Defining the Fc receptor-mediated trafficking of IgG-antigen complexes in macrophages

Macrophages represent the most abundant antigen presenting cells in inflammatory infiltrates and tumors. An important immunoregulatory function of macrophages is to present antigen to cognate T cells. Antibody (IgG)-antigen complexes are internalized into macrophages through potential interactions with multiple different Fc receptors and are subsequently delivered to subcellular compartments where peptides derived from the proteolyzed antigen can be loaded onto MHC molecules. However, the multitude of possible Fc receptor interactions with the antibody-antigen complexes influences the spatial and temporal behavior of antigen and consequent peptide-MHC repertoire through a complex, and poorly understood, network of subcellular trafficking pathways. We have developed advanced microscopy tools to enable the analysis of three-dimensional, dynamic cellular processes at unprecedented levels of spatiotemporal resolution. We will combine these approaches with antibody engineering and analyses in mouse models of cancer and autoimmunity to elucidate how the combination of antigen delivery vehicle, microenvironmental factors and macrophage phenotype interplay to result in specific antigen presentation outcomes. The two long term goals of these studies are: one, to develop novel mechanistic insights into the fundamental cell biological processes determining the repertoire of presented antigens; two, to define how to deliver antigen to macrophages to orchestrate a predictable immune response.