Multimodal profiling reveals site-specific adaptation and tissue residency hallmarks of æ T cells across organs in mice

gamma delta T cells perform heterogeneous functions in homeostasis and disease across tissues. However, it is unclear whether these roles correspond to distinct gamma delta subsets or to a homogeneous population of cells exerting context-dependent functions. Here, by cross-organ multimodal single-cell profiling, we reveal that various mouse tissues harbor unique site-adapted gamma delta subsets. Epidermal and intestinal intraepithelial gamma delta T cells are transcriptionally homogeneous and exhibit epigenetic hallmarks of functional diversity. Through parabiosis experiments, we uncovered cellular states associated with cytotoxicity, innate-like rapid interferon-gamma production and tissue repair functions displaying tissue residency hallmarks. Notably, our observations add nuance to the link between interleukin-17-producing gamma delta T cells and tissue residency. Moreover, transcriptional programs associated with tissue-resident gamma delta T cells are analogous to those of CD8+ tissue-resident memory T cells. Altogether, this study provides a multimodal landscape of tissue-adapted gamma delta T cells, revealing heterogeneity, lineage relationships and their tissue residency program. Sagar and colleagues provide a comprehensive single-cell multimodal landscape of gamma delta T cells in various mouse tissues, unveiling site-specific adaptations and highlighting key tissue residency features of gamma delta T cells.