CD4(+)CD25(+) regulatory T cells (Tregs) are potent modulators of immune 
responses. The transcriptional program distinguishing Tregs from the 
CD4(+)CD25(-) Th cells is unclear. NFAT, a key transcription factor, is reported 
to interact with forkhead box p3, allowing inhibitory and activating signals in 
T cells. In the current study, we hypothesize that distinctive NFAT regulation 
in Tregs as compared with Th cells, may contribute to specific functions of 
these cells. Tregs express basal levels of cytoplasmic NFATc1 and NFATc2. In 
contrast to Th cells, anti-CD3-mediated T cell activation did not induce nuclear 
translocation of NFATc1 or NFATc2 in Tregs. This effect was associated with 
altered regulation for NFAT in Tregs that included reduced calcium flux, 
diminished calcineurin activation, and increased activity of glycogen synthase 
kinase-3beta, a negative regulatory kinase for NFAT in Tregs relative to Th 
cells. These data suggested that NFAT inhibition in Th cells may induce 
regulatory function. Indeed, pharmacologically mediated NFAT inhibition induced 
Th cells to function as Tregs, an effect that was mediated by induction of 
membrane-bound TGF-beta on Th cells. Collectively, these data suggest that 
maintaining NFAT at basal levels is a part of the transcriptional program 
required for Tregs.