title: The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses.
abstract: T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain. We determined that interleukin-12 (IL-12) and interferon-γ (IFN-γ) were redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet did not contribute to its own expression when induced by IL-12 and IFN-γ. By contrast, T-bet and the transcription factor Stat4 were critical for IFN-γ production whereas IFN-γ signaling was dispensable for inducing IFN-γ. Loss of T-bet resulted in activation of an endogenous program driving Th2 cell differentiation in cells expressing T-bet-ZsGreen. Genome-wide analyses indicated that T-bet directly induced many Th1 cell-related genes but indirectly suppressed Th2 cell-related genes. Our study revealed redundancy and synergy among several Th1 cell-inducing pathways in regulating the expression of T-bet and IFN-γ, and a critical role of T-bet in suppressing an endogenous Th2 cell-associated program.
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jfzhu@niaid.nih.gov
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Oler
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Suveena
authors.initials: S
authors.lastname: Sharma
authors.forename: Gangqing
authors.initials: G
authors.lastname: Hu
authors.forename: Liying
authors.initials: L
authors.lastname: Guo
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yagi
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Yamane
authors.forename: George
authors.initials: G
authors.lastname: Punkosdy
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: William E
authors.initials: WE
authors.lastname: Paul
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D050990:GATA3 Transcription Factor / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000276:immunology; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D015847:Interleukin-4; D007371:Interferon-gamma