Background Emerging evidences indicate that a distinct CD11c+T-bet+ B cell subset termed age/autoimmune-associated B cells (ABCs) is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors (TFs) and metabolic programs to meet specific functional requirements is unclear. Our goal is to characterize the metabolism of ABCs and identify the regulators of metabolic pathways for developing new therapies for ABC-mediated autoimmunity.
Methods We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from Bm12 mice to induce lupus. Then CD11c+tdTomato+ B cells were sorted and conducted RNA sequencing and extracellular flux assay. Metabolic restriction to constrain ABC formation was tested on human and mouse B cells. The metabolic intervention was conducted in the Bm12-induced lupus model.
Results ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by IFN-Y signaling. T-bet, a downstream TF of IFN-Y, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of glycolysis inhibitor ameliorated ABCs accumulation and autoantibody production in Bm12-induced lupus model.
Conclusions T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulating ABC favored metabolic program could be a novel therapeutic approach for lupus.
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