Dermal Lymphatic Transport and Cutaneous Immune Balance

PROJECT SUMMARY While we have established a tremendous amount of knowledge interrogating intrinsic leukocyte biology to inform a breadth of immunotherapeutic approaches, more can be done to understand how cutaneous immune responses are regulated and to translate that understanding into therapies that combat cutaneous immune imbalance (autoimmunity, chronic inflammation, malignancies). The goal of this proposal is to elucidate mechanisms of lymphatic transport that contribute to local inflammation and adaptive immune induction to provide novel insight into how we may tune immune responses in vivo. Our published and preliminary work establishes the dermal lymphatic vasculature 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. Whether these same mechanisms are activated across cutaneous immune phenotypes and how changes in lymphatic transport directly impact immunity remains unknown. In this proposal we test the hypothesis that dermal lymphatic vessels exhibit active, context-dependent functional remodeling to coordinate cutaneous immune surveillance. This hypothesis will be tested along two aims: (1) we will evaluate the crosstalk between lymphatic transport and the interstitial, inflammatory microenvironment in skin; (2) determine the functional significance of lymphatic zippering in adaptive immune activation in draining lymph nodes. To complete these aims, we couple genetic tools with robust immunological assays and high-resolution imaging to resolve the systems-level interactions between skin and draining lymph nodes in vivo as a function of the connecting lymphatic vasculature. We propose that lymphatic vessel transport is a poorly understood but active determinant of cutaneous immune responses and that identification of specific molecular mechanisms that regulate their function provides novel therapeutic opportunities to tune immunity up or down. 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 manage immunological reactions in skin. In this way our work may help to inform clinical vaccine development and immunotherapy and may identify targets to maintain tolerance during homeostasis and in response to therapy (e.g. immune checkpoint blockade).