Distinct T cell remodeling patterns define divergent outcomes of vascular ageing
L Boccuni, C Schiffers, K Ahmad, R Breyer-Kohansal, S Hartl, W Johann, P J HohensinnerAbstract
Background
Whereas chronological aging is a predefined and linear process, biological aging reflects functional cellular decline. Pulse wave velocity (PWV), the gold-standard measure of arterial stiffness, enables stratification of individuals of similar chronological age into early (high PWV, stiffer vessels), normal, or late (low PWV, elastic vessels) vascular aging groups, with increased stiffness indicating premature biological aging.
Purpose
The aim of our study was to investigate whether premature or biologically young vascular aging influences immune composition, function, and endothelial-immune communication in a healthy, age-matched cohort.
Methods
Mass cytometry (CyTOF) was used to profile immune subsets across PWV-defined groups followed by ex vivo functional assays, RNA-seq and small RNA-seq.
Results
Both early and late aging donors exhibited distinct lymphocyte remodeling with reduction of CD8⁺ memory T cells and late NK cells, accompanied by an enrichment of CD4⁺CD57⁺ memory senescent T cells. Only late-aging individuals displayed increased CD4⁺ naïve-like effector T cells. Early aging was characterized by elevated ROS and DNA damage across lymphocytes. Functionally, CD4⁺ naïve T cells from late aging individuals showed enhanced tumor-cell killing capacity and produced more IFN-γ, whereas NK cells from both early and late groups displayed reduced cytotoxicity. Because endothelial-derived extracellular vesicles (EVs) are critical regulators of vascular-immune crosstalk, we analysed their functional impact across the three aging groups. EVs from early aging donors expressed higher levels of the senescence marker CAP1 and triggered a distinctive activation/exhaustion program in CD4⁺ naïve T cells while reducing cell viability. RNase pre-treatment fully abrogated these effects, indicating an RNA-dependent mechanism. Supporting this, small RNA-seq of these EVs revealed increased expression of miRNAs targeting pro-apoptotic and inflammatory pathways. Consistently, RNA-seq of CD4⁺ naïve T cells stimulated with early aging EVs demonstrated profound transcriptional reprogramming, including enrichment of inflammatory pathways and pro-apoptotic gene networks. Mechanistically, early aging EVs decreased Akt activation and induced downregulation of downstream survival-associated target genes. In contrast, late aging EVs induced only modest transcriptional changes relative to normal controls and preferentially preserved pro-survival and anti-inflammatory signaling programs.
Conclusions
Vascular aging involves coordinated lymphocyte remodeling. Early aging endothelial-derived EVs drive T cell exhaustion and cell death through miRNA-dependent mechanisms, whereas late aging individuals retain more functional CD4⁺ naïve T cells. These findings highlight coordinated immune-endothelial interactions and preserved CD4+ naïve T cell function as complementary hallmarks distinguishing premature from late vascular aging.