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 T-inn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of T-inn compared to conventional T cells (T-conv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of T-inn cells share an effector program driven by specific transcription factors, distinct from those governing T-conv cells. Conversely, only a fraction of thymic T-inn cells displays an effector phenotype, while others share transcriptional features with developing T-conv cells, indicating potential divergent developmental pathways. Unlike the mouse, human T-inn 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 T-inn cells in humans, which implies distinct immune regulatory mechanisms across species.