TY - JOUR
T1 - Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate
AU - Bibby, Jack A.
AU - Purvis, Harriet A.
AU - Hayday, Thomas
AU - Chandra, Anita
AU - Okkenhaug, Klaus
AU - Rosenzweig, Sofia
AU - Aksentijevich, Ivona
AU - Wood, Michael
AU - Lachmann, Helen J.
AU - Kemper, Claudia
AU - Cope, Andrew P.
AU - Perucha, Esperanza
N1 - Funding Information:
We thank all the healthy donors and patients for their support. This research was funded/ supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care This work was also supported by: the IMI-funded project BeTheCure (115142-2); EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure (777357) (both E.P. and A.P.C.); the National Institute for Health Research Biomedical Research Centre, at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London (J.A.B.); Intramural Research Programs of the National Human Genome Research Institute (I.A. and S.R.); MRC (MR/ M012328/2, K.O.); Wellcome Trust (206618/Z/17/Z, A.C.)
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/8
Y1 - 2020/7/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087660687&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17179-4
DO - 10.1038/s41467-020-17179-4
M3 - Journal articles
C2 - 32641742
AN - SCOPUS:85087660687
SN - 1751-8628
VL - 11
SP - 3412
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3412
ER -
