Abstract
BackgroundB lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors. BLyS has been shown to enhance the production of antibodies against heterologous antigens when present at elevated concentrations, supporting an immunostimulatory role for BLyS in vivo.MethodsWe constructed a fusion protein consisting of human BLyS and Pneumococcal Surface Adhesin A (PsaA) and used this molecule to immunize mice. The immunostimulatory attributes mediated by BLyS in vivo were evaluated by characterizing immune responses directed against PsaA.ResultsThe PsaA-BLyS fusion protein was able to act as a co-stimulant for murine spleen cell proliferation induced with F(ab')2 fragments of anti-IgM in vitro in a fashion similar to recombinant BLyS, and immunization of mice with the PsaA-BLyS fusion protein resulted in dramatically elevated serum antibodies specific for PsaA. Mice immunized with PsaA admixed with recombinant BLyS exhibited only modest elevations in PsaA-specific responses following two immunizations, while mice immunized twice with PsaA alone exhibited undetectable PsaA-specific serum antibody responses. Sera obtained from PsaA-BLyS immunized mice exhibited high titers of IgG1, IgG2a, IgG2b, and IgG3, but no IgA, while mice immunized with PsaA admixed with BLyS exhibited only elevated titers of IgG1 following two immunizations. Splenocytes from PsaA-BLyS immunized mice exhibited elevated levels of secretion of IL-2, IL-4 and IL-5, and a very modest but consistent elevation of IFN-γ following in vitro stimulation with PsaA. In contrast, mice immunized with either PsaA admixed with BLyS or PsaA alone exhibited modestly elevated to absent PsaA-specific recall responses for the same cytokines. Mice deficient for one of the three receptors for BLyS designated Transmembrane activator, calcium modulator, and cyclophilin ligand [CAML] interactor (TACI) exhibited attenuated PsaA-specific serum antibody responses following immunization with PsaA-BLyS relative to wild-type littermates. TACI-deficient mice also exhibited decreased responsiveness to a standard pneumococcal conjugate vaccine.ConclusionThis study identifies covalent attachment of BLyS as a highly effective adjuvant strategy that may yield improved vaccines. In addition, this is the first report demonstrating an unexpected role for TACI in the elicitation of antibodies by the PsaA-BLyS fusion protein.ReviewersThis article was reviewed by Jonathan Yewdell, Rachel Gerstein, and Michael Cancro (nominated by Andy Caton).
Highlights
B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors
Our results indicate that fusion of BLyS to the test pneumococcal antigen Pneumococcal Surface Adhesin A (PsaA), results in enhanced PsaA-specific cellular and antibody responses, compared to immune responses elicited by simple co-administration of BLyS together with PsaA or PsaA alone in the absence of conventional adjuvants
The development of protective vaccines against mucosal infection must incorporate the capacity for eliciting cell-mediated (CD4+ T cell) responses characterized by IFN-g and/or IL-17 production in response to antigens from such pathogens
Summary
B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors. B lymphocyte stimulator (BLyS, designated TALL-1, THANK, BAFF, TNFSF13b, and TNFSF20) is a member of the tumor necrosis factor superfamily of ligands [1,2]. Our laboratory has been interested in attempting to define mechanisms that influence the elicitation of antibody responses in the mammalian host In this regard, we have been interested in strategies that increase the magnitude and diversity of antibody isotypes and cellmediated immune responses to antigens of interest, while minimizing non-specific and frequently deleterious immune responses that normally accompany the use of powerful adjuvants such as complete Freund’s adjuvant (CFA) and other bacterially derived products [10]. Transgenic mice that over-express the human ortholog of BLyS exhibit marked splenomegaly characterized by elevated numbers of B cells, as well as elevated concentrations of serum antibodies [11,12]. A similar, though transitory elevation in serum immunoglobulin has been observed following daily administration of purified BLyS to mice
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