Metabolic Reprogramming Commits Differentiation Of Human Cd27(+)Igd(+) B Cells To Plasmablasts Or Cd27(-)Igd(-) Cells

B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-alpha markedly induced the differentiation of CD27(+)IgD(+) unswitched memory B cells into CD27(hi) CD38(hi) plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27(-)IgD(-) memory B cells with high cytokine production, but such differentiation was suppressed by IFN-alpha. AMP-activated protein kinase activation enhanced the differentiation to CD27(-)IgD(-) B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19(+) B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-alpha amplifies mTORC1-glycolysis pathways) or CD27(-)IgD(-) memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE.