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, having the ability to mount rapid responses following activation. In mice, this ability is acquired during thymic development. We explored the transcriptional landscape of T inn compared to conventional T cells (T conv ) in the human thymus and blood using single cell RNA sequencing and flow cytometry. We reveal that in human blood, the majority of T inn cells, including iNKT, MAIT, and Vδ2 + Vγ9 + T cells, share an effector program characterized by the expression of unique chemokine and cytokine receptors, and cytotoxic molecules. This program is 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 I/type III effector potential. To conduct a comprehensive cross-species analysis, we constructed a murine T inn developmental atlas and uncovered additional species-specific distinctions, including the absence of type II T inn cells in humans, which implies distinct immune regulatory mechanisms across species. The study provides insights into the development and functionality of T inn cells, emphasizing their role in immune responses and their potential as targets for therapeutic interventions.