The RNA-binding protein HuR is required for normal homeostatic control of IL-2 expression in activated CD4 T cells (IRM6P.713)

Upon T cell activation approximately 50% of genes are regulated at the posttranscriptional level by RNA-binding proteins(RBPs). HuR is a stabilizing RBP which regulates mRNA via interactions with AU-rich elements(ARE) in mRNA 3’UTRs. HuR has been shown to be crucial for T cell development, thymic selection and egression. However, it is unclear how HuR regulates T cell differentiation and cytokine expression. To further investigate these questions, we generated a novel conditional HuR KO mouse, distal-Lck Cre ROSA HuRfl/fl which ablates HuR in mature T cells prior to activation. HuR KO T cells develop and egress from thymus normally; however, they display aberrant cytokine and receptor expression upon activation. Activated HuR KO T cells show striking increases in IL-2 (20-30 fold) and display an inability to turn off IL-2 expression, but significant decreases in IL-4, IL-5 and IL-13 with no change in IFN-γ. Over 90% of HuR KO CD4 cells still make IL-2 five days after activation but display impaired IL-4, IL-5 and IL-13 secretion. Increases in IL-2 in HuR KO cells are due to augmentation of IL-2 transcription and mRNA stability. Moreover, there are significant decreases in proliferation and CD25 (IL-2Rα) expression in HuR KO cells as a result of reductions in CD25 transcription. Thus, HuR is required for cytokine homeostasis in CD4 cells and may well function as a critical off-switch for IL-2 expression during T cell activation.