B cell–intrinsic IFN-γ receptor signaling through STAT1 is required for the generation of spontaneous germinal centers, which can lead to pathogenic autoantibody production.

The transcription factor AhR modulates immunity at multiple levels. Here we report phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of interleukin 10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in murine systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice and an increased AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.

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.