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.