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 () and Esperanza Perucha ()
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Jack A. Bibby: School of Immunology and Microbial Sciences, King’s College London
Harriet A. Purvis: School of Immunology and Microbial Sciences, King’s College London
Thomas Hayday: School of Immunology and Microbial Sciences, King’s College London
Anita Chandra: University of Cambridge
Klaus Okkenhaug: University of Cambridge
Sofia Rosenzweig: National Institutes of Health
Ivona Aksentijevich: National Institutes of Health
Michael Wood: University College London and Royal Free Hospital London NHS Foundation Trust
Helen J. Lachmann: University College London and Royal Free Hospital London NHS Foundation Trust
Claudia Kemper: School of Immunology and Microbial Sciences, King’s College London
Andrew P. Cope: School of Immunology and Microbial Sciences, King’s College London
Esperanza Perucha: School of Immunology and Microbial Sciences, King’s College London

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17179-4

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