The RNA binding protein HuR is necessary for IL-2 homeostasis and CD4+ T cell differentiation

RNA binding proteins, such as HuR (ELAVL1), fine tune gene expression in activated T cells by interacting with their 3′ UTR AU-rich elements(AREs) via posttranscriptional gene regulation. IL-2 and many Th2 cytokine mRNAs contain 3′ UTR AREs. Thus, we hypothesized that HuR may play a critical role in CD4 + T cell differentiation by regulating IL-2 signaling pathways. We conditionally ablated HuR in CD4 + T cells (distal lck-Cre ROSA HuR fl/fl ) to test this hypothesis. HuR KO T cells are able to develop and egress the thymus normally. However, these cells cannot shut off IL-2 production and display defects in Th2 differentiation and cytokine expression. Proliferation defects, decreased p- stat5, and reductions in CD25 and prdm-1 transcription were also observed in the HuR KO T cells. In the absence of HuR, Il2ra (CD25) mRNA recruitment to heavy polysomesis reduced, indicating that HuR plays a critical role in its translation. This suggests that HuR regulates T cell activation and IL-2 homeostasis by controlling CD25 expression. When activated under Th0 conditions, 97% of HuR KO cells expressed IL-2 on day 5 compared to HuR WT cells (50%). HuR KO cells also had large increases in steady state IL-2 mRNA (30-fold) and 7-fold increases in secreted IL-2 protein. Furthermore, HuR KO cells produced scant amounts of the Th2 cytokines at the protein level. These findings led us to investigate the fate of other T cell lineages when HuR is absent. When polarized to Treg, Th17, and Tfh lineages, HuR KO T cells showed reduced levels of the signature transcription factors Foxp3, RoRγt, and Bcl6, respectively, as compared to controls. Thus, we conclude that HuR plays an indispensable role in normal IL-2 homeostasis and CD4 + T cell differentiation.