CD8⁺ T cell heterogeneity in aging: insights from single-cell profiling

Inflammation progressively increases with age, resulting in a broad remodeling of the CD8⁺ T cell compartment. Recent advances in single-cell RNA sequencing (scRNA-seq) have revealed a transcriptional heterogeneity within the CD8⁺ T cell subsets, challenging traditional classifications based on surface markers. This review summarizes current insights from scRNA-seq and multimodal profiling studies, demonstrating a heterogeneity of CD8⁺ T cell states defined by distinct and overlapping transcriptional programs. Notably, GZMK⁺ effector memory T cells expand with age, and recent studies in mouse models suggest that GZMK⁺ T cells can activate the complement system, positioning them as potential mediators of inflammation. In addition, emerging diversity within TEMRA and non-canonical T cell subsets challenges the conventional boundaries between established T cell subsets. Integrative single-cell approaches are essential for deciphering the dynamic interplay between immune aging and chronic disease, and for informing targeted interventions to restore immune resilience in older adults.