Chemokine basis of skin specific T cell homing

Yale University, New Haven CT

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Abstract

The discovery of a cutaneous T cell attracting chemokine (CTACK) expressed exclusively in skin is an exciting development. Because expression of the normally transient adhesion molecule E-selectin has been found to persist on the vascular endothelium of many human organs in addition to that of the dermal vascular endothelium, persistent expression of E-selectin is alone insufficient to explain the skin-specific homing of human memory T cells expressing cutaneous lymphocyte-associated antigen (CLA; an E-selectin ligand). CTACK is a novel CC chemokine expressed in human skin but not in other organs, and has been shown to preferentially recruit the subset of CLA+ skin-homing T cells. We hypothesize that homing of CLA+ T lymphocytes to inflamed dermal endothelium expressing E-selectin is skin specific due to presentation of CTACK by human dermal micro vascular endothelial cells (HDMEC). The questions addressed first by this proposal, HDMEC expression of CTACK, HDMEC transcytosis of CTACK, and HDMEC surface presentation of CTACK, are each distinct, important, and unanswered questions. They represent Aim 1 of a careful investigation relevant to basic EC biology as well as to skin disease and will be explored during the first year of funding. It is known that CTACK is chemotactic for skin-homing T cells, but not whether it is synergistic or redundant with E-selectin, or selective for TH1 CLA+ or TH2 CLA+ T cells. These first of these questions will be examined later in the first year (Aim 2) and pave the way for future experiments (Aims 3 and 4). The proposed first year experimental plan is thus a feasibility study in that it provides the groundwork for the more far reaching objectives of the later Aims. This is reflected in the project title and in the inclusion of Aims 3 and 4 as future objectives of the Research Plan.