Endothelial Protein C Receptor regulates skin gamma delta T cell functions

Abstract

Abstract The molecular interactions controlling gamma delta (γδ) T cell functions remains poorly understood as these cells do not express many of the costimulatory receptors known to regulate alpha beta T cell activation. Dendritic epidermal T cells (DETC) are prototypic γδ cells that promote tissue homeostasis by producing keratinocyte survival factors under steady state conditions and locally releasing epithelial cell mitogens upon stimulation by skin wounding. Endothelial Protein C Receptor (EPCR) is an MHC class I-like molecule recently demonstrated to be a TCR ligand for a subset of human γδ T cells. In the skin, EPCR is expressed by keratinocytes and has been implicated in skin wound repair in vitro. We therefore hypothesized that DETC recognize and are functionally dependent on cutaneous EPCR expression. We show that mutant mice with reduced expression of EPCR display delayed repair of experimental skin wounds. This wounding phenotype is associated with reduced cellular markers of activation and defective production of inflammatory cytokines by DETC. Conversely, EPCR is highly upregulated in normal keratinocytes proximal to wound sites. EPCR may engage DETC directly as a subset of these cells express the known EPCR binding partner, CD11b, and wound proximal DETC appear to bind a soluble form of EPCR. Collectively, our data indicates that EPCR serves a costimulatory molecule for skin-resident γδ T cells.