Antibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis.

Background: B 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 BLySin vivo.Methods: We 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 BLySin vivowere evaluated by characterizing immune responses directed against PsaA.Results: The PsaA-BLyS fusion protein was able to act as a co-stimulant for murine spleen cell proliferation induced with F(ab')₂fragments of anti-IgMin vitroin 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 followingin vitrostimulation 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.Conclusion: This 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.Reviewers: This article was reviewed by Jonathan Yewdell, Rachel Gerstein, and Michael Cancro (nominated by Andy Caton).

Design Challenges for HIV-1 Vaccines Based on Humoral Immunity

The seminal discovery in the early 1970s, credited to Peter Doherty and Rolf Zinkernagel, of major histocompatibility complex (MHC) restriction exhibited by cytotoxic T cells represented a major conceptual advance in understanding antigen recognition by conventional T cells. This advance also led to other major new insights into the ontogeny and immunobiology of T cells and catalyzed a renaissance in viral immunology. In this commentary in honor of Peter Doherty, I offer five brief reflections on different aspects of the phenomenon of MHC restriction and the process by which it was discovered and explained. In the first of these sections, I offer a reinterpretation of MHC restriction that reframes the constraints on self-MHC recognition in terms of the probabilities of recognizing a given nominal antigen peptide in the context of an MHC molecule that is nonself on the basis of differing in amino acid sequence from the self-restriction element at one or more positions. Subsequent sections address: (i) the ways in which general ideas, developed subsequent to the discovery of MHC restriction, about the intricacies of antigen recognition by antibodies apply to T cell receptors binding to MHC/peptide complexes; (ii) how to reconcile the existence of MHC restriction with the impressive magnitude of T cell responses to nonself MHC antigens; (iii) the possible relevance to MHC restriction and immune system function of ideas from mathematical logic that relate to the consequences of self-reference; and (iv) the implications for the philosophy of science of MHC restriction and the processes of its discovery and acceptance within the immunology research community.