NF-κB2/p100 deficiency impairs immune responses to T-cell-independent type 2 antigens

Eur J Immunol. 2014 Mar;44(3):662-72. doi: 10.1002/eji.201343484. Epub 2013 Dec 16.


Formation of the splenic marginal zone (MZ) depends on the alternative NF-κB signaling pathway. Recently, we reported that unrestricted activation of this pathway in NF-κB2/p100-deficient (p100(-/-) ) knock-in mice alters the phenotype of MZ stroma and B cells. Here, we show that lack of the p100 inhibitor resulted in an expansion of both MZ B and peritoneal B-1 cells. However, these cells failed to generate proliferating blasts in response to T-cell-independent type 2 (TI-2) Ags, correlating with dampened IgM and absent IgG3 responses. This phenotype was in part due to increased activity of the NF-κB subunit RelB. Moreover, p100(-/-) →B6 BM chimeras were more susceptible to infection by encapsulated Streptococcus pneumoniae bacteria, pathogens that induce TI-2 responses. In contrast to the TI-2 defect, p100 deficiency did not impair immune responses to the TI-1 Ag LPS and p100(-/-) MZ B cells showed normal Ag transportation into B-cell follicles. Furthermore, p100(-/-) MZ B and B-1 cells failed to respond to TI-2 Ags in the presence of WT accessory cells. Thus, NF-κB2/p100 deficiency caused a predominant B-cell-intrinsic TI-2 defect that could largely be attributed to impaired proliferation of plasmablasts. Importantly, p100 was also necessary for efficient defense against clinically relevant TI-2 pathogens.

Keywords: Alternative NF-κB pathway; B-1 cells; Marginal zone B cells; Streptococcus pneumoniae; TI-2 immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / genetics
  • Antibody Formation / immunology
  • Antigens, T-Independent / immunology*
  • Antigens, T-Independent / metabolism
  • B-Lymphocyte Subsets / drug effects
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism*
  • Bacteria / immunology
  • Bacterial Infections / genetics
  • Bacterial Infections / immunology
  • Cell Movement / genetics
  • Cytokines / pharmacology
  • Genetic Predisposition to Disease
  • Immunity, Humoral / genetics
  • Mice
  • Mice, Knockout
  • NF-kappa B p52 Subunit / deficiency*
  • NF-kappa B p52 Subunit / genetics
  • NF-kappa B p52 Subunit / metabolism
  • Protein Binding
  • Protein Transport
  • Receptors, Antigen, B-Cell / metabolism
  • Toll-Like Receptors / metabolism
  • Transcription Factor RelB / genetics
  • Transcription Factor RelB / metabolism


  • Antigens, T-Independent
  • Cytokines
  • NF-kappa B p52 Subunit
  • Receptors, Antigen, B-Cell
  • Toll-Like Receptors
  • Transcription Factor RelB