Altered Platelet–Lymphocyte Interaction associate with suppressed T-cell response and cognitive impairment in Long COVID-19

Long COVID is a chronic condition that may develop after SARS-CoV-2 infection, characterized by persistent symptoms, including respiratory, neurological, and thrombotic manifestations. Persistent immune dysregulation has been reported in Long COVID patients. As platelets can modulate immune responses through interactions with different leukocytes, we investigated platelet–T, B and NK cell interactions in patients with Long COVID with cognitive impairment. Participants were classified as Long COVID (n=26) or recovered (n=16) based on symptom persistence and cognitive assessment by trained neuropsychologists (REC #47489021200005147). Peripheral blood samples were collected at three timepoints after infection (T1=8.4±3.5, T2=13.2±4.0 and T3=16.5±3.2 months). T, B and NK cells and their interaction with platelets were assessed by flow cytometry. Platelet–CD4+ and platelet–CD8+ T-cell aggregates were reduced at T1 compared to Recovered patients. Cytokine levels in plasma revealed T cell dysfunction, particularly in Th1(lower IFN-γ and TNF-α), Th2 (lower IL-4) and Th17 (lower IL-17) compartments, with a trend toward recovery over time. Regarding T cell exhaustion, CTLA-4 expression on CD4+ and PD-1 expression on CD4+ and CD8+ T cells were increased at T1, with higher expression in platelet-associated T cells, suggesting a potential regulatory role of platelets. NK-cell frequency and platelet–NK aggregates were also reduced at T1. Platelet–B-cell aggregates were increased at T3, particularly in naïve and immature subsets, accompanied by increased naïve B-cell frequency. Importantly, suppressed platelet-T cell aggregate formation was associated with impaired executive function (STROOP3 test) in Long COVID. Overall, these findings suggest immune dysfunction in Long COVID, characterized by altered platelet–lymphocyte interactions, T-cell exhaustion, and reduced NK cells and inflammatory mediators. Further studies will investigate the mechanisms underlying these interactions.