Role of EPCR in gamma delta T cell wound healing functions

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DESCRIPTION (provided by applicant): The protein C pathway plays important roles in coagulation, inflammation and wound healing. The endothelial protein C receptor (EPCR) is the specific receptor for activated protein C (APC). EPCR is expressed by human keratinocytes and may promote cell survival, growth and migration in normal skin homeostasis and wound healing. Interestingly, EPCR was recently described as a stress- regulated molecule on endothelial cells and epithelial tumors that could directly bind to a human V?4V¿5 T cell receptor and elicit expansion of the T cells in response to CMV infection and malignancy. EPCR is a type 1 transmembrane protein that is structurally similar to MHC molecules and binds lipids analogous to CD1d. Together these findings raise the possibility that EPCR may stimulate the stress response of ?¿ T cells under different conditions, including tissue damage. Indeed, ?¿ T cells that reside in epithelial tissues provide a crucial first line of defense against infection, trauma and malignancy. In the skin, dendritic epidermal T cells (DETC) express a monoclonal V?3V¿1 TCR that recognizes an unknown antigen expressed by damaged or diseased keratinocytes. We propose to test the hypothesis that EPCR can provide a stress-signal of damage or disease in the epidermis to neighboring DETC to activate their wound healing functions. We will test this hypothesis by determining if the DETC TCR can interact with EPCR and by investigating whether EPCR expression during wound healing impacts epidermal ?¿ T cell wound healing responses. If found to be a prototypic stress-signal for ?¿ T cell activation, EPCR may then be a useful target in future strategies to improve healing of chronic wounds as well as other skin inflammatory diseases and malignancies.