title: Cutting edge: T follicular helper cell differentiation is defective in the absence of Bcl6 BTB repressor domain function.
abstract: T follicular helper (Tfh) cells are essential for germinal centers (GCs) and most long-term humoral immunity. Differentiation of Tfh cells depends on the transcriptional repressor B cell CLL/lymphoma 6 (Bcl6). Bcl6 mediates gene repression via the recruitment of corepressors. Currently, it is unknown how Bcl6 recruits corepressors to regulate gene expression of Tfh cells. In this article, we demonstrate, using a mutant form of Bcl6 with two BTB (bric-a-brac, tramtrack, broad-complex) mutations that abrogate corepressor binding, that the Bcl6 BTB domain is required for proper differentiation of Tfh and GC-Tfh cells in vivo. Importantly, we also observe a significant defect in GC B cell development. These results are consistent in multiple contexts, including a novel lymphocytic choriomeningitis virus nucleoprotein-specific TCR-transgenic mouse model. Taken together, these data suggest that the Bcl6 BTB domain is a key mediator of the differentiation of Tfh cells.
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: Genentech, South San Francisco, CA 94080; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Johnston
authors.affiliation: RIKEN Research Center for Allergy and Immunology, Yokohama City, Kanagawa 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; shane@lji.org.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000737:chemistry / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
chemical_list: D051560:Proto-Oncogene Proteins c-bcl-6