RNA-Binding Protein Hur Regulates CD4+ T Cell Differentiation and Is Required for Normal IL-2 Homeostasis and Allergic Airway Inflammation
Sunday, March 6, 2016: 1:30 PM
Room 403B (Convention Center)
Ulus Atasoy, MD FAAAAI, , , , ,
Rationale: The RNA binding protein (RBP), HuR, (elavl1) has been shown to posttranscriptionally regulate many cytokines including Th2/Th17 differentiation by controlling mRNA stability and translation. HuR over-expression results in increases in Th2 cytokines and differentiation. We hypothesized HuR regulates CD4+ T cell differentiation and is required for normal IL-2 homeostasis.

Methods: We made conditional HuR KO models to study HuR in CD4+ T cell activation. We used distal lck-cre-ROSA HuRfl/fl mice to ablate HuR during T cell differentiation and allergic airway inflammation. ROSA genes encodes YFP which identifies KO T cells.

Results: Activated YFP+ CD4+ T HuR KO cells had decreased Gata-3 and Th2 cytokines and could not shut off IL-2 (increased 30-fold mRNA and 700% protein). YFP+ HuR KO T cells had defects in proliferation, JAK-STAT signaling and CD25. We found increased IL-2 but decreased Gata-3, prdm-1, IL-4 and CD25 transcription. HuR KO mice had decreased BAL neutrophils, lymphocytes, eosinophils, IL-4 and IL-13 when challenged with ovalbumin. Remarkably, HuR KO mice had comparable levels of total lung inflammation as un-immunized controls. We demonstrated that HuR binds to IL-2Rα (CD25) and controls its translation but not stability. HuR KO T cells have decreased p-STAT5, blimp-1, have lost negative feedback inhibition of IL-2 and cannot efficiently develop into Th2 T cells.

Conclusions: These data suggest that HuR plays a major role in CD4+ T cell differentiation and IL-2 homeostasis by controlling expression of CD25 and other key regulators of T cell differentiation. HuR is also required for allergic airway inflammation.