Sequential involvement of NFAT and EGR transcription factors in fast regulation

The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 (DKO). DKO mice exhibit i ncreased lymphoproliferation, decreased activation-induced cell death, and impaired induction of Fast. The transcription factors Egr2 and Egr3 are pot ent activators of Fast expression. Here we find that Egr2 and Egr3 are NFAT target genes. Activation of Fast occurs via the NFAT-dependent induction o f Egr3, as demonstrated by the ability of exogenously provided NFATp to res tore Egr-dependent Fast promoter activity in DKO lymph node cells. Further, Egr3 expression is enriched in Th1 cells, suggesting a molecular basis for the known preferential expression of Fast in the Th1 versus Th2 subset.