Regulation of Age-associated B cells by IRF5 in systemic autoimmunity

Age-associated B cells (ABCs) are a T-bet–dependent B cell subset, which accumulates prematurely in autoimmune settings. The pathways regulating ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that controls both cytoskeletal dynamics and IRF4 activity. Notably, DEF6 is a newly identified human SLE-risk variant. Here we show that the lupus syndrome that developed in SWEF-deficient mice is accompanied by the accumulation of ABCs, which produce autoantibodies upon stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment in motifs bound by transcription factors of the IRF family, AP-1/BATF, and T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by interleukin 21 (IL-21) and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated IRF5 activity in response to IL-21 stimulation. These studies thus uncover a new genetic pathway controlling ABCs in autoimmunity.