New insights into the regulation of γδ T cells in diabetic wounds 2254952

Introduction Diabetes is a widespread metabolic disorder. One of its most severe complications is diabetic foot ulcers (DFUs)-open wounds characterized by chronic inflammation and delayed healing. DFUs are the leading cause of non-traumatic lower limb amputations globally due to poor repair capacity and increased infection risk. Gamma delta (γδ) T cells are key immune cells involved in the skin’s defense and repair processes, making them an important population to study in the context of DFUs. The activity of γδ T cells is shaped by butyrophilin-like (BTNL) proteins. One member of this family, BTNL2, regulates T cell activation and may be altered by chronic conditions such as diabetes. Methods Here, we utilize an STZ-induced diabetic mouse model to investigate the role of multiple γδ T cell subsets (Vγ1—4) in both diabetic and non-diabetic skin, at steady state and during wound healing. Using GFP γδ T cell reporter mouse, flow cytometry and immunofluorescence, we assess γδ T cell activation and localization. Additionally, we examine BTNL2’s role in modulating γδ T cell activity through in vitro coculture assay. Results Under hyperglycemic conditions, γδ T cell subsets are dysregulated, with an increase in pro-inflammatory Vγ1 cells and a decrease in pro-repair Vγ3 dendritic epidermal T cells (DETCs). Diabetic mice display delayed wound closure six days post-injury, confirmed by H&E and Keratin 6 staining. Using the GFP γδ T cell reporter mice, we observe γδ T cell localization at the wound edge, predominantly Vγ1 cells, alongside with increased BTNL2 expression. Coculture assays reveal that BTNL2 immunomodulates human Vδ1 but not Vïδ2 γδ T cells. Conclusion Overall, our findings highlight the distinct roles of skin γδ T cell subsets and BTNL2 expression during wound healing and provide important clues to design BTNL2-based therapeutics that can modulate the skin T cell immune responses in chronic inflammatory conditions.