Many tissue-restricted autoimmune and inflammatory disorders, including arthritis, psoriasis and cutaneous T cell lymphoma, are characterized by infiltrates of memory T cells. Development and progression of these disorders is influenced by the ability of memory T cells to home to their target sites in a highly specific fashion. Although lymphocyte trafficking to secondary immune tissues is well-studied, the mechanisms regulating T cell homing to non-immune tissues remain obscure. As with other leukocytes, T cells can tether and roll on vessel walls via selectins as the initial part of a multi-step pathway leading to extravasation into tissues. Chronically inflamed tissues have been found to express high levels of E-selectin (cutaneous) or P-selectin (joints). Leukocyte ligands for the endothelial selectins are sialylated, fucosylated carbohydrates expressed on surface glycoproteins. We have preliminary evidence that subpopulations of peripheral blood T cells express their primary ligands for E-selectin and P-selectin on the same protein scaffold, P-selectin glycoprotein ligand-1 (PSGL-1), and can regulate expression of the carbohydrate portion of these ligands independently. Reports suggest that PSGL-1 may also bear L-selectin ligand activity, though the relationship of this to other ligands is unknown. The specific hypotheses to be tested in this proposal are: 1) T cell E-selectin, P-selectin and L-selectin ligand activities are independently expressed on a common PSGL-1 protein scaffold as structurally and functionally distinct post-translational modifications; and 2) decoration of PSGL-1 with epitopes conferring selectin ligand activity is regulated via the activity of alpha-1,3- fucosyltransferases, the terminal component of the relevant carbohydrate biosynthesis cascade. These hypotheses will be directly tested as outlined in the specific aims of this proposal. Identification of the mechanisms controlling the production of leukocyte selectin ligands may define avenues for intervention in the regulation of T cell homing in chronic inflammatory disorders and lymphoid tumor metastasis.
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