T cell-driven sustained inflammation and immune dysregulation mimicking immunosenescence for up to three years post-COVID-19.

Long COVID has emerged as a major global health concern, yet the long-term trajectory of immune recovery and its contribution to persistent symptoms remain to be elucidated. Here, we conducted a three-year longitudinal follow-up of the 47 COVID-19 patients and applied single-cell RNA sequencing (scRNA-seq) and multiplex cytokine profiling to comprehensively characterize the peripheral immune landscape during convalescence. We observed persistent immune dysregulation up to three years post-infection, characterized by chronic inflammation and impaired restoration of naïve CD4⁺ T cells, naïve CD8⁺ T cells, and SLC4A10⁺ MAIT cells-features reminiscent of immunosenescence. Notably, Th17 cells, rather than monocytes, emerged as key drivers of chronic inflammation beyond one year. We identified two distinct Th17 subsets: RORC⁺ Th17 cells and LTB⁺ Th17 cells. While RORC⁺ Th17 cells were negatively correlated with inflammatory cytokine levels, LTB⁺ Th17 cells showed proinflammatory features and were positively associated with long COVID symptoms. Sustained elevation of S100A8 and IL-16 in follow-up patients may contribute to the persistent presence of LTB⁺ Th17 cells. Together, our study provides an in-depth longitudinal map of immune remodeling in COVID-19 convalescents, revealing key cellular and molecular drivers of sustained inflammation up to three years post-infection. Supplementary Information: The online version contains supplementary material available at 10.1007/s44466-025-00012-2.