Dermatitis is a common manifestation of lupus that can cause scarring and disfigurement. Lupus dermatitis is often difficult to treat and relatively little is known about its pathogenesis. The outer layer of the skin, the epidermis, contains two immune cells, the Langerhans cell (LC) and dendritic epidermal T cells (DETC). The relative simplicity of the skin makes it an ideal model for studying organ level immune tolerance. Recent studies have pointed to Langerhans cells as important regulators of skin tolerance. Our lab has recently shown that LC migration is impaired in mice prone to lupus dermatitis. DETCs are known to help promote wound healing but their overall function remains unclear. Exciting new data from our lab have shown a hereto- unknown function for the DETCs, that they regulate LC migration. Treatment with alpha-galactosylceramide (GalCer) improves dermatitis, increases DETC numbers in the epidermis, and restores LC migration in lupus prone mice. In this grant, we hypothesize that DETCs regulate the migration of LCs, and that LC-DETC interaction in the skin serves as a regulatory network that protects against skin inflammation. To test this hypothesis, we will: determine the role of DETC in LC migration, and investigate the mechanism or mechanisms by which DETCs regulate LC migration (Aim 1). In Aim 2, we will investigate the factors responsible for the LC migration defect seen in MRL mice. Guided by our preliminary findings that MRL-lpr mice also have a marked reduction in DETC numbers and that DETC-LC appear to interact with each other in vivo and in vitro, we hypothesize that impaired LC migration in lupus mice is due to reduced numbers of DETC in skin; increasing DETC numbers will enhance LC migration, and reduce skin inflammation. Future studies will start to transition our studies of DETCs and LC migration to human samples. Better understanding of the factors regulating LC migration may lead to novel therapies for the control of lupus dermatitis.