title: The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment.
abstract: Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.
authors.affiliation: Immunology and inflammation, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Sudha
authors.initials: S
authors.lastname: Rao
authors.forename: Louis M
authors.initials: LM
authors.lastname: Tsai
authors.forename: Sau K
authors.initials: SK
authors.lastname: Lee
authors.forename: Yiqing
authors.initials: Y
authors.lastname: He
authors.forename: Elissa L
authors.initials: EL
authors.lastname: Sutcliffe
authors.forename: Monika
authors.initials: M
authors.lastname: Srivastava
authors.forename: Michelle
authors.initials: M
authors.lastname: Linterman
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Nicholas
authors.initials: N
authors.lastname: Simpson
authors.forename: Julia I
authors.initials: JI
authors.lastname: Ellyard
authors.forename: Ian A
authors.initials: IA
authors.lastname: Parish
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D005810:Multigene Family; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors