Innate tissue immunosurveillance by ?d T cells has real-time dependence on the T cell receptor [ATAC-seq]

With clonotypic potential to engage different ligands, T cell receptor (TCR) ?d fulfils a key tenet of adaptive immunity. Nonetheless, many ?d repertoires are non-circulating, display limited diversity, and are commonly classified as innate-like, questioning any requirement for the TCR beyond the cells' development. Addressing this long-standing issue, we now show that the steady-state phenotypes of different tissue-intrinsic ?d T cell compartments share a dependence on constitutive TCR expression. Deprived of this, cells rapidly become dysregulated, losing their capacity to respond to wide-ranging tissue insults, including imiquimod, an innate inducer of psoriasis-like pathology, u.v. irradiation, and melanoma. Thus, beyond any developmental requirements, the TCR is required in real time to regulate the cells' innate-like tissue immunosurveillance. Biologically, this clearly distinguishes intrinsic ?d T cells from NK and other innate lymphoid cells, while clinically it stresses the importance of the TCR in delivering gd T cell-based immunotherapies. Overall design: Genetic deletion of TCR?d specifically in tissue-resident ?d T cells was achieved in C?1fl/fl mice in vivo by tamoxifen-inducible TCRd-CreERT2 for skin or Rosa26-CreERT2 for gut. TCR?d-deficient (KO) tissue-resident ?d T cells were purified from mouse epidermis, dermis and small intestine. TCR competent (WT) tissue-resident ?d T cells were identically purified as controls. Between 3 to 5 mice per genotype were analyzed per tissue. Each sample came from a individual mouse and corresponds to a biological replicate. Chromatin accesibility analysis of TCR?d KO cells was performed with ATAC-seq data to determine differences in chromatin landscape for each set of tissue-specific cells.