Temporal dissection of T-bet functions.
T-bet is a transcription factor of the T-box family that regulates the expression of numerous immune system-associated genes. T-bet directs the acquisition of the Th1-associated genetic program in differentiating CD4(+) lymphocytes. It also influences the development of NK and NKT cells through its regulation of the IL-2/IL-15Rbeta-chain (CD122) and the trafficking of these lymphocytes through CxCR3. The temporal requirements of T-bet activity for the production of IFN-gamma and the regulation of CD122 and CxCR3 expression remain undefined. We produced an ectopically controllable form of T-bet by fusing its C-terminal domain with a mutated ligand-binding domain of human estrogen receptor alpha. By temporally controlling the expression of T-bet-estrogen receptor alpha by the addition or removal of 4-hydroxytamoxifen (4-HT), we show that IFN-gamma, CD122, and CxCR3 are direct gene targets of T-bet whose expression are acutely regulated by T-bet activity.
Matsuda
Jennifer L
JL
Integrated Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Science Center, 1400 Jackson Street, Denver, CO 80206, USA.
George
Thaddeus C
TC
Hagman
James
J
Gapin
Laurent
L
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D053646:Interleukin-2 Receptor beta Subunit / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D000098815:T-bet Transcription Factor
C515187:CXCR3 protein, human; C515188:Cxcr3 protein, mouse; D004965:Estrogen Antagonists; C508022:Il2rb protein, mouse; D053646:Interleukin-2 Receptor beta Subunit; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D011960:Receptors, Estrogen; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D013629:Tamoxifen; C016601:afimoxifene; D007371:Interferon-gamma