RNA binding protein HuR is required for efficient function but not generation of Foxp3+ Treg

Abstract

Abstract The RNA-binding protein (RBP) HuR (Elavl1) controls differentiation of CD4+ T cells into Th2 and Th17 helper subsets through regulating transcript stability of multiple subset specific targets. We recently generated dLck-Cre HuRfl/fl mice, in which HuR is conditionally knocked out in T cells late during thymic development. There was a 5:1 skewing toward HuR sufficient Treg in these mice, though there was only a small reduction in the total number of peripheral Treg compared to controls. More interestingly, HuR deficient naïve CD4+ T cells from these mice are less susceptible to Treg polarization than control HuR competent T cells and fail to upregulate Foxp3 following activation. We conditionally ablated HuR in Tregs (Foxp3YFP-Cre HuRfl/fl mouse) (HuR KO). These mice have significant failure to thrive in both hemizygous Foxp3YFP-CreHuRfl/fl males (39% weight reduction) and homozygous Foxp3YFP-Cre/YFP-Cre HuRfl/fl females (30% reduction). However, heterozygous Foxp3YFP-Cre/WT HuRfl/fl females have normal weight gain over time. Heterozygous HuR KO females also have a significant shift in the ratio of HuR− Treg to HuR+ Treg indicating a possible survival bias toward Treg expressing WT levels of HuR. Both male and female HuR KO mice have features of scurfy mice, including alopecia and stippled tails. This coincides with multiorgan inflammation which includes lung, skin, stomach and liver. Additionally, naïve HuR KO mice have significantly reduced peripheral Treg and increases in Foxp3− effector T cells with an activated phenotype. Together, these data suggest HuR is critical for effective Treg function and generation of iTreg.