Type I IFN Receptor Signaling on B Cells Promotes Antibody Responses to Polysaccharide Antigens

Abstract

Abstract We previously reported monophosphoryl lipid A (MPL) and synthetic cord factor trehalose-6,6′-dicorynomycolate (TDCM) significantly increase Ab responses to T cell–independent type 2 Ags (TI-2 Ags) in a manner dependent on B cell–intrinsic TLR4 expression, as well as MyD88 and TRIF proteins. Given the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which type I IFN receptor (IFNAR) signaling was required for TI-2 responses and adjuvant effects. Using Ifnar1−/− mice and IFNAR1 Ab blockade, we found that IFNAR signaling is required for optimal early B cell activation, expansion, and Ab responses to nonadjuvanted TI-2 Ags, including the pneumococcal vaccine. Further study demonstrated that B cell–intrinsic type I IFN signaling on B cells was essential for normal TI-2 Ab responses. In particular, TI-2 Ag–specific B-1b cell activation and expansion were significantly impaired in Ifnar1−/− mice; moreover, IFNAR1 Ab blockade similarly reduced activation, expansion, and differentiation of IFNAR1-sufficient B-1b cells in Ifnar1−/− recipient mice, indicating that B-1b cell–expressed IFNAR supports TI-2 Ab responses. Consistent with these findings, type I IFN significantly increased the survival of TI-2 Ag–activated B-1b cells ex vivo and promoted plasmablast differentiation. Nonetheless, MPL/TDCM adjuvant effects, which were largely carried out through innate B cells (B-1b and splenic CD23− B cells), were independent of type I IFN signaling. In summary, our study highlights an important role for B-1b cell–expressed IFNAR in promoting responses to nonadjuvanted TI-2 Ags, but it nonetheless demonstrates that adjuvants which support innate B cell responses may bypass this requirement.