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.