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.
journal_name
Sci Signaljournal_title
Science signalingauthors
Farmer JR,Allard-Chamard H,Sun N,Ahmad M,Bertocchi A,Mahajan VS,Aicher T,Arnold J,Benson MD,Morningstar J,Barmettler S,Yuen G,Murphy SJH,Walter JE,Ghebremichael M,Shalek AK,Batista F,Gerszten R,Pillai Sdoi
10.1126/scisignal.aaw5573subject
Has Abstractpub_date
2019-10-22 00:00:00issue
604eissn
1945-0877issn
1937-9145pii
12/604/eaaw5573journal_volume
12pub_type
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