Inhibitory function of two NFAT family members in lymphoid homeostasis andTh2 development

Nuclear factor of activated T cells (NFAT) is a critical regulator of early gene transcription in response to TCR-mediated signals. Here, we show that mice lacking both NFATp and NFAT4 develop a profound lymphoproliferative d isorder likely due to a lowered threshold for TCR signaling coupled with in creased resistance to apoptosis secondary to defective Fast expression. NFA T mutant mice also have allergic blepharitis, interstitial pneumonitis, and a 10(3) to 10(4) fold increase in serum IgG1 and IgE levels, secondary to a dramatic and selective increase in Th2 cytokines. This phenotype may be a scribed to unopposed occupancy of the IL-4 promoter by NFATc. Our data demo nstrate that lymphoid homeostasis and Th2 activation require a critical bal ance among NFAT family members.