Weakened IL-15 Production and Impaired mTOR Activation Alter Dendritic Epidermal T Cell Homeostasis in Diabetic Mice

Abstract

Diabetes is associated with impaired wound healing, which may be caused primarily by a deficiency in dendritic epidermal T cells (DETCs). In the epidermis, IL-15, IGF-1, and mTOR are known to regulate the maintenance of DETCs; however, it is unclear how these molecules may intersect to regulate DETC homeostasis in diabetes. Here, we show that the reduction of DETCs in the epidermis of diabetic mice is caused by altered homeostasis mediated by a reduction in IL-15 levels. Both impaired mTOR activation and reduction of IL-15 in the epidermis play important roles in DETC homeostasis. Moreover, IGF-1 drives keratinocytes to produce IL-15. The activation of IL-15 is dependent on mTOR, and conversely, mTOR regulates IGF-1 production in DETC, in a classic feedback regulatory loop. Our data suggest that in the setting of diabetes, reduced IGF-1, impaired mTOR pathway activation and reduced IL-15 in the epidermis function coordinately to promote altered DETC homeostasis and delayed skin wound closure.