The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma.
The transcription factor GATA3 is crucial for the differentiation of naive CD4(+) T cells into T helper 2 (Th2) cells. Here, we show that deletion of Gata3 allowed the appearance of interferon-gamma (IFN-gamma)-producing cells in the absence of interleukin-12 (IL-12) and IFN-gamma. Such IFN-gamma production was transcription factor T-bet independent. Another T-box-containing transcription factor Eomes, but not T-bet, was induced both in GATA3-deficient CD4(+) T cells differentiated under Th2 cell conditions and in Th2 cells with enforced Runx3 expression, contributing to IFN-gamma production. GATA3 overexpression blocked Runx3-mediated Eomes induction and IFN-gamma production, and GATA3 protein physically interacted with Runx3 protein. Furthermore, we found that Runx3 directly bound to multiple regulatory elements of the Ifng gene and that blocking Runx3 function in either Th1 or GATA3-deficient "Th2" cells results in diminished IFN-gamma production by these cells. Thus, the Runx3-mediated pathway, actively suppressed by GATA3, induces IFN-gamma production in a STAT4- and T-bet-independent manner.
Yagi
Ryoji
R
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Junttila
Ilkka S
IS
Wei
Gang
G
Urban
Joseph F
JF
Zhao
Keji
K
Paul
William E
WE
Zhu
Jinfang
J
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D050677:Core Binding Factor Alpha 3 Subunit; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C493730:Runx3 protein, mouse; D007371:Interferon-gamma
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