title: B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells.
abstract: T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell-expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6(+) T cells appear at the T-B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6(+) PD-1(hi) T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6(+) T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Sau K
authors.initials: SK
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rigby
authors.forename: Dimitra
authors.initials: D
authors.lastname: Zotos
authors.forename: Louis M
authors.initials: LM
authors.lastname: Tsai
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kawamoto
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Roybel R
authors.initials: RR
authors.lastname: Ramiscal
authors.forename: Tyani D
authors.initials: TD
authors.lastname: Chan
authors.forename: Dominique
authors.initials: D
authors.lastname: Gatto
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000172:deficiency / Q000378:metabolism; D008211:Lymphocyte Cooperation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012481:Salmonella Infections, Animal / Q000276:immunology; D019779:Salmonella enterica; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018183:Transplantation Chimera / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D000098546:Interleukin-21