Unraveling the phenotypic states of human innate-like T cells: Comparative insights with conventional T cells and mouse models

The “innate-like” T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species. [Display omitted] •Comprehensive atlas of human Tinn cells in thymus and blood•Most postnatal thymic Tinn cells resemble naive Tconv cells•Adult blood Tinn cells display a mixed type 1/type 17 effector program•Human Tinn cells do not form distinct subsets like mouse Tinn cells Our study presents a comprehensive atlas of human innate T (Tinn) cells in the thymus and blood, highlighting their blended type 1 and type 17 transcriptional profiles. Loh et al. use single-cell RNA sequencing and flow cytometry to reveal species-specific distinctions and potential divergent developmental pathways of Tinn compared to conventional T cells.