title: Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3.
abstract: T follicular helper (Tfh) cells are essential providers of help to B cells. The transcription factor B-cell CLL/lymphoma 6 (Bcl6) is a lineage-defining regulator of Tfh cells and germinal center B cells. In B cells, Bcl6 has the potential to recruit distinct transcriptional corepressors through its BTB domain or its poorly characterized middle domain (also known as RDII), but in Tfh cells the roles of the Bcl6 middle domain have yet to be clarified. Mimicked acetylation of the Bcl6 middle domain (K379Q) in CD4 T cells results in significant reductions in Tfh differentiation in vivo. Blimp1 (Prdm1) is a potent inhibitor of Tfh cell differentiation. Although Bcl6 K379Q still bound to the Prdm1 cis-regulatory elements in Tfh cells, Prdm1 expression was derepressed. This was a result of the failure of Bcl6 K379Q to recruit metastasis-associated protein 3 (MTA3). The loss of Bcl6 function in Bcl6 K379Q-expressing CD4 T cells could be partially rescued by abrogating Prdm1 expression. In addition to Prdm1, we found that Bcl6 recruits MTA3 to multiple genes involved in Tfh cell biology, including genes important for cell migration, cell survival, and alternative differentiation pathways. Thus, Bcl6 middle domain mediated repression is a major mechanism of action by which Bcl6 controls CD4 T-cell fate and function.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037;
authors.forename: J Philip
authors.initials: JP
authors.lastname: Nance
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Simon
authors.initials: S
authors.lastname: Bélanger
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Johnston
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Joyce K
authors.initials: JK
authors.lastname: Hu
authors.affiliation: Center for Integrated Medical Sciences, RIKEN, Yokohama 230-0045, Japan;
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takemori
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037; Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92037 shane@lji.org.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology*; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017434:Protein Structure, Tertiary; D051560:Proto-Oncogene Proteins c-bcl-6; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D017931:DNA Primers; D004268:DNA-Binding Proteins; C435499:Mta3 protein, mouse; D009363:Neoplasm Proteins; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: B-cell help; T follicular helper cells; germinal centers