Vascular Immune Remodeling: A CD4⁺ T Cell-Driven Immune Trajectory Associated With Arterial Stiffness

Arterial stiffness is a hallmark of vascular aging and a major risk factor for cardiovascular disease. While immune aging-typically characterized by reduced T cell receptor (TCR) diversity and CD8⁺ memory expansion-contributes to this process, growing evidence suggests that peripheral immune dysregulation may impair vascular function through mechanisms distinct from classical immunosenescence. To investigate this, we profiled peripheral TCRβ repertoires from 563 adults without clinically overt cardiovascular disease and assessed their association with pulse wave velocity (PWV), a gold-standard marker of arterial stiffness. Surprisingly, individuals with elevated PWV exhibited a paradoxical increase in TCR diversity, driven by broad remodeling of numerous low-frequency CD4⁺ clonotypes that preferentially mapped to a naive-like/early-differentiation CD4⁺ compartment. Single-cell transcriptomic analyses further indicated chronic activation, proliferative restraint, and dysfunctional immune states in these PWV-associated CD4⁺ T cells. Furthermore, a machine learning model trained on these PWV-associated repertoire features accurately identified individuals with high PWV (AUC = 0.817), suggesting potential utility in subclinical vascular risk stratification. These findings define a distinct, CD4⁺ T cell-driven immune remodeling process-termed "vascular immune remodeling"-that is dissociable from classical immunosenescence and may contribute to arterial stiffening, uncovering an unexpected immune trajectory in early vascular aging and offering new avenues for immune-based vascular risk assessment and intervention.