T-Cell Activation Reflects the Intersection of Inflammation, Metabolic Dysfunction, and Vascular Risk in Prediabetic Obesity 2256824

Abstract Introduction Chronic low-grade inflammation is a hallmark of obesity and a key driver of metabolic dysfunction and cardiovascular disease. However, the immunological mechanisms linking inflammation to early metabolic and vascular risk in prediabetes remain unclear. Activated CD8+HLA-DR+ T cells represent a marker of sustained immune activation, yet their contribution to β-cell stress and cardiometabolic dysfunction has not been defined. Methods A cross-sectional study of 198 adults was conducted, stratified as lean healthy (n = 88), healthy obese (n = 69), and prediabetic obese (n = 41). Circulating CD8+HLA-DR+ T cells were quantified by flow cytometry and correlated with metabolic (glucose, insulin, C-peptide, HOMA-B%) and cardiovascular markers (lipids, blood pressure, MMP-9). Plasma cytokines were measured using a 38-plex Luminex assay. Findings were validated using public whole-blood transcriptomic data (GSE145412). Results Prediabetic obese individuals exhibited significantly higher frequencies of CD8+HLA-DR+ T cells compared with healthy obese and lean groups (p < 0.001). These activated T cells correlated positively with C-peptide, IL-6, TNF-α, IFN-γ, and IL-17A, and inversely with HOMA-B%, linking immune activation to β-cell stress and inflammation. CD8+HLA-DR+ frequency also associated with diastolic pressure, triglycerides, and MMP-9; multivariable analysis identified MMP-9 as an independent correlate (p = 0.04). Transcriptomic validation confirmed parallel immune-metabolic signatures in obese diabetic subjects. Conclusion Activated CD8+HLA-DR+ T cells emerge as key immune biomarkers linking inflammation, β-cell dysfunction, and cardiovascular risk in prediabetic obesity. Their association with MMP-9 highlights a potential immunometabolic axis driving vascular remodeling. These findings identify CD8+HLA-DR+ T-cell activation as a promising early indicator and therapeutic target for cardiometabolic risk prevention. Funding Source Kuwait Foundation for the Advancement of Science (KFAS)-RA MoH-2022-002 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)