Proliferation and survival of activated B cells requires sustained antigen receptor engagement and phosphoinositide 3-kinase activation.
In this study, we investigate the extracellular and intracellular signals that drive cell cycle progression of activated B cells in the absence of T cell help. We find that brief engagement of the B cell receptor is sufficient to induce a single cell division in a fraction of cells, but that survival during successive cell divisions requires sustained receptor stimulation. In contrast, T cells have been shown previously to commit to multiple cell divisions following brief TCR engagement. Both early and late B cell receptor signals are blocked by inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin and are associated with S6 kinase activation and increased cell size. The requirement for ongoing Ag receptor signaling can be overcome by engagement of CD40 but only partially by IL-4. Proliferation driven by LPS also requires sustained exposure to the stimulus. These findings reveal checkpoints that may limit T-independent B cell responses when Ag exposure is transient.
Donahue
Amber C
AC
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
Fruman
David A
DA
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D019703:Calcineurin / Q000502:physiology; D002453:Cell Cycle / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D019703:Calcineurin; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D011947:Receptors, Antigen, B-Cell; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse