The NFAT family of transcription factors are key regulators of inducible gene expression in the immune system. We examined the function of two NFAT proteins after naïve T helper (TH) cell activation. We found that naïve TH precursors that are doubly deficient in NFATc2 and NFATc3 intrinsically differentiate into TH2-secreting cells, even in the absence of interleukin 4 (IL-4) production. We also found that lack of NFATc2 and NFATc3 obviates the necessity for engagement of CD28 on naïve cells and controls the time required to reach the first cell division upon activation. These results demonstrate a key role for NFATc2 and NFATc3 in modulating T cell receptor responsiveness and regulating subsequent cell division and TH2 differentiation.
