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 int CD27 - 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.