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Immune dysregulation in prolonged Long-COVID: lymphocytes emerge as key mediators of persistent inflammation, exhaustion and cytotoxicity - Journal of Translational Medicine Background Long-COVID affects at least 10% of COVID-19 survivors, displaying debilitating symptoms across multiple organ systems. Despite the widespread prevalence, Long-COVID aetiology remains poorly understood, but emerging evidence points to immune dysregulation as a potential mechanism involved in its development or persistence. Methods This study presents a unique analysis of the peripheral blood mononuclear cell transcriptomic profile of COVID-19 and Long-COVID patients at single-cell resolution. We reconstructed the cell state and intercellular communication using differentially expressed gene profiling and ligand–receptor interaction analyses. Results Our results reveal altered T and natural killer cell subset proportions, diminished proliferating lymphocyte and B cell signalling capacity, and the expression of exhaustion and cytotoxicity associated genes 1.5–2 years post-infection, suggesting incomplete immune recovery. Distinct interferon responses in these cell populations at the acute phase for patients who go on to develop Long-COVID indicate early disease mediator potential. Conclusions Collectively, these findings provide insight into the immune processes underlying the progression of COVID-19 into a chronic Long-COVID state. The observed changes in immune cell subsets at the acute phase of the infection may be predictive of Long-COVID progression and could be useful in understanding disease aetiology while the observed long-term effects are crucial to developing therapeutic and diagnostic tools. https://doi.org/10.1186/s12967-026-08081-6