title: The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells.
abstract: 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-γ 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-γ 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-γ 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.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Hôpital Saint Louis, 1 avenue Claude Vellefaux, Paris Cedex 10, France.
authors.forename: Hai Vu
authors.initials: HV
authors.lastname: Nguyen
authors.forename: Enguerran
authors.initials: E
authors.lastname: Mouly
authors.forename: Karine
authors.initials: K
authors.lastname: Chemin
authors.forename: Romain
authors.initials: R
authors.lastname: Luinaud
authors.forename: Raymonde
authors.initials: R
authors.lastname: Despres
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Fermand
authors.forename: Bertrand
authors.initials: B
authors.lastname: Arnulf
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bories
mesh_terms: D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000502:physiology*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; C494042:Ets1 protein, mouse; D006657:Histones; D007074:Immunoglobulin G; D053631:Interleukin Receptor Common gamma Subunit; D008070:Lipopolysaccharides; D050784:Proto-Oncogene Protein c-ets-1; C499308:Rag2 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma