Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells


  • E. Derudder
  • S. Herzog
  • V. Labi
  • T. Yasuda
  • K. Köchert
  • M. Janz
  • A. Villunger
  • M. Schmidt-Supprian
  • K. Rajewsky


  • Proceedings of the National Academy of Sciences of the United States of America


  • Proc Natl Acad Sci U S A 113 (18): 5065-5070


  • 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 I{kappa}B 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.