Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells

Naive Itk-deficient CD4(+) T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFN gamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin, In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFN gamma expression.