IFN gamma-induced IRF1 synergizes with TLR7 signals to tune the IRF4-IRF8 axis and drive pathogenic effector B cell fate
Owiredu, E.-W.; Denslow, A. J.; Chen, S.; Mousseau, B.; Foote, J.; Yang, G.; Peel, J. N.; Burnham, R.; Browning, K.; Scharer, C. D.; Randall, T. D.; Zumaquero-Martinez, E.; Lund, F. E.
Show abstract
Interferon regulatory factor 1 (IRF1), a transcription factor encoded within the 5q31 locus harboring systemic lupus erythematosus (SLE) associated variants, promotes inflammatory responses by T and myeloid cells. Although IFN{gamma}-activated B cells also express IRF1, its role in B cell biology and SLE is unclear. Here, we use a mouse SLE model, single-cell multiomics, and human B cells to show that IRF1 intrinsically regulates Irf4 gene chromatin accessibility and expression in B cells to control the balance between the antibody secreting cell (ASC) lineage commitment factor, IRF4, and the B cell identity factor, IRF8. We demonstrate that IRF1, through its integration of IFN{gamma} and TLR7 induced transcriptional programs, tips B cells toward a terminal effector inflammatory AC fate at the expense of preserving more stem-like, resting and regulatory B cells that do not elicit autoantibody-associated pathology in SLE. Thus, IRF1 serves as a central node controlling B cell-driven autoimmune disease.
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