Transcriptional Programs of Human γδ T Cells Across Age Define Divergent Neonatal and Adult CMV Responses

ABSTRACT: Single-cell transcriptomic technologies offer unprecedented resolution to uncover cellular heterogeneity and lineage trajectories. By integrating newly generated and public single-cell RNA sequencing (scRNA-seq) datasets, we analyzed ~119k γδ T cells from 225 individuals spanning the human lifespan (0–90 years). We constructed a comprehensive γδ T cell atlas of 10 transcriptionally distinct clusters with marked age-associated shifts, including a progressive decline of CCR9⁺SOX4⁺ naïve Vδ1 subset and a striking transition from GZMK+ to GZMB+ cells at both RNA and protein levels. Moreover, aged γδ T cells were also characterized by diminished mitochondrial and developmental programs alongside enrichment of effector modules. The pronounced baseline differences between neonates and adults, particularly the low cytotoxic signatures in neonates, prompted us to focus on neonatal–adult comparisons in the context of acute cytomegalovirus (CMV) infection. Our analysis reveals that both neonates and adults mounted robust Vδ1 T cell responses but via distinct strategies. Neonatal Vδ1 T cells underwent de novo effector differentiation alongside balanced Type1- and Type2-associated transcriptional profiles (e.g., IL4R and ICOS). In contrast, adult Vδ1 T cells, already pre-armed for cytotoxic signatures at steady state, responded primarily through proliferative expansion and Type1-skewed antiviral programs (e.g., IFNG and IFITM3). This suggests that neonatal γδ T cells, by tempering inflammatory polarization while mounting an effective response, may mitigate potential immunopathology and safeguard the developing immune system. Taken together, our study delineates the developmental and aging trajectories of human γδ T cells, uncovers age-specific antiviral strategies, and provides a resource for understanding γδ T cell biology in health and infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306377 | GEO | 2026/08/26

REPOSITORIES: GEO