Submitted March 5, 2007
Accepted October 9, 2007
Multiple signaling pathways promote B lymphocyte stimulator (BLyS)-dependent B cell growth and survival
Robert T Woodland*, Casey J Fox, Madelyn R Schmidt, Peter S Hammerman, Joseph T Opferman, Stanley J Korsmeyer, David M Hilbert, and Craig B Thompson
Dept of Molecular Genetics and Microbiology, and the Immunology and Virology Program, University of Massachusetts Medical School, Worcester, MA, United States
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
Howard Hughes Medical Institute, Harvard Medical School, Dana Farber Cancer Center, Boston, MA, United States
Human Genome Sciences, Inc, Rockville, MD, United States
* Corresponding author; email: robert.woodland{at}umassmed.edu.
We investigated the mechanism by which BLyS / BAFF, a TNF superfamily ligand, promotes B cell survival and resistance to atrophy. BLyS stimulation activates two independent signaling pathways, Akt/mTOR and Pim 2, associated with cell growth and survival. BLyS blocks the cell volume loss (atrophy) that freshly isolated B cells normally undergo when maintained in vitro while concurrently increasing glycolytic activity and overall metabolism. This atrophy resistance requires Akt/mTOR. We used a genetic approach to resolve the contributions of Akt/mTOR and Pim kinase pathways to BLyS-mediated survival. Pim 2 deficient B cells are readily protected from death by BLyS stimulation but this protection is completely abrogated by treatment with the mTOR inhibitor rapamycin. Furthermore, rapamycin treatment in vivo significantly reduces both follicular and marginal zone B cells in Pim deficient but not normal hosts. BLyS-dependent survival requires the anti-apoptotic protein Mcl-1. Mcl-1 protein levels rise and fall in response to BLyS addition and withdrawal respectively and conditional deletion of the mcl-1 gene renders B cells refractory to BLyS-mediated protection. As BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could potentially target pathogenic B cells.
