Research ArticleImmunometabolism

Induction of metabolic quiescence defines the transitional to follicular B cell switch

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Science Signaling  22 Oct 2019:
Vol. 12, Issue 604, eaaw5573
DOI: 10.1126/scisignal.aaw5573

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AMPing up B cell maturation

Glycolysis provides an important energy source during B cell activation. In contrast, Farmer et al. found that metabolic quiescence was important for the development of human follicular B cells from transitional B cell precursors. In comparison to transitional B cells, mouse and human follicular B cells had reduced expression of genes involved in aerobic respiration, increased AMPK activation, and greater amounts of the cell surface ectoenzymes CD39 and CD73, which generate extracellular adenosine. Transitional human B cells that expressed CD73 or were treated with an AMPK agonist preferentially acquired a follicular B cell phenotype. These data identify a previously uncharacterized metabolic checkpoint in B cell development.

Abstract

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5′-monophosphate–activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

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