title: B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6.
abstract: Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed. In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development. In contrast, B cells functioning as antigen-presenting cells initiate CD4(+) T cell activation and IFN-γ production, and strikingly, B cell-intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity. Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development. Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein. Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98105 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Jackson
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98105.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Jacobs
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98105.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Arkatkar
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Dam
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98105.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Scharping
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98105 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: Nikita S
authors.initials: NS
authors.lastname: Kolhatkar
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Baidong
authors.initials: B
authors.lastname: Hou
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98105 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195 drawling@uw.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology*; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D001323:Autoantibodies; D007371:Interferon-gamma; D051560:Proto-Oncogene Proteins c-bcl-6; D017471:Receptors, Interferon; D051193:Toll-Like Receptors; D000096743:Interferon gamma Receptor; C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; C000611649:IFNG protein, mouse