RNA-binding protein HuR controls IL-2 homeostasis in activated T cells by regulating CD25 expression (CCR3P.202)

Abstract

Abstract Posttranscriptional gene regulation by RNA binding proteins (RBPs) and their microRNA (miRNAs) partners is known to affect 50% of genes during T cell activation. The RBP, HuR regulates mRNAs by binding to AU-rich elements (AREs) in transcript 3’UTRs. Many Th2 cytokines and IL-2 possess AREs. We hypothesized that HuR may play a critical role in T cell activation and differentiation via regulation of IL-2 signaling pathways. To test this, we generated a conditional HuR KO mouse, distal-lck Cre ROSA HuRfl/fl, in order to ablate HuR prior to T cell activation. HuR KO T cells developed and egressed from thymus normally. However, they displayed an inability to shut off IL-2 and maintain stable cell surface expression of IL-2Ra (CD25). HuR KO T cells had striking increases in IL-2 mRNA and protein but decreases in Th2 cytokines. They also had proliferation defects, decreased p-stat5 and reductions in CD25 and prdm-1 transcription. We determined that HuR protein binds to IL-2 and CD25 mRNAs by two independent methods. CD25 mRNA stability was unchanged despite increased IL-2. We quantitated polysomal loading in HuR KO T cells compared to controls and discovered significant reductions in CD25 mRNA recruitment to heavy polysomes. Therefore, HuR regulates T cell activation and IL-2 homeostasis by controlling CD25 expression and enabling translational efficiency. We conclude that HuR plays an indispensible role in normal IL-2 homeostasis and T cell activation.