Tissue niche occupancy determines the contribution of fetal- versus bone-marrow-derived macrophages to IgG effector functions

Understanding the mechanisms underlying cytotoxic immunoglobulin G (IgG) activity is critical for improving therapeutic antibody activity and inhibiting autoantibody-mediated tissue pathology. While prior research highlights the important role of the mononuclear phagocytic system for removing opsonized target cells, it remains unclear which monocyte or macrophage subsets stemming from fetal or post-natal bone-marrow (BM)-associated definitive hematopoiesis are involved in target cell depletion. By using a titrated irradiation approach as well as Kupffer-cell-specific deletion of activated Fcγ receptor signaling, we establish conditions under which the contribution of BM-derived monocytes versus yolk-sac-derived liver-resident macrophages to cytotoxic IgG activity can be studied. Our results demonstrate that liver-resident macrophages originating from either fetal or adult hematopoiesis play a central role in IgG-mediated depletion of opsonized target cells from the peripheral blood under steady-state conditions, highlighting the impact of the tissue niche and not macrophage origin for cytotoxic antibody activity. [Display omitted] •IgG-opsonized cells in the peripheral blood become depleted in the liver•Fetal-derived Kupffer cells are the main effector cell population•Bone-marrow-derived macrophages can functionally replace Kupffer cells•Niche occupancy, and not macrophage origin, determines cytotoxic IgG activity Cytotoxic antibodies are a central component in the therapeutic toolbox to treat cancer and autoimmunity. In this study, Wöhner et al. show that liver-resident macrophages mediate cytotoxic antibody-dependent depletion of target cells in the peripheral blood.