The continuous migration of immune cells to lymph nodes (LN) is of utmost importance for the induction of both protective immunity as well as immunological tolerance. Despite this pivotal role, little is known regarding migration paths and the molecular cues regulating homing of immune cells that arrive via afferent lymphatic vessels to LN. This conspicuous lack of knowledge is primarily due to profound technical limitations. My team and I have recently developed a highly innovative technique of micromanipulator-guided injections into afferent lymph vessels that drain into the popliteal LN of living mice allowing precise delivery of very low numbers of cells into a LN. This approach, in combination with multicolor 2-photon in vivo microscopy, will now allow new and ground-breaking insights in routes, cellular and molecular mechanisms that regulate entry of cells reaching LNs via afferent lymphatics. Specifically, we aim to 1) characterize the homing potential of lymph-derived naïve B cells, naïve CD8 T cells, and regulatory T cells and study their contribution to LN homeostasis; 2) initiate and quantify primary immune responses to model antigens as well as pathogens mediated by naïve T cells that homed to LN via afferent lymphatics; 3) characterize memory immune responses mediated by different subpopulations of effector/memory cells that homed to LN via afferent lymphatics; 4) study the role of neutrophilic and eosinophilic granulocytes in adaptive immune responses; 5) identify homing molecules and mechanisms that allow DCs and metastasizing tumor cells to penetrate the floor of the LN subcapsular sinus.
Results obtained from these studies will provide fundamentally new insights in processes that regulate immune cell homing to LN and the induction of primary and recall memory immune responses. Furthermore, this information will build a broad basis for the development of novel vaccination strategies and to understand how to interfere with tumor spread to LNs.
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