RNA binding protein HuR posttranscriptionally regulates antigen-specific T cell proliferation and allergen induced airway inflammation

Abstract

Abstract RNA binding protein HuR (ELAVL1) governs transcript stability of IL-4, IL-13 and GATA-3 mRNAs, thereby controlling Th2 differentiation. We hypothesized that HuR plays a role in antigen induced T cell activation and initiation of allergic airway inflammation. We conditionally ablated HuR in T cells prior to activation (distal lck-Cre ROSA HuRfl/fl mouse). Half of mature CD4+ T cells were HuR deficient in these mice. To determine the effects of HuR KO in T cells, mice were immunized with OVA, boosted 10 days later, and antigen specific proliferative responses were measured in vitro. Despite being fully capable of proliferation upon anti-CD3/CD28 stimulation, YFP+ (HuR KO) T cells were unable to proliferate in response to antigen while YFP− control cells had no proliferative defects. We then used the OVA challenge model of airway inflammation to ascertain effects of HuR KO in vivo. HuR KO mice had significantly less total cellular inflammation, as well as significant reductions in BAL IL-13. To determine the mechanism of suppression, we conducted in vitro activation experiments. HuR KO CD4+ T cells were sorted into YFP+ and YFP− pools and activated. YFP+ T cells had significant decreases in IL-4, IL-5, IL-13 but not IFNγ protein. Gata-3, IL-4 and IL-2Ra (CD25) transcription were significantly reduced. KO T cells have reductions in pSTAT5 signaling which is required for robust Th2 differentiation. While only 50% of CD4+ T cells lack HuR, there was total suppression of Th2 differentiation in airway inflammation. These data elucidate a critical role for HuR in regulating Th2 differentiation and allergic airway inflammation.