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. 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.