Chemokine Receptor CCR7 In Tissue-Specific T Cell Imprinting and Autoimmunity

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DESCRIPTION (provided by applicant): Chemokine receptor CCR7 is a key regulator of both the initiation and anamnestic phases of T cell mediated immune responses. By controlling dendritic cell (DC) and T cell movements throughout the body, CCR7 can influence the balance of T cell responses towards either immunity or tolerance. Much of our knowledge relevant to the function of this receptor comes from studies of mice genetically deficient in CCR7 itself or its ligands. CCR7-deficiency results in dramatic effects throughout the immune system. Abnormalities include a global paucity of T cells; absence of naive T cells from lymph nodes; absence of various dendritic cell (DC) subsets from lymphoid organs and an increased occurrence of autoimmune symptoms. Importantly, CCR7- deficiency results in profound morphological abnormalities of the secondary lymphoid organs. Our preliminary data demonstrate that many of the abnormalities observed in these mice are most likely secondary effects of the abnormal lymph node architecture. Thus, many effects previously attributed directly to CCR7 function are in reality caused by a paucity of lymphoid microenvironments able to support normal immune function. We believe that this new, paradigm-shifting information requires us to take a "back-to-the-drawing-board" approach to more fully understand the various roles played by CCR7 in the development of immune responses within mature animals. We propose experiments that will ask: 1) How can CCR7-/- cells participate normally in tissue- specific immune responses when their precursors are exceedingly rare in the sites believed to generate tissue- specific responses? 2) Is CCR7 truly required to influence the balance between immunity and tolerance by regulating the generation of Treg cells? Our recent findings will allow us to explore CCR7 as a potential target for clinical intervention in various human autoimmune diseases, tumor immunogenicity and graft rejection. PUBLIC HEALTH RELEVANCE: CCR7 is a receptor expressed by various cells in the immune system, and it is tough to allow these cells to interact with one another to generate an immune response. This receptor has been well studied, and mice lacking this receptor have many abnormalities in their ability to mount normal immune responses. However, we have recently discovered that many of the abnormalities associated with this receptor are actually the result of malformed lymph nodes, where immune cells interact, rather than direct results of the missing receptor. This new finding requires us to re-evaluate the role played by this receptor in immune responses, which we hope to explore if this project is funded. If the conclusions from our initial findings prove correct, drugs targeting CCR7 may be useful for treating diseased that involve an over-active immune system.