Regulation of interferon-gamma gene expression by nuclear factor of activated T cells

Transcription factors of the nuclear factor of activated T cells (NFAT) fam ily are thought to regulate the expression of a variety of inducible genes such as Interleukin-2 (IL-2), IL-4, and tumor necrosis factor-alpha. Howeve r, It remains unresolved whether NFAT proteins play a role In regulating tr anscription of the Interferon-gamma (IFN-gamma) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-gamma production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4-independent defect in expression of IFN-g amma mRNA and protein. Reduced IFN-gamma production by NFAT1(-/-)x IL-4(-/- ) T cells is observed after primary in vitro stimulation of naive CD4(+) T cells, Is conserved through at least 2 rounds of T-helper cell differentiat ion, and occurs by a cell-intrinsic mechanism that does not depend on overe xpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT 1(-/-) x IL-4(-/-) mice show increased susceptibility to infection with the intracellular parasite Leishmania major. Moreover, IFN-gamma production in a murine T-cell clone Is sensitive to the selective peptide inhibitor of N FAT, VIVIT. These results suggest that IFN-gamma production by T cells is r egulated by NFAT1, most likely at the level of gene transcription. (C) 2001 by The American Society of Hematology.