Journal
NATURE IMMUNOLOGY
Volume 18, Issue 3, Pages 303-312Publisher
NATURE PORTFOLIO
DOI: 10.1038/ni.3664
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Funding
- US National Institutes of Health [R01AI41649]
- Lilly Research Award Program
- Deutsche Forschungsgemeinschaft
- Cancer Centers Council (C3)
- Arthritis National Research Foundation
- Canadian Institutes of Health Research
- NCI award [5P30CA030199]
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B cells predominate in a quiescent state until an antigen is encountered, which results in rapid growth, proliferation and differentiation of the B cells. These distinct cell states are probably accompanied by differing metabolic needs, yet little is known about the metabolic control of B cell fate. Here we show that glycogen synthase kinase 3 (Gsk3) is a metabolic sensor that promotes the survival of naive recirculating B cells by restricting cell mass accumulation. In antigen-driven responses, Gsk3 was selectively required for regulation of B cell size, mitochondrial biogenesis, glycolysis and production of reactive oxygen species (ROS), in a manner mediated by the co-stimulatory receptor CD40. Gsk3 was required to prevent metabolic collapse and ROS-induced apoptosis after glucose became limiting, functioning in part by repressing growth dependent on the myelocytomatosis oncoprotein c-Myc. Notably, we found that Gsk3 was required for the generation and maintenance of germinal center B cells, which require high glycolytic activity to support growth and proliferation in a hypoxic microenvironment.
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