Abstract

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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Acknowledgements

We thank the SBP vivarium staff for animal care, M. Shlomchik (University of Pittsburgh) for providing the hCD20-TamCre mice, D. Kitamura (Tokyo University of Science) for providing the CD40LB cell line and C. Lyssiotis (University of Michigan) for discussions. Supported by US National Institutes of Health grant R01AI41649 (R.C.R.), the Lilly Research Award Program (R.C.R.), fellowships from the Deutsche Forschungsgemeinschaft (J.J.) and the Cancer Centers Council (C3) (P.R.-R.) and grants from the Arthritis National Research Foundation (J.J.) and the Canadian Institutes of Health Research (J.W.). The Animal Resources and Cancer Metabolism Cores at SBP are supported by NCI award 5P30CA030199.

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Affiliations

  1. Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, California, USA.

    • Julia Jellusova
    • , Matthew H Cato
    • , John R Apgar
    • , Parham Ramezani-Rad
    • , Charlotte R Leung
    • , Cindi Chen
    •  & Robert C Rickert
  2. NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

    • Julia Jellusova
    • , Matthew H Cato
    • , John R Apgar
    • , Parham Ramezani-Rad
    • , Charlotte R Leung
    • , Cindi Chen
    • , Adam D Richardson
    •  & Robert C Rickert
  3. Eli Lilly and Company, La Jolla, California, USA.

    • Elaine M Conner
    •  & Robert J Benschop
  4. Lunenfeld–Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • James R Woodgett
  5. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

    • James R Woodgett

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Contributions

J.J. designed and performed the majority of the experiments, analyzed the data and, together with R.C.R., wrote the manuscript; M.H.C. performed and analyzed the NP–KLH immunization experiment and contributed to the initial phenotypic analysis of Gsk3-deficient mice; J.R.A. performed and analyzed the CyTOF experiments and annexin V stainings; P.R.-R. performed and analyzed the in vivo CD40 stimulations and contributed to the experiments analyzing B cell proliferation in vivo and in vitro; C.R.L. and C.C. provided technical assistance with the experiments; A.D.R. helped perform and interpret the analysis of B cell metabolism; E.M.C. and R.J.B. provided advice, resources and assistance with the CyTOF experiments; J.R.W. provided mice and conceptual input to the manuscript; and R.C.R. conceived of and coordinated the study, interpreted the data and wrote the manuscript.

Competing interests

E.M.C. and R.J.B. are paid employees of Eli Lilly and Company.

Corresponding author

Correspondence to Robert C Rickert.

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DOI

https://doi.org/10.1038/ni.3664

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