A unique cytotoxic CD4⁺T cells signature defines critical COVID-19

Abstract

Background and objectives. SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T cell response to the resolution or progression of disease is still unclear. Optimal protective immunity may require activation of distinct immune pathways. As such, defining the contribution of individual T cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. To address this, we performed immunophenotyping of T cell responses in unvaccinated individuals, representing the full spectrum of COVID-19 clinical presentation. Methods. Spectral cytometry was performed on peripheral blood mononuclear cell samples from patients with PCR-confirmed SARS-CoV-2 infection. Computational and manual analyses were used to identify T cell populations associated with distinct disease states through unbiased clustering, principal component analysis and discriminant analysis. Results. Critical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+ (CTL) cells of a T follicular helper (TFH) or effector memory re-expressing CD45RA (TEMRA) phenotype. These CD4+ CTLs were largely absent in those with less severe disease. In contrast, those with asymptomatic or mild disease were associated with high proportions of naive T cells and reduced expression of activation markers. Conclusion. Highly activated and cytotoxic CD4+ T cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Potential for induction of these detrimental T cell responses should be considered when developing and implementing effective COVID-19 control strategies.