Cholesterol metabolism drives regulatory B cell function

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) was required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications controlled signaling through PI3K{delta}-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 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. Graphical abstractMKD = Mevalonate kinase deficiency O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/893982v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@e23fd0org.highwire.dtl.DTLVardef@1cb9611org.highwire.dtl.DTLVardef@e9769corg.highwire.dtl.DTLVardef@16a1d0f_HPS_FORMAT_FIGEXP M_FIG C_FIG