The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells

被引:34
作者
Hai Vu Nguyen [1 ]
Mouly, Enguerran [1 ]
Chemin, Karine [1 ]
Luinaud, Romain [1 ]
Despres, Raymonde [1 ]
Fermand, Jean-Paul [1 ,2 ]
Arnulf, Bertrand [1 ,2 ]
Bories, Jean-Christophe [1 ]
机构
[1] Univ Paris Diderot, Inst Univ Hematol, EA3963, Paris, France
[2] Hop St Louis, Dept Immunohematol, F-75475 Paris 10, France
关键词
NF-KAPPA-B; IFN-GAMMA; DIFFERENTIATION; INDUCTION; ENHANCER; GENE; REARRANGEMENTS; RESTRICTION; ACTIVATION; LOCUS;
D O I
10.1182/blood-2011-09-378182
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In response to antigens and cytokines, mouse B cells undergo class-switch recombination (CSR) and differentiate into Ig-secreting cells. T-bet, a T-box transcription factor that is up-regulated in lymphocytes by IFN-gamma or IL-27, was shown to regulate CSR to IgG2a after T cell-independent B-cell stimulations. However, the molecular mechanisms controlling this process remain unclear. In the present study, we show that inactivation of the Ets-1 transcription factor results in a severe decrease in IgG2a secretion in vivo and in vitro. No T-bet expression was observed in Ets-1-deficient (Ets-1(-/-))B cells stimulated with IFN-gamma and lipopolysaccharide, and forced expression of T-bet in these cells rescued IgG2a secretion. Furthermore, we identified a transcriptional enhancer in the T-bet locus with an activity in B cells that relies on ETS-binding sites. After IFN-gamma stimulation of Ets-1(-/-) B cells, activated Stat1, which forms a complex with Ets-1 in wild-type cells, no longer binds to the T-bet enhancer or promotes histone modifications at this site. These results demonstrate that Ets-1 is critical for IgG2a CSR and acts as an essential cofactor for Stat1 in the regulation of T-bet expression in B cells. (Blood. 2012;119(18):4174-4181)
引用
收藏
页码:4174 / 4181
页数:8
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