NF-κB2/p100 deficiency impairs immune responses to T-cell-independent type 2 antigens.
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.
Leibniz-Institute for Age Research - Fritz-Lipmann-Institute, Jena, Germany.
Branislav
B
Krljanac
Debra
D
Weih
Ilse D
ID
Jacobsen
Desheng
D
Hu
Ievgen
I
Koliesnik
Katrin
K
Reppe
Martin
M
Witzenrath
Falk
F
Weih
D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D000955:Antigens, T-Independent / Q000276:immunology* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D001419:Bacteria / Q000276:immunology; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D056724:Immunity, Humoral / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism
D000955:Antigens, T-Independent; D016207:Cytokines; D052003:NF-kappa B p52 Subunit; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors; D051841:Transcription Factor RelB
Alternative NF-κB pathway; B-1 cells; Marginal zone B cells; Streptococcus pneumoniae; TI-2 immune response