CD8+ effector memory and regulatory T cell dynamics predict subclinical atherosclerotic plaque formation in healthy aging

Abstract

<title>Abstract</title> Background Subclinical atherosclerotic plaque (SAP) develops silently in older adults. Early biological changes that predict plaque formation are not well defined. We examined whether immunological, and metabolic or functional measures identify vascular vulnerability before clinical disease. Methods In a three-year longitudinal study, 49 healthy older adults (63.8 ± 3.8 years) underwent carotid ultrasound, T cell phenotyping, serum protein profiling, body composition assessment, and fitness testing at baseline and follow up. At follow up, participants were classified as no SAP, new SAP or persistent SAP. We analyzed baseline determinants and within person changes to predict incident plaque formation. Results New SAP occurred in 30.3% of those initially plaque-free. At baseline, lower frequencies of CD8 ⁺ effector memory (EM) T cells and higher frequencies of CD8 ⁺ effector memory re-expressing CD45RA (EMRA) T cells and regulatory T cells (Tregs) were associated with higher odds of new SAP. Over time, expansion of CD8 ⁺ EM T cells was the strongest independent predictor of new SAP, accompanied by declines in Tregs and in the Treg/Teff ratio. Vascular cell adhesion molecule-1 (VCAM-1) at baseline was an additional independent predictor. Increases in visceral fat and declines in VO ₂ peak were linked to new SAP, but immune markers were more robust than metabolic variables or serum cytokines. Conclusion Adaptive immune remodeling follows a phase dependent pattern in which early CD8 ⁺ EM reductions and later CD8 ⁺ EM expansion with Treg decline signal emerging vascular vulnerability. These immune signatures, together with VCAM-1, may improve early plaque risk prediction.