The Regulation of Dendritic Epidermal T Cell Function by C-C Motif Chemokine Ligand 20

The skin is the largest organ in the body and provides a first line of defense from foreign pathogens. Many different cell types within the skin work together to aid in wound repair when damage occurs. Dendritic epidermal T cells (DETC) play key roles in tissue repair by secreting growth factors, cytokines, and chemokines to facilitate keratinocyte proliferation and regulate inflammatory responses following tissue damage. Cellular receptors such as the γδ T cell receptor (TCR) are necessary for regulating DETC in vivo. C-C Chemokine Receptor 6 (CCR6) regulates dermal γδ T cell migration to the epidermis during tissue damage and infection, however, little is known about how this receptor works with the TCR to regulate DETC. Previous work in our laboratory identified CCR6 as a receptor that is downregulated by murine DETC during obesity and type 2 diabetes. The major ligand for CCR6 is C-C Motif Chemokine Ligand 20 (CCL20), which induces cellular migration. In this study, I investigated the role of CCR6 in regulating DETC function in the murine epidermis. DETC were harvested and stimulated in the presence or absence of CCL20 and anti-CD3 to determine how CCL20 regulates DETC cytokine and chemokine production using flow cytometry, Luminex analysis and immunofluorescent microscopy. Our studies indicate that CCR6 is expressed by DETC upon activation, allowing the identification of 3 subpopulations: CCR6- CD25-, CCR6- CD25+ and CCR6+ CD25+ cells. While dermal γδ T cells that express CCR6 show the ability to migrate toward CCL20, our data suggests that CCL20 prevents DETC from becoming migratory. Beyond migration, CCL20 stimulates DETC to produce several proinflammatory cytokines and chemokines including IP-10, IL-6, MIP-2 and Eotaxin. In addition, CCL20 costimulates TCR activation in DETC with the production of IL-2, IL-6, TNF-α, MCP-1, MIP-2 and Eotaxin along with several cytokines and chemokines at lower levels. Our studies validate that CCL20 induces TNF-α and IL-17A production by DETC which may play key roles in wound healing. Our findings indicate DETC express CCR6 upon TCR activation and CCL20 ligation can differentiate distinct subsets of DETC that may have Th17 functions. Future studies will be conducted on murine models with obesity and type 2 diabetes to discern how CCL20 is involved with proinflammatory cytokines in regards to wound healing.