title: B cells in T follicular helper cell development and function: separable roles in delivery of ICOS ligand and antigen.
abstract: B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand (ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells provide different, yet compensatory, signals for Tfh cell differentiation, while reconciling conflicting data indicating a requirement for ICOS-L expression on cognate B cells for Tfh cell development with those demonstrating that the latter requirement could be bypassed in lieu of that tendered by noncognate B cells. Our findings clarify the separable roles of delivery of Ag and ICOS-L by cognate B cells for Tfh cell maturation and function, and have implications for using therapeutic ICOS blockade in settings of abundantly available Ag, such as in systemic autoimmunity.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Jason S
authors.initials: JS
authors.lastname: Weinstein
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bertino
authors.forename: Sairy G
authors.initials: SG
authors.lastname: Hernandez
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Poholek
authors.forename: Taylor B
authors.initials: TB
authors.lastname: Teplitzky
authors.forename: Heba N
authors.initials: HN
authors.lastname: Nowyhed
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009596:Nitrophenols / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010648:Phenylacetates / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D018941:Antigens, CD19; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D009596:Nitrophenols; D010648:Phenylacetates; D051560:Proto-Oncogene Proteins c-bcl-6; C026242:4-hydroxy-5-nitrophenyl acetic acid; D010047:Ovalbumin