Synergistic Induction of Interferon α through TLR-3 and TLR-9 Agonists Identifies CD21 as Interferon α Receptor for the B Cell Response

Abstract

Maternal antibodies inhibit seroconversion and the generation of measles virus (MeV)-specific antibodies (both neutralizing and non-neutralizing antibodies) after vaccination whereas T cell responses are usually unaffected. The lack of seroconversion leaves individuals susceptible to vaccine-preventable infections. Inhibition of antibody secretion is due to the inhibition of B cells through a cross-link of the B cell receptor with the inhibitory FcγIIB receptor (CD32) by maternal antibody/vaccine complexes. Here, we demonstrate that a combination of TLR-3 and TLR-9 agonists induces synergistically higher levels of type I interferon in vitro and in vivo than either agonist alone. The synergistic action of TLR-3 and TLR-9 agonists is based on a feedback loop through the interferon receptor. Finally, we have identified CD21 as a potential receptor for interferon α on B cells which contributes to interferon α-mediated activation of B cells in the presence of maternal antibodies. The combination leads to complete restoration of B cell and antibody responses after immunization in the presence of inhibitory MeV-specific IgG. The strong stimulatory action of type I interferon is due to the fact that type I interferon uses not only the interferon receptor but also CD21 as a functional receptor for B cell activation.

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…Maternal antibodies may bind critical viral epitopes, thereby preventing access by naive B cells; maternal antibodies may also neutralize the DENV vaccine, thus preventing viral replication and, in turn, impairing the immune response; finally, the third mechanism involves the formation of immune complexes between maternal antibodies and dengue virions that crosslink B cell receptor and inhibitory FcγRIIB, thereby leading to a negative intracellular signaling event that blocks B cell activation (29). Overcoming this inhibition requires signaling through CD21 and type I IFN receptor (62). Of note, the absence of type I IFN receptor in the A129 mouse strain may imply a predisposition to maternal antibody interference in these mice.…”

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

“…The products of the reaction were subjected to reducing SDS-PAGE gels and silver stained as described in Materials and Methods. rats (CR) mimics natural infection (70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83). MV replicates in CR lung tissue with peak titers occurring on day 4 or 5, and infection is overcome by day 8.…”

Comparisons of the effect of naturally acquired maternal pertussis antibodies and antenatal vaccination induced maternal tetanus antibodies on infant's antibody secreting lymphocyte responses and circulating plasma antibody levels

“…20 Presumably natural infection produced a more diverse array of antibodies than vaccines in the subclinical maternal pertussis infection as observed in our study. Nevertheless, inhibition of B cell responses can also be mediated by binding Fc region of passive antibody-vaccine Ag complex to the B cell Fcg-receptor IIB, results in a stronger negative signal that inhibits both the proliferation 21 and the antibodies secretion of B cells. 20 In this study, we observed a 9-fold increase in plasma anti-TT-IgG at 1 wk after three doses of primary immunizations (at 1.5, 2.5 and 3.5 mo of age), while at 1 y of age, it was decreased by about 5-fold from the peak and had returned to the pre-vaccination level (Fig.…”