Distinction of skin homing T cells that bind P-selectin

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DESCRIPTION (provided by applicant): T cells play a pathogenic role in many inflammatory and particular malignant skin diseases. The cutaneous lymphocyte-associated antigen (CLA) distinguishes human T cells that selectively home to the skin. CLA is a sialyI-Lewis x-related carbohydrate and its detection indicates the expression of certain glycosyltransferases necessary for the biosynthesis of carbohydrate ligands for the vascular adhesion molecules E-selectin and P-selectin. However, the carbohydrate structures recognized by E- and P-selectin on T cells are not identical. The biosynthesis of E-selectin carbohydrate ligands requires the enzyme al,3- fucosyltransferase-VII (FucT-VII), whereas P-selectin carbohydrate ligands require both FucT-VII and the Oglycan branching enzyme core 2 beta1,6 N-acetylglucosaminyltransferase (C2GnT). Importantly, these enzymes are regulated by different signals during T cell differentiation, which may result in effector T cells polarized in their expression of carbohydrate ligands for E-, P-selectin, or both. A limitation of CLA is that its biosynthesis does not require C2GnT and so its detection would not directly indicate the expression of Pselectin carbohydrate ligands nor would this phenotypic marker distinguish E- vs. P-selectin binding T cell subsets. We have characterized a novel mAb (CHO-131) that requires the expression of both FucT-Vll and C2GnT for reactivity and selectively recognizes a core 20-glycan when terminated with sialyI-Lewis x. This carbohydrate motif has been directly shown to confer high-affinity binding by P-selectin. CHO-131 stains a population of effector/memory lymphocytes that represent a subset of CLA* T cells. These findings provide important new evidence that CLA* T cells may be a mixed population consisting of subsets that differentially bind to E- and P-selectin. We hypothesize that CHO-131" T cells preferentially express high affinity carbohydrate ligands for P-selectin and infiltrate T cell-mediated skin lesions. Our first objective is to compare the E- and P-selectin binding capacity of CHO-131*/CLA* and CHO-131/CLA* T cells. Our second objective is to determine the level of infiltration by CHO-131" T cells and CLA* T cells in various T cellmediated skin diseases. The rationale for the proposed study is that preventative and therapeutic T cellbased treatments may be optimized if the components, mechanisms, and regulation of T cell trafficking to the skin can be understood and manipulated.