Control of antigen-mediated proliferation and activation of CD4+ T cells by the RNA binding protein HuR

Abstract

Abstract The RNA binding protein HuR (elavl1) stabilizes target mRNAs and aids in their transport to the heavy polysomes, ultimately resulting in increased protein expression. We have previously shown that HuR plays a critical role in T helper cell fate decisions, with HuR deficient mice having significant impairment in Th2 differentiation. Interestingly, HuR deficiency also leads to large increases in IL-2 production. We hypothesized that HuR is important for normal T cell activation and expansion. To investigate this, we used mouse models in which HuR was conditionally ablated during T cell development either early at the double positive stage (CD4-Cre ROSA HuRfl/fl) or late (distal Lck-Cre ROSA HuRfl/fl). Upon activation in vitro, HuR KO T cells had significant reductions in CD25 (IL-2Ra) protein and RNA. An in vivo OVA challenge model was used to determine ascertain the effects of HuR KO on airway inflammation. Despite only half of CD4+ T cells in dLck-Cre HuR KO mice lacking HuR, there was a significant decrease in total inflammation, with essentially no T cell infiltrate. These mice also had significantly reduced BAL IL-13. Furthermore, mice were immunized with either OVA or KLH, boosted 10 days later, and antigen specific proliferative responses measured in vitro. T cells lacking HuR had profound proliferation defects compared to control cells, regardless of the antigen system employed. Interestingly, non-specific CD3/CD28 stimulation only partially restored these proliferative defects. RNA-Seq analysis of activated HuR deficient T cells indicated altered expression in multiple genes associated with T cell activation and function. We conclude HuR function is vital for normal antigen-specific activation and proliferation in CD4+ T cells.