Spatially-resolved single cell transcriptomics reveal a critical role for γδ T cells in the control of skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei 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 a murine model of infection. First, we detected a significant expansion of IL-17A-producing γδ T cells (primarily Vγ6+) in the infected murine skin compared to naïve controls that occur mainly in the subcutaneous adipose tissue. Second, interstitial preadipocytes located in the subcutaneous adipose tissue upregulate several genes involved in inflammation and antigen presentation, including T cell activation and survival. In silico cell-cell communication suggests that adipocytes trigger γδ T cell activation locally via Cd40, Il6, Il10, and Tnfsf18 signalling, amongst others. Third, mice deficient in IL-17A-producing γδ T cells show extensive inflammation, increased frequency of skin-resident IFNγ-producing CD8+ T cells and limited subcutaneous adipose tissue wasting compared to wild-type infected controls, independent of TH1 CD4+ T cells and parasite burden. Based on these observations, we proposed a model whereby adipocytes as well as Vγ6+ cells act concertedly in the subcutaneous adipose tissue to limit skin inflammation and tissue wasting. These studies shed light onto the mechanisms of γδ T cell-mediated immunity in the skin in the context of African trypanosome infection, as well as a potential role of immature and mature adipocytes as homeostatic regulators in the skin during chronic infection. ### Competing Interest Statement The authors have declared no competing interest.