IL-12 up-regulates T-bet independently of IFN-gamma in human CD4+ T cells.
T-bet is an important Th1 driving transcription factor regulated by IFN-gamma/STAT1 pathway. T-bet turns on IFN-gamma transcription in CD4+ T cells and T-bet-deficient cells fail to differentiate to Th1 direction. Previous reports have characterized function of T-bet mainly in murine cells and very little is known about its functions in human cells. Here, we studied T-bet expression kinetics in parallel with GATA3 during Th1/Th2 polarization. We demonstrate that in addition to CD3/CD28 activation, cytokines IL-12 and IFN-alpha in the presence of neutralizing anti-IFN-gamma enhanced T-bet mRNA and protein expression in human CD4+ cells. T-bet is known to be a potent inducer of IFN-gamma. Even though IFN-gamma and IL-12 stimulation induced similar levels of T-bet protein in human CD4+ cells, IFN-gamma-treated cells produced considerably less IFN-gamma than cells treated with IL-12. Therefore, high T-bet protein expression does not necessarily correlate with IFN-gamma production. In addition, we show that the immunosuppressive cytokine TGF-beta inhibits T-bet and GATA3 protein expression only if it is present prior to primary T cell activation and is maintained in the cultures during the early polarization of Th1/Th2 cells. In conclusion, we report new insights into the cytokine regulation of T-bet in human CD4+ T cells.
Ylikoski
Emmi
E
Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
Lund
Riikka
R
Kyläniemi
Minna
M
Filén
Sanna
S
Kilpeläinen
Maritta
M
Savolainen
Johannes
J
Lahesmaa
Riitta
R
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*; D000098815:T-bet Transcription Factor
D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma