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 pro duction, even when primed in Th2-inducing conditions. In contrast, IFN gamm a production was little affected. Failure to express IL-4 occurred even amo ng cells that had gone through multiple cell divisions and was associated w ith 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, It k-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant ro le for Itk in modulating signals from the TCR/CD28 pathways that are specif ic for the establishment of stable IL-4 but not IFN gamma expression.