B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells

Abstract

Summary: Type 1 interferon (T1IFN) signaling promotes inflammation and lupus pathology, but its role in autoreactive B cell development in the antibody-forming cell (AFC) and germinal center (GC) pathways is unclear. Using a lupus model that allows for focused study of the AFC and GC responses, we show that T1IFN signaling is crucial for autoreactive B cell development in the AFC and GC pathways. Through bone marrow chimeras, DNA-reactive B cell transfer, and GC-specific Cre mice, we confirm that IFNαR signaling in B cells promotes autoreactive B cell development into both pathways. Transcriptomic analysis reveals gene expression alterations in multiple signaling pathways in non-GC and GC B cells in the absence of IFNαR. Finally, we find that T1IFN signaling promotes autoreactive B cell development in the AFC and GC pathways by regulating BCR signaling. These data suggest value for anti-IFNαR therapy in individuals with elevated T1IFN activity before clinical disease onset. : The B-cell-intrinsic mechanisms of type 1 interferon (T1IFN) signaling in regulating B cell tolerance is unclear. Domeier et al. show that T1IFN signaling in B cells causes loss of B cell tolerance, promoting autoreactive B cell development into the antibody-forming cell and germinal center pathways by regulating BCR signaling. Keywords: B cells, spontaneous germinal centers, antibody-forming cells, B cell tolerance, autoimmunity, systemic lupus erythematosus, type 1 interferon signaling