- It has become clear that many chronic skin diseases characterized by cutaneous inflammation, such as psoriasis, cutaneous T cell lymphoma (CTCL), and atopic dermatitis are mediated by T cells. Furthermore, memory T lymphocytes bear cell surface molecules that permit them to home preferentially to various tissues, including skin. A subset of memory T cells bear a marker called cutaneous lymphocyte antigen (CLA) recognized by a unique monoclonal antibody HECA-452. CLA is found on T cells in cutaneous infiltrates in a wide variety of skin diseases including CTCL, psoriasis, atopic dermatitis, and graft versus host disease, but is not found on T cells that infiltrate other organs. In vitro, expression of CLA also correlates with binding of T cells to E selectin, perhaps the earliest requisite step in the extravasation of T cells through postcapillary venules walls into the dermis. Beyond the presence of a sLex-related tetrasaccharide structure recognized by HECA-452, the structure of CLA is completely obscure. The applicant has generated significant preliminary data that address the molecular identity of CLA; these data are made possible by the identification of culture conditions that allow for the generation of homogenous populations of CLA-positive T cells (as well as matched control CLA-negative T cells) and the analysis of their tethering and rolling properties in a flow chamber. Western analysis, using antibodies to PSGL-1 and HECA-452 antibody, indicate that both recognize similar, if not identical, antigens on CLA+ and E-selectin-binding T cells. The specific hypotheses that this grant proposal will test are as follows: (i) The protein core of CLA is similar, if not identical, to PSGL-1, a widely expressed leukocyte P-selectin ligand, and (ii) differential post-translational modification of PSGL-1 by a specific alpha (1,3) fucosyltransferase, FucTVII, determines both the expression of the CLA/HECA-452 reactive epitope on T cells and their capacity to bind well to E-selectin. A related hypothesis is also adavanced: (iii) T cell expression of FucTVII is a central determinant of whether a T cell that undergoes the naive-to-memory transition becomes a CLA+ skin homing T cell. These hypotheses will be directly tested. If as indicated by preliminary data, FucTVII regulation defines T cell homing to skin, this enzyme and its substrates may represent important targets for drug discovery relevant to diseases such as CTCL, atopic dermatitis, and graft versus host disease.
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