Long-term cytotoxic skewing of CD4+CD8+ T cells after STEMI: association with immune senescence in COVID-19 patients
O Parkhomenko, O Shumakov, V Kyryk, O Tsupykov, A Ustymenko, O Skarzhevskyi, D KhomyakovAbstract
Background
ST-elevation myocardial infarction (STEMI) induces long-term immune remodeling. Double-positive (DP) CD3+CD4+CD8+ T-lymphocytes represent a minor but functionally plastic subset involved in chronic inflammation and immune adaptation. However, their long-term dynamics following STEMI, particularly in patients with concomitant COVID-19, remains unclear.
Purpose
To compare immune profiles 3-4 years after STEMI in patients (pts) treated before the COVID-19 pandemic and in pts with STEMI and concomitant COVID-19, focusing on DP T-cells and their associations with metabolic, inflammatory, endothelial, and senescence-associated markers.
Methods
Sixty post-STEMI pts were examined: 30 pts experienced STEMI in pre-pandemic period (group 1, G1), and 30 – during pandemic with concomitant COVID-19 (group 2, G2). Peripheral blood immunophenotyping was performed by flow cytometry. Senescent-associated heterochromatin foci (SAHF) were assessed by fluorescent microscopy. In addition, glucose metabolism markers, neutrophil-to-lymphocyte ratio (NLR), and brachial artery flow-mediated dilation (FMD) were analyzed. Correlations between DP T-cells (%) and clinical or immunological variables were evaluated.
Results
In group 1, DP T-cells were integrated into a classical acute-phase inflammatory profile characterized by higher NLR, relative lymphopenia and monocytosis (Table 1). Their positive association with FMD suggests that this inflammatory pattern was not accompanied by endothelial dysfunction. Group 2 demonstrated higher proportions of CD31−CD38+ and SAHF-positive cells, along with elevated glucose and HbA1c levels compared with group 1 indicating persistent immune activation and features of senescence. In this group, DP T-cells were increased and showed a strong positive correlation with SAHF-positive cells, as well as an inverse correlation with CD31−CD38+ activated lymphocytes accompanied by a loss of associations with NLR and FMD. An inverse relationship between CD4+CD8+ and CD4+CD8− cells, together with a direct correlation with CD4−CD8+ cells was observed. This pattern may reflect functional plasticity of DP T cells with a relative CD8-dominant phenotype, consistent with cytotoxic skewing in the context of chronic immune activation.
Conclusion
Years after STEMI, CD4+CD8+ DP T-cells in non-COVID survivors remain associated with acute-phase inflammatory markers and preserved endothelial and metabolic function, suggesting coordinated immune adaptation. In contrast, concomitant STEMI and COVID-19 are associated with persistent immunosenescence and long-term metabolic dysregulation, along with a cytotoxic shift in the DP subset, potentially reflecting a compensatory response to the accumulation of senescence-prone T-cells following combined ischemic and viral injury.Table 1