TCRβ Repertoire Remodeling Reveals CD4⁺ T Cell Dysfunction as an Early Driver of Vascular Aging

Background: Arterial stiffening is a hallmark of vascular aging and a major risk factor for cardiovascular disease, yet its immune underpinnings remain insufficiently understood. While chronological aging is a known contributor, the role of adaptive immune alterations in vascular dysfunction has not been clearly delineated. Methods: We analyzed peripheral blood T cell receptor β-chain (TCRβ) repertoires from 574 healthy adults and assessed associations with arterial stiffness, as quantified by pulse wave velocity (PWV). Clonotype function were further characterized using single-cell transcriptomics, and machine learning models were applied to evaluate the predictive value of repertoire features. Results: We found that Individuals with elevated PWV exhibited higher levels of systemic inflammation and expansion of low-frequency CD4⁺ T cell clonotypes, resulting in increased repertoire diversity. This immune remodeling was distinct from classical immunosenescence, which primarily involves MAIT cell depletion, and instead reflected chronic antigenic stimulation and CD4⁺ T cell dysfunction. Single-cell transcriptomic profiling revealed features of persistent immune activation and impaired proliferative capacity in these clonotypes. Machine learning models trained on stiffness-associated TCR clonotypes demonstrated robust performance in predicting individuals with elevated PWV across independent cohorts. Conclusions: Collectively, our findings delineate low-frequency clonal expansion and CD4⁺ T cell dysfunction as central features of vascular immune remodeling, and establish peripheral TCRβ repertoire alterations as early biomarkers of vascular aging. These results uncover novel mechanistic links between immune dysregulation and vascular aging, and suggest immune-targeted strategies for the early detection and prevention of cardiovascular disease.