Post-COVID-19 sequelae are associated with sustained SARS-CoV-2-specific CD4+ immune responses

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to widespread post-acute sequelae of COVID-19 (PASC), affecting multiple body systems. Despite its prevalence, PASC’s pathogenesis remains unclear, with hypotheses suggesting viral persistence, immune activation, and autoimmune responses among the pathogenetic mechanism. This study aimed to evaluate T cell memory response in PASC patients, one year post-hospital discharge and correlate it with clinical parameters to identify a potential PASC-associated fingerprint. Methods Peripheral blood mononuclear cells (PBMCs) from PASC patients and healthy controls (HC) were stimulated with a pool of spike peptides. CD4+ and CD8+ T cell responses were evaluated by flow cytometry using the activation-induced markers assay (AIM). Results Findings showed significant activation of the CD4+ T cell compartment, with a higher proportion of responders among PASC patients. Central memory (CM) T cells expressing pro-inflammatory cytokines were more prevalent in responders. Clinical correlations revealed higher SARS-CoV-2-specific T cell responses in patients with reduced diffuse lung capacity for carbon monoxide (DLCO) and residual symptoms. Conclusion These immune changes, especially in CM T cells, could play a pivotal role in PASC’s development and persistence, impacting patients’ daily lives.