c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.

B cells secreting IL-10 functionally are recognized as functional regulatory B (B_reg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting B_reg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10⁺ functional B_reg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8⁺ T cell tolerance and cause them to induce a pathogenic CD4⁺ T cell response. Functional B_reg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24^intCD27^-CD38^-CD69^+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional B_reg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional B_reg cells.