An intact NF-kappa B signaling pathway is required for maintenance of mature B cell subsets.
Members of the NF-kappaB/Rel transcription factor family are expressed constitutively during B cell development and are further induced by mitogen activation. Mice harboring germline disruptions in individual NF-kappaB subunits exhibit distinct defects in B lymphocyte activation and survival. However, the role of NF-kappaB in the production and maintenance of B cell subsets has been difficult to dissect in these knockout animals due to functional impairment of other immune cells. To directly address the cell autonomous requirements for NF-kappaB in humoral immune compartments, transgenic mice were generated that express a transdominant form of Ikappa-Balpha in B lineage cells. Whereas expression of the inhibitor had only modest effects on basal or LPS-induced levels of NF-kappaB, transgenic B cells were significantly impaired for cellular proliferation and NF-kappaB induction in response to B cell receptor (BCR) crosslinking. Furthermore, the trans-dominant inhibitor produced a dose-dependent reduction in the population of mature splenic B cells. This cellular defect was more pronounced in long-lived B lymphocyte subsets that recirculate to the adult bone marrow. Together, these results indicate that BCR-mediated signaling must maintain NF-kappaB levels above a stringent threshold for proper regulation of B cell homeostasis.
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Bendall
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Sikes
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Ballard
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Oltz
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D001853:Bone Marrow; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D020672:I-kappa B Proteins; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011947:Receptors, Antigen, B-Cell; D000072000:NF-KappaB Inhibitor alpha