Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells.
Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and IκB kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage. Marginal zone (MZ) B and B1 cells were not rescued, indicating a possible role of canonical NF-κB signals beyond the control of cell survival in these subsets. When canonical NF-κB signaling was ablated specifically in mature B cells, the differentiation and/or persistence of MZ B cells was still abrogated, but follicular B-cell numbers were only mildly affected. However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-κB signals contribute to their long-term persistence and functional fitness.
Program of Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115; Immune Disease Institute, Harvard Medical School, Boston, MA 02115; Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
Emmanuel
E
Derudder
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria;
Sebastian
S
Herzog
Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
Verena
V
Labi
Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
Tomoharu
T
Yasuda
Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
Karl
K
Köchert
Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-University Hospital Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany;
Martin
M
Janz
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria; Tyrolean Cancer Research Institute, 6020 Innsbruck, Austria;
Andreas
A
Villunger
Program of Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115; Immune Disease Institute, Harvard Medical School, Boston, MA 02115; Department of Hematology and Oncology, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Marc
M
Schmidt-Supprian
Program of Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115; Immune Disease Institute, Harvard Medical School, Boston, MA 02115; Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; klaus.rajewsky@mdc-berlin.de.
Klaus
K
Rajewsky
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology*; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D016328:NF-kappa B
NF-κB; canonical signaling; follicular B cells; persistence