Dempsey, M. | Search bioRxiv

bioRxiv2026

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↗

bioRxiv2025

Xylazine exacerbates fentanyl-induced respiratory depression and prevents rescue by naloxone in mice

Xylazine is a veterinary sedative and widespread adulterant of illicit opioids, where it is commonly combined with the highly potent synthetic {micro} opioid receptor (MOR) agonist fentanyl. Xylazine adulteration of fentanyl is associated with increased risk of lethal overdose and decreased efficacy of reversal by the MOR antagonist naloxone. Here we use whole body plethysmography in mice to show that xylazine produces profound respiratory depression at subanesthetic doses. Xylazine rapidly and dose-dependently suppressed minute ventilation, tidal volume, and respiratory frequency. These effects were dependent on -2 adrenergic receptors and were fully blocked by coadministration of the -2 adrenergic antagonist atipamezole. Atipamezole, administered alone, produced only modest reversal of fentanyl-induced respiratory depression. Xylazine, when combined with a dose of fentanyl with modest respiratory effects, suppressed breathing with greater efficacy than when administered alone. Strikingly, doses of naloxone sufficient to completely reverse fentanyl-induced respiratory depression were ineffective in reversing the respiratory suppression induced by xylazine-adulterated fentanyl. By contrast, combinations of naloxone with atipamezole rapidly and fully reversed the suppression of breathing induced by xylazine-adulterated fentanyl. Our results show that xylazine suppresses breathing via activation of -2 receptors, an effect enhanced by coadministration with the MOR agonist fentanyl. Respiratory suppression inflicted by the mixture of xylazine and fentanyl resisted reversal by naloxone but was fully reversible by subsequent coadministration of both naloxone and atipamezole. These observations have profound implications for the current opioid epidemic.

neuroscience↗