- 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041707-02
Application #
2673071
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1997-09-08
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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