PROJECT SUMMARY/ABSTRACT IgG antibodies are central mediators of human immunity that can both protect against infections and have the potential to mediate autoimmune diseases. While antibody-mediated immunity has been studied for decades, the heterogeneity that exists among people in IgG-mediated effector capabilities is only now being fully appreciated. This heterogeneity arises from differences in the structural determinants of IgG Fc domains; this, in turn, impacts Fc-Fc receptor interactions which mediate antibody effector functions. Our ongoing experiments have defined distinctions in immune functioning and susceptibility to diseases that arise from Fc domain diversity. Specifically, we have found that specific Fc domain repertoires can enhance vaccine responses and increase susceptibility to disease during dengue infection. Given these findings, a critical question emerges: how is the Fc domain repertoire regulated? Studies in this proposal are designed to identify regulators of the IgG Fc domain repertoire. We will define how heritable influences, age and sex influence the repertoire. In addition, we will study how basal Fc domain repertoires impact durable B and T cell responses to vaccination. Mechanisms regulating the Fc domain repertoire are of great interest since shifting the repertoire could potentially be done for therapeutic benefit in diseases responsive to IVIG treatment, to enhance the activity of anti-tumor antibodies, to prevent autoantibody-mediated tissue diseases, or to enhance the quality of antibodies generated during vaccination.