biostudies-literatureBibby JAIntramural Research Programs of the National Human Genome Research InstituteInnovative Medicines InitiativeMedical Research CouncilNational Institute for Health Research (NIHR)RCUK | Medical Research CouncilWellcome Trust3412https://www.ebi.ac.uk/biostudies/studies/S-EPMC7343868biostudies-literatureUnknown11(1)Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cellNature communicationsCholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate.PMC7343868206618/Z/17/Z777357115142-2MR/M012328/2Rosenzweig SPerucha EBibby JAOkkenhaug KChandra AHayday TKemper CCope APPurvis HALachmann HJAksentijevich IWood MfalseCholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate.Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cell2020-01-01T00:00:00Z2020 Jul2025-04-22T19:34:37.595Z2025-04-06T02:47:32.855ZS-EPMC73438683264174210.1038/s41467-020-17179-4