IRF1 tunes the IRF4—IRF8 axis to drive effector B-cell fates in autoimmunity and inflammaging 2258675

Abstract Introduction Interferon regulatory factor 1 (IRF1) links IFNs and TLR signals to lymphocyte programs, yet its role in B cells and systemic lupus erythematosus (SLE), a disease driven by IFN-induced dysregulated B cell responses, is unclear. Methods Results We show that human SLE B cells have higher IRF1 mRNA levels and increased chromatin accessibility at IRF1 binding motifs compared to healthy donor B cells. In keeping with this, enforced IRF1 expression in human B cells induced a core effector gene module (TBX21, STAT1, IRF4), increased proliferation and enhanced antibody-secreting cell (ASC) differentiation. Consistent with this, global or B cell—intrinsic Irf1 deletion in aging B6 and lupus-prone Yaa.Fcγr2b—/— mice contracted ASCs and age-associated B cells (ABCs), while expanding germinal-center (GCB) and memory B cell (Bmem) pools. These shifts resulted in lower autoAb production, attenuated glomerular immune-complex deposition, reduced renal pathology and extended survival. Mechanistically, IRF1 regulated the transcriptome and epigenome of B cells to drive inflammatory ASC, ABC and effector Bmem programs enriched for expression of IFN-stimulated genes, proliferation, and secretory/stress modules that are required for pathogenic B cell identity. Loss of Irf1 prevented activation of these programs and redirected B-cell programs toward a resting-like memory fate, in part by controlling the balance of Irf4 and Irf8 expression in ASC-precursors. Multimodal integrated regulatory potential modeling following probabilistic in silico deletion of TF binding regions revealed that IRF1 regulates Irf4 by tuning the chromatin accessibility surrounding the Irf4 gene. Consistent with the multi-omics data, Irf1-deficient B cells exhibited a lower IRF4/IRF8 ratio and failed to proliferate and differentiate into ASCs in vitro. Conclusion Thus, IRF1 serve as a rheostat that controls the balance of IRF4 and IRF8 to regulate B cell differentiation programs. Funding Source NIH (R01 AI110508 & R01AI153365) Topic Categories Basic Autoimmunity (BA)