The RNA-Binding Protein Hur Is Required to Control Cytokine Expression in CD4+ T Cells
Monday, March 3, 2014: 2:45 PM
Room 15AB (Convention Center)
Rationale: During T cell activation, up to 50% of changes occur at the posttranscriptional level, which is mediated by RNA-binding proteins (RBPs). HuR is a stabilizing RBP which regulates mRNA target expression via AU-rich elements present in mRNA 3’UTRs. It is permissive for Th2 and Th17 differentiation. Methods: Previously, we showed HuR regulates GATA-3, IL-4, IL-13 and other Th2 restricted transcripts, as well as IL-17. We hypothesized that HuR is required for Th2 differentiation and Th2 associated disease such as asthma. To avoid defects in T cell development, we utilized a HuR KO mouse model in which HuR is ablated in mature CD4+ T cells, using distal Lck-Cre-ROSA-HuRfl/fl. Results: Activated or Th2 polarized HuR KO CD+4 T cells showed striking increases in IL-2 secretion and an inability to shut off IL-2 expression. These also mice had profound reductions in Th2 and Th17 cytokine expression. We used the ova challenge model of airway inflammation to further investigate HuR KO under antigenic conditions. HuR KO mice had profound reductions in BAL IL-4 and IL-13, and in pulmonary cellular infiltration with suppression of neutrophils, lymphocytes and eosinophils. The levels of cellular infiltration in HuR KO mice resembled un-immunized controls. Conclusions: HuR appears to be required for Th2 and Th17 but not Th1 differentiation and cytokine production. Furthermore, HuR functions as an off switch for IL-2 expression during T cell activation. These results may have implications for understanding mechanisms of tolerance under antigen challenge as well as in allergen driven airway lung inflammation.