Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID

Abstract

T cell cytotoxicity plays a major role in antiviral immunity. Anti-SARS-CoV-2 immunity may determine acute disease severity, but also the potential persistence of symptoms (long COVID). We therefore measured the expression of perforin, a cytotoxic mediator, in T cells of patients recently hospitalized for SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to Intensive Care Units (ICUs) or non-ICU, and 29 age- and sex-matched healthy controls (HCs). Amounts of intracellular perforin and granzyme-B, as well as cell surface expression of the degranulation marker CD107A were determined by flow cytometry. The levels of 15 cytokines in plasma were measured by Luminex. The frequency of perforin-positive T4 cells and T8 cells was higher in patients than in HCs (9.9 ± 10.1% versus 4.6 ± 6.4%, p = 0.006 and 46.7 ± 20.6% vs 33.3 ± 18.8%, p = 0.004, respectively). Perforin expression was neither correlated with clinical and biological markers of disease severity nor predictive of death. By contrast, the percentage of perforin-positive T8 cells in the acute phase of the disease predicted the onset of long COVID one year later. A low T8 cytotoxicity in the first days of SARS-CoV-2 infection might favor virus replication and persistence, autoimmunity, and/or reactivation of other viruses such as Epstein-Barr virus or cytomegalovirus, paving the way for long COVID. Under this hypothesis, boosting T cell cytotoxicity during the acute phase of the infection could prevent delayed sequelae.

Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response

“…Further studies may look deeper into the early phase of the disease, including more extensive analyses of anti-SARS-CoV-2 humoral and adaptive T-cell specific responses, and its consequence on long term. Thus, a recent study suggested low perforin expression in CD8 + T cells during the acute phase is associated the persistence of symptoms 120 . Also, once our cohort is mainly constituted by hospitalised patients, it would be ideal to have enlarged our sample to include more patients who never required hospitalisation.…”

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

“…When we examined NK cell natural cytotoxicity (NC) and ADCC function in MIS-C, we found that NK cells in MIS-C had decreased degranulation and cytokine production in NC and ADCC. Furthermore, NK cells in children with MIS-C had decreased perforin; this is likely attributed to NK cell training, as opposed to a primary perforin defect based on previous studies in severe COVID-19 in adults (Kundura et al, 2024). One hypothesis for why the NK cells may be hypofunctional was that the pro-inflammatory milieu drove them to exhaustion.…”

Severely ill and high-risk COVID-19 patients exhibit increased peripheral circulation of CD62L+ and perforin+ T cells

“…This suggests that either cytotoxic T cell responses to SARS-CoV-2 are either inhibited in patients of advanced age or that older patients already have a higher baseline level of cytotoxic CD8+ T cells pre-infection, the latter explanation being the most consistent with previous studies. Additionally, several studies have demonstrated the increased presence of cytotoxic T cells in severe COVID-19, and recent studies suggest that the cytotoxic T cell response may be associated with the persistence of COVID-19 symptoms after the acute phase of infection (95)(96)(97). Given the important role of cytotoxic T cells in killing virus-infected cells and their potential to cause endothelial damage (97), further studies examining the functions of cytotoxic T cells in severe COVID-19 patients of all ages are prudent.…”