Cholesterol metabolism drives regulatory B cell function

Abstract

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. Thiscapacity 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 25 by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses.Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kd-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase 30 deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was 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. 40Comparable suppressive activity has been demonstrated in human regulatory B cells in vitro, suggesting that these cells also contribute toward regulating inflammatory responses in humans 5,6 . In support of this, IL-10 producing B cells have been demonstrated to be numerically depleted or functional impaired, ex vivo, in patients with inflammatory disease 5,11,12 . 45Despite the importance of IL-10 production by B cells, relatively little is known about the molecular mechanisms that govern its expression. Typically, induction of a regulatory phenotype in both human and murine B cells has been achieved through ligation of TLR9 or CD40 5,6,13 . Downstream, PI3K and ERK signals appear to be important for IL-10 expression 14,15 . This is in broad agreement with in vivo data from mouse models suggesting that both TLR and CD40 signals are required for the induction of 50 IL-10 in response to inflammatory stimuli 3,13 . However, precise details of the signaling cascades or cellular profiles underpinning the induction of a regulatory program in B cells are poorly understood.Control of immune cell metabolism is critical in regulating fundamental immunological processes 16,17 . However, in comparison to innate cell and T cell lineages, there has been relatively little work 55 aimed at understanding the metabolic regulation of B cell biology [18][19][20] . Furthermore, there is currently no understanding toward the metabolic requirements of regulatory B cells. An emerging concept from studies of regulatory T cells and M2 macrophages is their heightened reliance on lipid metabolism in comparison to the metabolic requirements of inflammatory immune cell lineages. Much of this work has focused on fatty acid oxidation, defining this as a central pathway that underpins polarization and 60 effector functions in regulatory cells 21 . In contrast, the contribution of cholesterol metabolism (the multi-step conversion of HM...