Role of EPCR in gamma delta T cell wound healing functions

描述(申请人提供)：蛋白C途径在凝血、炎症和伤口愈合中发挥重要作用。内皮蛋白C受体(EPCR)是活化蛋白C(APC)的特异性受体。EPCR是由人角质形成细胞表达的，可能促进细胞在正常皮肤动态平衡和伤口愈合中的存活、生长和迁移。有趣的是，EPCR最近被描述为内皮细胞和上皮性肿瘤上的一种应激调节分子，它可以直接与人的V？4V？5T细胞受体结合，并在CMV感染和恶性反应中诱导T细胞的扩张。EPCR是一种结构类似于MHC分子的1型跨膜蛋白，与CD1d类似的脂类结合。总而言之，这些发现提出了一种可能性，即EPCR可能会刺激T细胞在不同条件下的应激反应，包括组织损伤。事实上，位于上皮组织中的T细胞为抵御感染、创伤提供了至关重要的第一道防线。 和恶毒。在皮肤中，树突状表皮T细胞(DETC)表达一种识别受损或疾病角质形成细胞表达的未知抗原的单抗V？3V？1TCR。我们建议检验这一假设，即EPCR可以向邻近的DETC提供表皮损伤或疾病的应激信号，以激活它们的伤口愈合功能。我们将通过确定DETC TCR是否可以与EPCR相互作用以及通过调查伤口愈合过程中EPCR的表达是否影响表皮T细胞伤口愈合反应来检验这一假说。如果被发现是T细胞激活的原型应激信号，那么在未来改善慢性伤口以及其他皮肤炎症性疾病和恶性肿瘤的愈合的策略中，EPCR可能是一个有用的目标。

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.