MECHANISMS OF T LYMPHOCYTE MIGRATION INTO SKIN

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The group of cutaneous T cell lymphomas (CTCL) typified by mycosis fungoides is characterized by the persistent infiltration of memory T lymphocytes into the epidermis. Alternatively, other cutaneous lymphomas (e.g., cutaneous B cell lymphoma or CBCL) are not characterized by epidermal migration. Rather, in CBCL the infiltrating cells are localized to the reticular (or deep dermis). These histological findings imply a specific recognition of the epidermis by T cells in mycosis fungoides. However, the precise mechanisms by which T cells penetrate the basement membrane and accumulate in the epidermis are unknown. The underlying hypothesis of the present proposal is that keratinocyte adhesion molecules are pivotal to epidermal migration of T cells in CTCL. This includes matrix molecules synthesized by keratinocytes (basement membrane) as well as their cell surface components (cell adhesion molecules or CAMs). Although the CD18/ICAM pathway has been postulated to play a major role in determining T cell adhesion to activated keratinocytes, ICAM is not expressed in basement membranes, and focal exocytosis of T cells has been observed in the absence of ICAM expression on nearby keratinocytes. These findings suggest that ICAM independent adhesion pathways exist in the skin that can be utilized by epidermotropic T cells. In this proposal we will identify ICAM independent pathways which operate in the adhesive recognition of keratinocytes by cutaneous T cells. As a model system we will use a cultured T cell line derived from patients with CTCL (HUT 78), freshly derived T cells from the skin and blood of patients with CTCL, and basal keratinocytes derived from neonatal foreskins (HFKs). This proposal has three objectives: 1) To determine how cutaneous T cells interact with the extracellular matrix deposited by cultured keratinocytes. These experiments will be focused on the function and regulation of the alpha3beta1 integrin receptor. 2) To determine how T cells interact with keratinocyte cell surface adhesion molecules other than ICAM. These experiments will be focused on the function and regulation of E-cadherin expressed by cutaneous T cells. 3) To determine how these adhesive events are coordinated in CTCL and contribute to epidermal homing in an in vivo model. These studies will provide valuable new information on the role of adhesion molecules in T cell epidermal trafficking in CTCL and cutaneous inflammation.