RNA binding protein HuR is required for robust antigen-mediated CD4+ T cell allergic airway inflammation

Abstract

Abstract RNA binding protein HuR (ELAVL1) controls helper T cell differentiation by modulating the stability of multiple target mRNAs through interactions with 3′ UTR AU-rich elements. We hypothesized that HuR regulates antigen induced T cell activation and initiation of Th2 driven allergic airway inflammation. HuR was conditionally ablated in developing T cells prior to thymic egress (distal Lck-Cre ROSA HuRfl/fl mouse). Upon in vitro activation, YFP+ (HuR KO) T cells produced significantly less IL-4, IL-5, and IL-13 than control cells and considerably more IL-2. We also observed reductions in Gata-3, IL-4 and IL-2Rα (CD25) nascent transcription. The OVA challenge model of airway inflammation was used to ascertain the effects of HuR KO in vivo. While only 50% of CD4+ T cells in HuR KO mice lack HuR, there was total suppression of Th2 responses and these mice had complete amelioration of lung inflammation. Lung infiltrating CD4+ T cells had reductions in IL-2 and CD25 expression, and OVA challenged HuR KO mice had significantly reduced BAL IL-13. In parallel, mice were immunized with either OVA or KLH, boosted 10 days later, and antigen specific proliferative responses measured in vitro to investigate antigen-specific T cell responses in the absence of HuR. HuR KO T cells had profound proliferation defects compared to controls, and CD3/CD28 stimulation only partially restored proliferation defects. HuR KO T cells had reductions in STAT5/STAT6 signaling, pathways which are key for Th2 differentiation and function. We conclude HuR plays an indispensable role in regulating antigen specific allergic airway inflammation and Th2 differentiation.