Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Jack A. Bibby*, Harriet A. Purvis, Thomas Hayday, Anita Chandra, Klaus Okkenhaug, Sofia Rosenzweig, Ivona Aksentijevich, Michael Wood, Helen J. Lachmann, Claudia Kemper, Andrew P. Cope, Esperanza Perucha

*Corresponding author for this work


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 cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

Original languageEnglish
Article number3412
JournalNature Communications
Issue number1
Pages (from-to)3412
Publication statusPublished - 08.07.2020

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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