Elevated LDL-C induces T-cell metabolic dysfunction and increases inflammation and oxidative stress in midlife adults.

T-cells may contribute to chronic, low-grade, sustained inflammation and oxidative stress commonly observed with aging and chronic disease. T-cell metabolic alterations impact T-cell differentiation, inflammation, and oxidative stress in animal models. Low-density lipoprotein cholesterol (LDL-C) has been identified as a novel antigen that activates T-cells via a canonical pathway. However, in humans, little is known about the direct effect of LDL-C on T-cells. Endogenous LDL-C concentration peaks during midlife in humans and may contribute to midlife chronic disease risk by inducing T-cell dysfunction. Thus, this study investigated the effects of exogenous LDL-C exposure on CD4⁺ and CD8⁺ T-cells from midlife adults. Compared with a physiologically "low" LDL-C concentration, we hypothesized that exposure to "borderline high" LDL-C would induce activation, alter metabolism, and increase mitochondrial reactive oxygen species and inflammatory cytokine production in T-cells from midlife adults. T-cell metabolism was assessed using extracellular flux analysis, and all other outcomes were assessed using flow cytometry. Our findings indicate that exposure to a borderline high concentration of LDL-C induced CD4⁺ and CD8⁺ T-cell activation, impaired mitochondrial respiration, and increased glycolytic metabolism. Further, we observed exogenous LDL-C exposure induced T-cell differentiation toward activated effector memory and effector memory re-expressing CD45RA subpopulations and increased inflammatory cytokine and mitochondrial reactive oxygen species production. These data suggest that borderline high LDL-C induces T-cell dysfunction that may increase the risk for age-related diseases. Future observational and clinical research should investigate the effects of endogenous LDL-C and other blood lipids on in vivo T-cell function and the implications for disease risk.NEW & NOTEWORTHY We evaluated the effect of low-density lipoprotein cholesterol (LDL-C) exposure on human T-cells isolated from midlife adults. T-cells were exposed to physiologically low and borderline high concentrations of LDL-C. We observed that high LDL-C exposure increased intracellular lipids, activated T-cells, and induced metabolic dysfunction. Additionally, high LDL-C exposure induced T-cell differentiation, a senescent-like phenotype, and induced inflammatory cytokine and mitochondrial reactive oxygen species production.