Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression.
T cell-specific deletion of Blimp-1 causes abnormal T cell homeostasis and function, leading to spontaneous, fatal colitis in mice. Herein we explore the role of Blimp-1 in Th1/Th2 differentiation. Blimp-1 mRNA and protein are more highly expressed in Th2 cells compared with Th1 cells, and Blimp-1 attenuates IFN-gamma production in CD4 cells activated under nonpolarizing conditions. Although Blimp-1-deficient T cells differentiate normally to Th2 cytokines in vitro, Blimp-1 is required in vivo for normal Th2 humoral responses to NP-KLH (4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin) immunization. Lack of Blimp-1 in CD4 T cells causes increased IFN-gamma, T-bet, and Bcl-6 mRNA. By chromatin immunoprecipitation we show that Blimp-1 binds directly to a distal regulatory region in the ifng gene and at multiple sites in tbx21 and bcl6 genes. Our data provide evidence that Blimp-1 functions in Th2 cells to reinforce Th2 differentiation by repressing critical Th1 genes.
Cimmino
Luisa
L
The Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Martins
Gislaine A
GA
Liao
Jerry
J
Magnusdottir
Erna
E
Grunig
Gabriele
G
Perez
Rocio K
RK
Calame
Kathryn L
KL
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000098815:T-bet Transcription Factor
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1