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

With clonotypic potential to engage different ligands, T cell receptor (TCR) γδ fulfils a key tenet of adaptive immunity. Nonetheless, many γδ 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 γδ 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 γδ 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.