Single-Cell Transcriptomics Identifies the Adaptation of Scart1+ Vγ6+ T Cells to Skin Residency as Activated Effector Cells

IL-17-producing γδ T cells express oligoclonal Vγ4+ and Vγ6+ TCRs, mainly develop in the prenatal thymus, and later persist as long-lived self-renewing cells in all kinds of tissues. However, their exchange between tissues and the mechanisms of their tissue-specific adaptation remain poorly understood. Here, single-cell RNA-seq profiling identifies IL-17-producing Vγ6+ T cells as a highly homogeneous Scart1+ population in contrast to their Scart2+ IL-17-producing Vγ4+ T cell counterparts. Parabiosis demonstrates that Vγ6+ T cells are fairly tissue resident in the thymus, peripheral lymph nodes, and skin. There, Scart1+ Vγ6+ T cells display tissue-specific gene expression signatures in the skin, characterized by steady-state production of the cytokines IL-17A and amphiregulin as well as by high expression of the anti-apoptotic Bcl2a1 protein family. Together, this study demonstrates how Scart1+ Vγ6+ T cells undergo tissue-specific functional adaptation to persist as effector cells in their skin habitat. [Display omitted] •Single-cell RNA-seq reveals differential tissue-specific adaptation of Vγ6+ T cells•Skin Vγ6+ T cells show an activated IL-17- and amphiregulin-producing effector phenotype•Expression of Bcl2a1 family proteins protect activated skin Vγ6+ T cells from apoptosis•Skin Vγ6+ and Vγ4+ T cells can be distinguished by Scart1 versus Scart2 expression Tan et al. apply single-cell transcriptome analysis of tissue-resident Vγ6+ T cells and identify molecular determinants that mediate the functional adaptation and longevity of Scart1+ Vγ6+ T cells within tissues.