NFAT1 and NFAT2 are positive regulators of IL-4 gene transcription

The nuclear factor of activated T cells (NFAT) plays a key role in gene transcription in both immune and non-immune cell types. Genetic ablation of individual NFAT proteins produces complex phenotypes in mice; in particular, NFAT1(-/-) and NFAT2(-/-) T cells show overproduction and underproduction of IL-4, respectively. We have taken a positive approach to the question of whether these two NFAT family members differentially regulate IL-4 gene transcription. Using constitutively-active NFAT proteins with alanine substitutions instead of phosphorylated serine residues in the regulatory domain, we find that NFAT1(-/-) and NFAT2 are both positive regulators of IL-4 gene transcription, intrinsically very similar in their ability to induce and sustain transcription of the IL-4 gene. Thus the disparate phenotypes of NFAT1(-/-) and NFAT2(-/-) T cells do not reflect differences in DNA-binding or transcriptional activity at the IL-4 gene, but most likely arise from differential regulation of the two proteins or other indirect effects.