Murine IgG1 and IgG3 Isotype Switch Variants Promote Phagocytosis of Cryptococcus neoformans through Different Receptors

Almost 3 decades ago, murine IgG3 was proposed to interact with a different receptor than the other IgG subclasses, but the issue remains unresolved. The question of whether a specific receptor exists for IgG3 is critically important for understanding Ab-mediated immunity against Cryptococcus neoformans, where the different isotypes manifest profound differences in protective efficacy. In this study, we revisited this question by analyzing IgG1- and IgG3-mediated phagocytosis with variable region-identical mAbs using mouse macrophages deficient in various receptors and in conditions of FcgammaR and complement receptor blockage with specific Abs. IgG3 was an efficient opsonin for C. neoformans in FcgammaR- and CD18-deficient cells and in the presence of blocking Abs to FcgammaR and complement receptor. Like IgG1, IgG3-mediated phagocytosis was associated with fungal residence in a mature phagosome that was followed by intracellular replication and exocytosis events. We conclude that a specific receptor for IgG3 exists in mice that is structurally different from the known FcgammaRs.