B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6

Abstract

Abstract Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although type 1 interferons (IFNs) are most frequently associated with lupus pathogenesis, type 2 interferon (IFN-γ) has also been shown to promote SLE. However, the respective impact of these cytokines in promoting B cell activation during humoral autoimmunity has not been addressed. Here, 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 via B cell MHCII expression, resulting in prominent T cell IFN-γ production. Strikingly, B cell-intrinsic deletion of the IFN-γ receptor was sufficient to abrogate autoimmune GCs, class-switched autoantibodies and systemic autoimmunity. Mechanistically, although IFN-γ receptor signals increased B cell T-bet expression, B cell-intrinsic deletion of T-bet exerted an isolated impact on class-switch recombination to pathogenic IgG2c autoantibody subclasses without impacting GC development. Rather, in both murine and human B cells, IFN-γ synergized with BCR, TLR and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, BCL-6. Finally, IFN-γ driven BCL-6 expression in B cells was blocked using clinically-relevant Janus kinase inhibitors, ruxolitinib and tofacitinib. Our combined findings identify a novel B cell-intrinsic mechanism whereby interferon signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.