Gamma Delta T cell and keratinocyte cross-talk in diabetic wounds

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Dendritic epidermal T cells (DETC) reside in murine skin where they monitor epithelial cells for damage. DETC express a monoclonal gamma-delta T cell receptor (TCR) which is used to recognize an unknown antigen expressed by damaged or stressed keratinocytes. We have previously shown that DETC play roles in skin homeostasis and wound repair via the production of insulin-like growth factor-1 (IGF-1) and keratinocyte growth factors (KGFs). Work in diabetic mice and humans indicate that diminished levels of IGF-1 and KGFs at the wound site contribute to impaired wound repair. We hypothesize that impaired growth factor production and defective proliferation of keratinocytes in the diabetic wound are the result of DETC dysfunction. Initially we will determine whether DETC are functional in diabetic wounds by examining DETC activation, proliferation, and growth factor production. In addition we will investigate which mechanisms may contribute to DETC dysfunction in diabetes including: changes in insulin receptor (IR) signaling, inhibition by glucocorticoids, and decreased IGF-1 receptor (IGF-1 R) signaling. By developing an understanding of DETC-keratinocyte cross-talk during wound healing in diabetic mice we may uncover new mechanisms that can be exploited to increase the efficiency of wound repair and provide insight into the timing of IR and IGF-1 R signaling. The proposed experiments are exploratory in nature and involve type I and type II diabetic mouse models of wound repair. Diabetic non-healing wounds are a debilitating complication and treatment is a considerable burden to health services. Results from this proposal may lead to new directions aimed at targeting DETC for future therapies and studying intra-epithelial gamma-delta T cells in other tissues affected by diabetes such as the gut.