title: IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.
abstract: Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Domeier
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Sathi Babu
authors.initials: SB
authors.lastname: Chodisetti
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Chetna
authors.initials: C
authors.lastname: Soni
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schell
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Elias
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Wong
authors.affiliation: Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033 Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, 162 0825 Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033 zrahman@hmc.psu.edu.
authors.forename: Ziaur S M
authors.initials: ZS
authors.lastname: Rahman
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology; D000096743:Interferon gamma Receptor
chemical_list: D001323:Autoantibodies; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse