NFAT is a calcium-regulated transcription factor which consists of four family members. It plays a crucial role in the transcriptional regulation of several cytokine-encoding genes, including the genes for IL-2 and Il-2R. NFAT is composed of a nuclear subunit, , which is activated by, and a cytosolic subunit, which translocates into the nucleus to assemble with AP-1 after dephosphorylation by the phosphatase cacineurin. The later is activated by the elevation in intracellular Ca2+, triggered by TCR engagement.
NFAT (nuclear factor of activated T cells) was first described as a protein that regulated the activation-induced trnascription of the IL-2 gene in T cells. The term is now used to denote a family of transcription factors that regulate the activation-dependent expression of many genes that function both within and outside the immune system. These proteins are not restricted to T cells. At least five distinct genes encode the various family members.
Most NFAT family members exist as laten cytoplasmic factors that undergo calcineurin-dependent dephosphorylation upon cell stimulation, a process inhibited by the immunosuppressive drugs cyclosporin and FK506. Dephosphorylation unmasks a nuclear localization signal that allows shuttling to the nucleus and subsequent association with AP-1 and relevant gene elements.
NFAT confers TCR inducibility to the IL-4 promoter and other factors, including C/EBP, NF-Y, AP-1, NF-kB, HMGI(Y), GATA-3, Jun B, STAT6, c-maf, and NIP45 have been found to bind to and or regulate the activity of the IL-4 promoter. The IL-4 responsive transcription factor STAT6 plays an essential role in Th2 differentiation, since T helper cells from STSAT6-/- mice are incapable of producing Th2 cytokines such as IL-4.
TCR signals induce nuclear translocation of NFAT1, which selectively binds and transactivates the Ifngpromoter in Th1 cells and the Il4 promoter in Th2 cells.