We observed modest changes in CD4 T cell population frequencies at steady state. Current work using In vitro skewing suggests that Akt phosphorylation of hnRNPA1 influences Treg fate. This project suggests a novel mechanism by which Akt modulates T cell fate.