RNA-binding protein HuR is required for suppressive function but not development of Foxp3+ CD4+ Tregs

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Abstract The RNA-binding protein (RBP) HuR (Elavl1) controls differentiation of CD4+ T cells into multiple helper subsets through regulating transcript stability of multiple T helper subset-specific targets. We generated dLck-Cre HuRfl/fl mice, in which HuR is conditionally knocked out in T cells late in thymic development. There was a 5-fold skewing toward HuR sufficient regulatory T cells (Treg) in these mice. HuR KO naïve CD4+ T cells from these mice are also less susceptible to Treg polarization than controls and fail to upregulate Foxp3 following activation. We conditionally ablated HuR in Tregs (Foxp3YFP-Cre HuRfl/fl mouse) (HuR KO). Heterozygous Foxp3YFP-Cre/WT HuRfl/fl females have normal weight gain over time. In stark contrast, both hemizygous Foxp3YFP-CreHuRfl/fl males (39% weight reduction) and homozygous Foxp3YFP-Cre/YFP-Cre HuRfl/fl females (30% reduction) have significant failure to thrive. Heterozygous HuR KO females also have a 5:1 shift in the ratio of HuR− Treg to HuR+ Treg indicating a possible survival bias toward Treg expressing WT levels of HuR. HuR KO mice have features of scurfy mice, including alopecia and stippled tails, as well as multi-organ inflammation which includes lung, skin, stomach and liver. Additionally, naïve HuR KO mice have significantly reduced peripheral Tregs and increases in activated Foxp3− effector T cells. In vitro suppression assays showed reduced suppressive capacity of HuR KO Tregs relative to WT Tregs. Together, these data suggest that HuR is critical for effective Treg function, but is dispensable for the development of Foxp3+ CD4+ Tregs.