Induction of extracellular adenosine salvage and metabolic quiescence regulate the transitional to follicular B cell checkpoint in humans.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA576910 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10259022_1.fastq.gz | Fastqsanger.gz | |||
| SRR10259022_2.fastq.gz | Fastqsanger.gz | |||
| SRR10259023_1.fastq.gz | Fastqsanger.gz | |||
| SRR10259023_2.fastq.gz | Fastqsanger.gz | |||
| SRR10259024_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional profiling of transitional and follicular B cells showed that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice, characterized by an orchestrated reduction of mTORC1 signaling, aerobic respiration and expression of genes involved in ribosome biogenesis.
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Project description:In patients with CTLA4 deficiency, CD40L-expressing T cells inhibit transitional to follicular B cell maturation in the T cell zone of lymph nodes through the induction of mTORC1 signaling in transitional B cells. We apply scRNA-seq to identify upregulation of PI3K, mTORC1, and oxidative phosphorylation pathways in patients with CTLA4 deficiency, and to characterize resolution of follicular block after treatment with abatacept.
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Project description: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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Project description:Congenital T cell activation blocks transitional to follicular B cell maturation in humans
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Project description:Cells arrest growth and enter a quiescent state upon nutrient deprivation. However, the molecular processes by which cells respond to different starvation signals to regulate exit from the cell division cycle and initiation of quiescence remains poorly understood. To study the role of protein expression and signaling in quiescence we combined temporal profiling of the proteome and phosphoproteome using stable isotope labeling with amino acids in cell culture (SILAC) in Saccharomyces cerevisiae (budding yeast). We find that carbon and phosphorus starvation signals activate quiescence through largely distinct proteome and phosphoproteome remodeling. However, increased expression of mitochondrial proteins is essential for quiescence establishment in response to both starvation signals. Whereas the quiescent proteome is established within 6 hours of starvation the quiescent phosphoproteome undergoes continuous changes for at least 30 hours following initial starvation. Deletion of the putative quiescence regulator RIM15, which encodes a serine-threonine kinase, results in reduced survival of cells starved for phosphorus and nitrogen, but not carbon. However, we identified common protein phosphorylation roles for RIM15 in quiescence that are enriched for RNA metabolism and translation. We also find evidence for RIM15-mediated phosphorylation of some targets, including IGO1, prior to starvation consistent with a functional role for RIM15 beyond quiescence regulation. Finally, we find evidence for widespread catabolism of amino acids in response to nitrogen starvation, indicating widespread amino acid recycling via salvage pathways in conditions lacking environmental nitrogen. Our study defines an expanded quiescent proteome and phosphoproteome in yeast, and highlights the multiple coordinated molecular processes at the level of protein expression that are required for quiescence.
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