Integrated spatial and single cell transcriptomic analyses reveal a critical role for Vg6+ T cells in the control of skin inflammation during infection

African trypanosome parasites colonise the skin in a process important for parasite transmission. However, how the skin responses to trypanosome infection remain unresolved. Here, using a combination of spatial and single cell transcriptomics, coupled with in vivo genetic models, we investigated the local immune response of the skin in both a murine model of infection. Our results provide several novel key findings previously unappreciated in the context of parasitic infections in the skin. First, we detected a significant expansion of a population of IL-17A-producing Vg6 gdT cells in the infected murine skin compared to naïve controls that occur mainly in the subcutis, which we further validated at the protein level by flow cytometry. Second, interstitial preadipocytes located in the subcutis upregulate several genes involved in inflammatory signalling and antigen presentation, including T cell activation and survival. In silico cell-cell communication suggests that adipocytes trigger gdT cell activation locally via Cd40, Il6, Il10, and Tnfsf18 signalling, amongst others. Third, mice deficient of IL-17A-producing gdT cells show extensive inflammation, increased frequency of dermal IFNg-producing CD8⁺ T cells and limited subcutaneous adipose tissue wasting compared to wild-type infected controls, independent of T_H1 CD4⁺ T cells and parasite burden. Based on these observations, we proposed a model whereby adipocytes as well as Vg6 gdT cells act concertedly in the subcutis to limit skin inflammation and tissue wasting. These studies shed light into the mechanisms of gdT cell-mediated immunity in the skin in the context of African trypanosomes infection, as well as a potential role of immature and mature adipocytes as homeostatic regulators in the skin during chronic infection.