Lymphatic control of germinal centers

PROJECT SUMMARY The immune system relies on a carefully orchestrated network of spatially organized compartments to function effectively. These architectural ‘hubs’ exist in the form of secondary and tertiary lymphoid organs. Immune cells traffic through immune organs via the lymphatic vasculature, a network of vessels which, in addition to providing a transport route for antigens, cells, and metabolites, also plays active roles in regulating host immunity. Our published and preliminary work establishes the lymphatic vasculature in the skin as a necessary route for both immune activation (ON) and immune resolution (OFF) signals. Further, we have demonstrated that dermal lymphatic vessels remodel their inter-endothelial junctions (termed ‘zippering’) with functional consequences for pathogen dissemination and immune induction. Our preliminary data now indicates that infection-induced lymphatic remodeling tunes the germinal center response and thereby facilitates the generation of antibody- dependent protective immunity. What regulates perifollicular lymphatic growth in the context of inflammation and whether lymphatic vessels play an architectural role in dictating germinal center area remains completely is unknown. In this proposal we aim to test the hypothesis that peri-follicular lymphangiogenesis shapes germinal center responses by constraining GC size and thereby optimizing the search space for GC B cell selection and antibody output. We will test this hypothesis in two aims: (1) we will elucidate the mechanisms governing lymphangiogenesis in acute and homeostatic inflammation in different tissue microenvironments; (2) determine the functional consequences of lymphatic encapsulation of B cell follicles on germinal center dynamics. To complete these aims, we couple genetic tools with robust immunological assays and high-resolution imaging to resolve the systems-level interactions between lymphoid organ organization, germinal centers, and antibody responses in vivo as a function of the connecting lymphatic vasculature. We propose that lymphatic vessel transport is a poorly understood but active determinant of germinal center fitness and that identification of specific molecular mechanisms that regulate their function provides novel therapeutic opportunities to direct the quality of antibody responses. Our work will not only develop our physiological understanding of lymphatic transport and its contribution to immunity but further suggest novel design principles for how to instruct optimal immunological reactions during vaccination, infections, or autoimmunity. In this way our work may help to inform clinical vaccine development and immunotherapy and may identify targets to maintain tolerance during homeostasis.