The ability of the immune system to deliver the appropriate effector T cell to the anatomically correct place at the right time is essential for successful host defense. A widely held paradigm states that after initial exposure to antigen in lymph nodes draining a particular organ (e.g., skin), effector memory T cells are generated that express cell surface markers and chemokine receptors that facilitate their entry selectively into that organ (skin), but not into others (e.g., lung, gut). These markers include Cutaneous Lymphocyte antigen (CLA, a ligand for E and P selectin which we characterized extensively in the first cycle of funding), the chemokine receptor CCR4, and LFA-1. In parallel, a population of central memory T cells that express L selectin (ligand for PNAd expressed in lymph node postcapillary venules) and the chemokine receptor CCR& (ligand for Secondary Lymphoid Chemokine or SLC) are generated in the skin draining lymph node; these cell surface markers permit central memory cells to traffic like na?ve I cells and enter lymph node from blood. It was previously thought that the above CLA+ population of T cells lost either L selectin, CCR7, or both, and thus could not access the lymph node from blood like central memory T cells. We have demonstrated, however, that a large population of T cells in peripheral blood bears markers of both central memory T cells (L selectin, CCR7) and effector memory T cells (CLA, CCR4). We predict that these cells have the capacity to not only enter skin (particularly inflamed skin), but also lymph nodes throughout the body. In this proposal, we will analyze the phenotype and function of each of these populations of T cell, derived from blood and skin, with regards to their potential to extravasate at different anatomic sites. Moreover, we will examine T cells from skin and blood of patients with Cutaneous I Cell Lymphoma at different stages of disease, as we hypothesize that CTCL is a malignancy of the skin homing memory T cell. These experiments should help address questions about the plasticity of the organ specific homing response. Finally, we will use newly developed transgenic models and newly developed reagents to rigorously test the hypothesis that where a naive T cell encounters antigen determines its subsequent homing potential. This hypothesis is supported by substantial evidence; however, most of it is circumstantial. Taken together, these studies will allow us to further advance the paradigm of organ specific homing of effector and memory T cells. This should add to our fundamental understanding of both normal immunosurveillance as well as T cell mediated organ specific inflammatory disease.
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