Signaling through Itk Promotes T Helper 2 Differentiation via Negative Regulation of T-bet

The Tec family tyrosine kinase, Itk, is critical for PLC-γ1 activation downstream of the TCR. Studies of Itk−/− mice have demonstrated a requirement for Itk in Th2 cytokine production and protective immunity to parasitic infections. Here we address the mechanism by which Itk regulates Th2 differentiation. We find that naive Itk−/− CD4+ T cells respond normally to cytokine skewing signals and can differentiate efficiently into either Th1 or Th2 lineage cells. In the absence of skewing cytokines, wild-type CD4+ T cells stimulated with low-avidity ligands preferentially express GATA-3 mRNA and differentiate into Th2 cells. Under these same stimulation conditions, Itk−/− T cells produce large amounts of T-bet mRNA and differentiate into IFN-γ-producing cells. Furthermore, Itk is upregulated during Th2 differentiation, while Rlk, a related Tec kinase, disappears rapidly from differentiating Th2 cells. Together, these findings provide a molecular explanation for the essential role of Itk in Th2 differentiation.