Induction of Metabolic Quiescence Defines the Transitional to Follicular B Cell Switch
Digital Object Identifier (DOI)
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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Citation / Publisher Attribution
Science Signaling, v. 12, issue 604, art. eaaw5573
Scholar Commons Citation
Farmer, Jocelyn R.; Allard-Chamard, Hugues; Sun, Na; Ahmad, Maimuna; Bertocchi, Alice; Mahajan, Vinay S.; Aicher, Toby; Arnold, Johan; Benson, Mark D.; Morningstar, Jordan; Barmettler, Sara; Yuen, Grace; H. Murphy, Samuel J.; Walter, Jolan E.; Ghebremichael, Musie; Shalek, Alex K.; Batista, Facundo; Gerszten, Robert; and Pillai, Shiv, "Induction of Metabolic Quiescence Defines the Transitional to Follicular B Cell Switch" (2019). Pediatrics Faculty Publications. 25.