Transcriptomic profiling of human γδ T cells reveals non-linear immune aging characterized by childhood transitions and relative stability in adulthood

Abstract γδ T cells are one of the first T cell subsets developing in early ontogeny and show various effector functions in immune homeostasis and response in the young and the old. However, their maturation trajectories from infancy to children, adults and elderly have not been systematically defined. Here, we generated a single-cell transcriptome atlas of 106,711 γδ T cells from 223 individuals spanning infancy to old age. Our analysis reveals that γδ T cell aging is non-linear, characterized by pronounced childhood transitions followed by relative stability throughout adulthood despite marked inter-individual variability. In childhood, changes from developmental and mitochondrial programs toward cytotoxicity and inflammaging were evident. This includes maturation trajectories from GZMK⁺ intermediates to GZMB + Perforin + effectors at both RNA and protein levels. Taken together, our study delineates the aging trajectories of human γδ T cells, establishes γδ T cells as a cellular paradigm of non-linear immune aging, and provides a comprehensive resource for investigating γδ T cell biology across the human lifespan.