Background Dysregulated germinal centrecenter (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 impacts of these cytokines in promoting B cell activation during humoral autoimmunity have not been addressed.

Materials and methods We recently developed a chimeric murine lupus model in which Wiskott-Aldrich syndrome protein (WAS)-deficient B cells promote spontaneous humoral autoimmunity (Jackson, et al. J Immunol 2014). An important advantage of the WAS chimaera model is that dysregulated immune responses are limited to the B cell compartment, allowing genetic manipulation in a B cell-intrinsic fashion. In the current study, we contrast the impact B cell-intrinsic type 1 IFN vs. IFN-γ signals on autoimmune GC formation and the pathogenesis of SLE.

Results Although type 1 IFN prominently enhanced B cell responses in vitro, B cell-intrinsic IFNAR deletion exerted surprisingly minimal impacts on class-switched autoantibody titers and spontaneous GC formation in vivo. This finding suggested that other cytokines promote B cell activation in the WAS chimaera model. Notably, B cells directly initiated CD4⁺ T cell activation and T follicular helper cell formation via MHC Class II (MHC-II)-dependent antigen presentation. In addition, activated T cells exhibited prominent IFN-γ production that was lost following B cell-intrinsic MHC-II deletion, suggesting a direct role for IFN-γ in promoting autoimmune GC formation. Strikingly, B cell-intrinsic deletion of the IFN-γ receptor was sufficient to abrogate spontaneous 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 BCL-6 expression. Finally, IFN-γ driven BCL-6 expression in B cells was blocked using clinically-relevant Janus kinase inhibitors, ruxolitinib and tofacitinib.

Conclusions Our study demonstrates that B cell-intrinsic IFN-γ receptor signals promote lupus pathogenesis via formation of spontaneous, autoimmune GCs. In addition, we have uncovered a novel cell-intrinsic program whereby IFN-γ, together with BCR-, TLR- and/or CD40 signals, orchestrates B cell expression of the GC master transcription regulator BCL-6. Our combined findings suggest that this IFN-γ signalling program may be a potential therapeutic target in SLE.

Acknowledgements This work was supported by the National Institutes of Health under award numbers: R01HL075453 (DJR), R01AI084457 (DJR), R01AI071163 (DJR), DP3DK097672 (DJR) and K08AI112993 (SWJ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support provided by the Benaroya Family Gift Fund (DJR); by the ACR REF Rheumatology Scientist Development Award (SWJ); and by the Arnold Lee Smith Endowed Professorship for Research Faculty Development (SWJ).