Associations of circulating T-cell subsets with endothelial function: the Multi-Ethnic Study of Atherosclerosis

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Background: Endothelial dysfunction has emerged as a risk factor for many age-related diseases such as cardiovascular disease (CVD). Recently, pro-inflammatory T-lymphocytes (T-cells) have been identified as important mediators of endothelial dysfunction in multiple pre-clinical models. Pro-inflammatory and senescent T-cell subsets have also been associated with endothelial dysfunction in middle-aged adults with hypertension. However, the relationships between T-cell subpopulations and endothelial dysfunction have not been explored in large, population-based cohorts. Therefore, the purpose of this study was to evaluate the associations of T-cell populations with endothelial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA), an observational cohort study of adults free from CVD at the baseline exam (2000-02). Based on prior literature, we hypothesized that higher proportions of pro-inflammatory (CD4 + IFN-γ + ) and senescence-associated (CD4 + CD28 - CD57 + ) T-cells would be associated with lower endothelial function. Methods: Peripheral blood T-cell subpopulations were measured by flow cytometry using cryopreserved cells collected at the baseline Exam (N=968). Endothelial function was assessed at baseline using flow-mediated dilation (FMD) of the brachial artery by duplex ultrasound. Associations of T-cells, analyzed per 1-SD increment, with FMD were assessed using multivariable linear regressions with adjustment for CVD risk factors. The primary analysis examined associations between CD4 + IFN-γ + and CD4 + CD28 - CD57 + T-cells with FMD. A secondary analysis examined associations between 27 additional immune cell populations in MESA with FMD percent change, using an FDR p<0.05 to correct for multiple hypothesis testing. Results: CD4 + IFN-γ + and CD4 + CD28 - CD57 + T-cells were not significantly associated with FMD. In secondary analysis, higher pan CD4 + and CD8 + T-cells were significantly associated with lower (β=-0.4, P=0.0002, 95%CI=-0.6, -0.19) and higher (β=0.029, P=0.006, 95%CI=0.006) FMD percent change, respectively. Similar results were observed with absolute FMD. Conclusions: Thedata from a large multi-ethnic cohort study suggest that higher CD4 + and lower CD8 + T-cell proportions are associated with endothelial dysfunction as measured by FMD. The cross-sectional findings warrant additional longitudinal human studies, and greater T-cell phenotyping, to understand the influence of CD4 + and CD8 + T-cell balance on endothelial function. The research reported in this article was supported by R01HL120854, and R01HL135625 from the National Heart, Lung, and Blood Institute and T32AG033534. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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