Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation.
The maintenance of mature B cells hinges on signals emitted from the BAFF-R cell-surface receptor, but the nature of these signals is incompletely understood. Inhibition of canonical NF-kappaB transcription factor activity through ablation of the essential scaffold protein NEMO arrests B cell development at the same stage as BAFF-R deficiency. Correspondingly, activation of this pathway by constitutively active IkappaB Kinase2 renders B cell survival independent of BAFF-R:BAFF interactions and prevents proapoptotic PKCdelta nuclear translocation. In addition, canonical NF-kappaB activity mediates differentiation and proper localization of follicular and marginal zone B cells in the absence of BAFF-R, but not CD19. By replacing BAFF-R signals, constitutive canonical NF-kappaB signaling, a hallmark of various B cell lymphomas, causes accumulation of resting B cells and promotes their proliferation and survival upon activation, but does not per se induce lymphomagenesis. Therefore, canonical NF-kappaB activity can substitute for BAFF-R signals in B cell development and pathogenesis.
Sasaki
Yoshiteru
Y
The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115. Electronic address: sasaki@cbr.med.harvard.edu.
Derudder
Emmanuel
E
The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115.
Hobeika
Elias
E
Max-Planck Institute of Immunobiology, Stübeweg 51, D-79108 Freiburg, Germany.
Pelanda
Roberta
R
Max-Planck Institute of Immunobiology, Stübeweg 51, D-79108 Freiburg, Germany.
Reth
Michael
M
Max-Planck Institute of Immunobiology, Stübeweg 51, D-79108 Freiburg, Germany.
Rajewsky
Klaus
K
The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115.
Schmidt-Supprian
Marc
M
The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115. Electronic address: supprian@cbr.med.harvard.edu.
D021581:Active Transport, Cell Nucleus; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000201:enzymology; D049109:Cell Proliferation; D006965:Hyperplasia; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000032:analysis / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000473:pathology
D018941:Antigens, CD19; D053265:B-Cell Activation Factor Receptor; D008565:Membrane Proteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C486662:Tnfrsf13c protein, mouse; D051550:I-kappa B Kinase; D051745:Protein Kinase C-delta