Model specific role of B cell-intrinsic IFNαR signaling in promoting spontaneous germinal centers and autoimmunity

Abstract

Abstract In systemic lupus erythematosus (SLE), germinal centers can form spontaneously (Spt-GCs) in the absence of foreign antigen and drive high-affinity autoantibody (autoAb) production. Overexpression of Type 1 interferon (IFNα) accelerates autoimmunity and alters B cell selection in certain SLE mouse models, but in another model, B cell intrinsic IFNαR signaling is shown to be dispensable for autoimmune GC response and autoimmunity. Using B6.Sle1b autoimmune mice derived from the NZM2410 SLE mouse model, we show here that IFNαR signaling is not required for Spt-GC formation but is important for elevated Spt-GC response and autoreactive B cell selection into AFCs. IFNα receptor1 deficient B6.Sle1b mice (B6.Sle1b.IFNαR1−/−) have lower Spt-GC and Tfh responses, reduced CD86 expression on B cells and diminished autoAb titers as compared to B6.Sle1b mice. We also observe lower Ca2+ flux in B cells deficient in IFNα receptor compared to control B cells upon BCR cross-linking in vitro. Consistently, we find that B cell-intrinsic IFNαR signaling promotes differentiation of Sle1b-expressing DNA-reactive B cells into GC B cells. RNA sequencing studies show that B6.Sle1b and B6.Sle1b.IFNαR1−/− GC B cells have distinct transcriptional profiles that are associated with proliferation, cell survival, and antigen presentation pathways. Compared to B6.Sle1b control, B6.Sle1b.IFNαR1−/− B cells fail to form stable conjugates with T cells in vitro and GC B cells express reduced levels of ICOS-ligand in vivo, suggesting B6.Sle1b.IFNαR1−/− B cells may not acquire adequate T cell help. These data reveal novel information about the model specific role of B cell-intrinsic IFNαR signaling in the regulation of Spt-GCs and autoimmunity.