Antibody-mediated immunity to Cryptococcus neoformans : Understanding the role of murine IgG3
Saylor, Carolyn Alice
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Cryptococcus neoformans (Cn) is an encapsulated yeast that causes life-threatening meningitis in immunocompromised patients. Understanding the immune response and developing new therapeutics are critical to control this disease. Cellular immunity is important for controlling Cn infection, and although the role of antibody (Ab) is less clear, administering specific Ab to Cn can alter disease progression.;Observations of passive Ab modulation of Cn infection have shown that the isotype of Ab has a profound impact, where one isotype confers protection while another is non-protective or even disease-enhancing. To explore the mechanism of this isotype difference, we compared the in vivo effects of IgG1 or IgG3 isotype switch variants of a Cn-specific monoclonal antibody (mAb) on the course of infection, showing that the protective effect depended on both amount of mAb and size of Cn inocula, such that a protective effect was not a fixed quality of either IgG1 or IgG3.;We hypothesized that the different effects of these mAbs in vivo could be explained by their interactions with effector cells, so we compared the IgG1 and IgG3 mAbs in the interaction of Cn and macrophages. Almost three decades ago murine IgG3 was proposed to interact with a different receptor than the other IgG subclasses, but this receptor has not been identified. We found that IgG3 was an efficient opsonin for Cn in both (1) FcgammaR-deficient cells in the presence of CR blockage, and (2) CD18-deficient cells in the presence of FcgammaR blockage, whereas IgG1 phagocytosis was abrogated in these conditions. Using Scatchard analysis, we confirmed that IgG3 binds specifically to cells lacking FcgammaRs, whereas IgG1 does not. We conclude that a specific receptor for IgG3 exists in mice that is structurally different from known FcgammaRs.;Determining that IgG3 uses a receptor that is different from the known FcgammaRs has a profound impact on our understanding of the action of Abs in mice, as well as the development of mAb treatments for humans.