The Role of CCR4 in Skin Lymphocyte Homing and Immunity

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DESCRIPTION (provided by applicant): Expression patterns of the chemokine receptor CCR4 and its ligand CCL17 in humans suggests that interaction between these two molecules may contribute to skin-specific T lymphocyte homing and cutaneous inflammation. However, this assumption relies upon circumstantial evidence, and requires direct testing. Fortunately, CCR4 expression is also associated with cutaneous lymphocyte homing in the mouse, which allows the role of CCR4 in skin-specific T cell homing to be directly tested animal models. Current efforts to study the role of chemokine receptors in murine skin-specific T cell homing have relied largely upon a topical DNFB-induced inflammation model. We have recently demonstrated that DNFB-induced cutaneous edema occurs in T cell-deficient mice with the same intensity as it occurs in wild type (WT) mice. This suggests that the DNFB model (at least with its currently-used readout) is T cell independent, and therefore may not be relevant to human T cell-mediated skin inflammation. We have therefore developed a truly T cell-dependent model of skin inflammation, in which we will use targeted-gene-deficient mice and pharmacological inhibitors to precisely determine the roles of CCR4 and other skin-associated homing molecules (including CCR10 and E- and P-selectin) in cutaneous T cell trafficking and inflammation. We will: 1) use an anti-OVA-TCR-transgenic adoptive-transfer model to examine the role of skin-associated T cell homing molecules in cutaneous inflammation; 2) use a direct cutaneous OVA sensitization-and-challenge protocol to determine the role of these homing molecules in development of T cell memory responses to cutaneous antigens; and 3) use a competitive adoptive transfer approach to determine whether T cells lacking skin-associated homing receptors can participate in cutaneous inflammatory skin responses in the presence of competing WT cells. These studies may help determine the best candidates for medical intervention in human cutaneous inflammatory disorders, such as allergic dermatitis and psoriasis.