Regulation of interferon-gamma gene expression by nuclear factor of activated T cells.
Transcription factors of the nuclear factor of activated T cells (NFAT) family 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. However, it remains unresolved whether NFAT proteins play a role in regulating transcription 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-gamma 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 differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1(-/-)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 NFAT, VIVIT. These results suggest that IFN-gamma production by T cells is regulated by NFAT1, most likely at the level of gene transcription.
Kiani
A
A
Department of Pathology, Harvard Medical School, and The Center for Blood Research, Boston, MA 02115, USA.
García-Cózar
F J
FJ
Habermann
I
I
Laforsch
S
S
Aebischer
T
T
Ehninger
G
G
Rao
A
A
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C121611:VIVIT peptide; D015847:Interleukin-4; D007371:Interferon-gamma