IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity

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-gamma receptor ( IFN-gamma R) and STAT1 signaling are required for Spt-GC and follicular T helper cell ( Tfh cell) development. We further demonstrate that IFN-gamma R and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-gamma production by B cells. Global or B cell-specific IFN-gamma R deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG(2c) and IgG(2b) 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-gamma R signaling, suggesting that IFN-gamma R signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-gamma R deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-gamma R signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-gamma R signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.