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Leon-Lara, X.

Publications and source records attributed to Leon-Lara, X..

2 recordsLinked to original sources

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

{gamma}{delta} 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 {gamma}{delta} T cells from 223 individuals spanning infancy to old age. Our analysis reveals that {gamma}{delta} 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 {gamma}{delta} T cells, establishes {gamma}{delta} T cells as a cellular paradigm of non-linear immune aging, and provides a comprehensive resource for investigating {gamma}{delta} T cell biology across the human lifespan.

immunology↗

Adult thymus-derived cMaf+ RORγt+ γδ T cells lack Scart2 chromatin accessibility and do not reach periphery

T cell receptor (TCR) V{gamma}4+ expressing {gamma}{delta} T cells can be divided into IFN-{gamma} and IL-17-producing effector T cell subsets. A bias towards {gamma}{delta}17 effector fate decisions is observed during early ontogeny. In contrast, the existence of V{gamma}4+ {gamma}{delta}17 cells derived from adult thymus is still controversial. In the present work, we used a mouse model where T cells are exclusive generated within an adult thymus. Additionally, we employed single-cell chromatin state analysis from thymocytes of normal mice. A small, but considerable population of immature Cd24+ Gzma+ V{gamma}4 cells was found that exhibit molecular programs of {gamma}{delta}17 cells. These adult thymus-derived immature Cd24a+ cMaf+ V{gamma}4 cells secrete small amounts of IL-17A and IL-17F. Interestingly, do not reach the periphery under steady-state conditions. Furthermore, de novo generated {gamma}{delta}17-like cells from adult thymus lack transcriptional activity of the Scart2 encoding gene, suggesting that Scart2 is a distinct trait of fetal {gamma}{delta} T cell precursors. Together, this study provides valuable insights into developmental traits of V{gamma}4 cells during adulthood and raises the question on signals suppressing the full maturation and/or thymic export of {gamma}{delta}17-like cells within the adult thymus. HighlightsO_LITranscriptional and epigenetic profiling identifies developmental plasticity of Gzma+ Cd24a+ V{gamma}4 cells in adult thymus. C_LIO_LIThymic c-Maf+ and ROR{gamma}t+ V{gamma}4 T cells can be generated during adulthood, but do not reach the periphery under steady-state conditions. C_LIO_LIInnate CD44highCD45RBneg {gamma}{delta}17 cells are completely absent upon induction of T cell development during adulthood. C_LIO_LIScart2 expression might be a key molecule to track developmental traits of fetal-derived {gamma}{delta}17 cell precursors. C_LI

immunology↗