B cell-intrinsic IFN-g promotes CD11c+ age-associated B cell differentiation and compromises affinity-based germinal center selection in lupus
Lupus patients respond less efficiently to vaccinations and are more susceptible to infections. Previously, we have shown, in lupus models, that excessive CD11c+ age-associated B cells (ABCs) not only contribute to autoantibody production but also compromise antigen-specific germinal center (GC) B cell selection and affinity maturation by promoting aberrant T cell activation. Yet, how CD11c+ ABC differentiation is regulated is not fully understood. Here we show that B cell-intrinsic IFN-? is required for excessive CD11c+ ABC differentiation in lupus mice. B cell-intrinsic IFN-? is mainly produced by CD11c+ ABCs. IFN-?-deficiency leads to decreased expression of ABC characteristic genes, including Zeb2, an ABC-specific transcription factor recently described. We further show that ablating IFN-? can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-? in promoting CD11c+ ABC differentiation and compromising affinity-based germinal center selection and affinity maturation in lupus, providing a potential target for lupus treatment. Overall design: To understand the impact of B cell-intrinsic IFN-g on CD11c+ ABC differentiation,  we sorted CD11c+ ABCs from spleens of ShipDBIfng-/- and ShipDB mice. Following total RNA extraction, we employed SMART-seq for comprehensive transcriptomic profiling.