Regulation of metabolic supply and demand during B cell activation and subsequent differentiation

Abstract

B cell activation and differentiation are associated with marked changes in proliferative and effector functions. Each stage of B cell differentiation thus has unique metabolic demands. New studies have provided insight on how nutrient uptake and usage by B cells are regulated by B cell receptor signals, autophagy, mammalian target of rapamycin, and transcriptional control of transporters and rate-limiting enzymes. A recurring theme is that these pathways play distinct roles ranging from survival to antibody production, depending on the B cell fate. We review recently published data that define how these pathways control metabolic flux in B cells, with a particular emphasis on genetic and in vivo evidence. We further discuss how lessons from T cells can guide future directions.

Figure 1:. Metabolic changes following initial B cell activation.

Resting naïve B cells import relatively little glucose, in part due to repression by the transcription factors Pax5 and Ikaros. After ligation of the BCR and co-ligation of either CD40 or Toll-like receptors (TLR), an influx of glucose and glutamine is triggered. Accompanying this elevated nutrient import, the size of the cell expands, mitochondrial mass increases, and transcriptional changes are enacted to support metabolic function.

Figure 2:. Metabolic and transcriptional regulation of germinal center B cell response.

B cell clones that express BCRs with higher affinity than neighboring clones are selected by follicular helper T cells. The selected clones upregulate transcription factors c-MYC and AP4 and activate mTORC1 to support their rapid proliferation, which may be modulated by local environmental factors, such as hypoxia or nutrient deprivation.

Figure 3:. Metabolic, but not transcriptional changes distinguish short-from long-lived plasma cells.

Short-lived plasma cells import less of a fluorescent glucose analog and amino acids than do long-lived plasma cells. However, these cell types are highly similar in ER stress responses and transcriptional profiles. Adapted from [35].