Cytolytic CD8+T cell response to SARS-CoV-2 and non-SARS-CoV-2-related viruses is associated with severe manifestation of COVID-19

Little is known about the CD8+ T cell functionality in the coronavirus disease 2019 (COVID-19). Therefore, we examined twenty-five hospitalized COVID-19 patients with moderate (MD) or severe disease (SD) as well as seventeen SARS-CoV-2-unexposed persons regarding the cytolytic and cytokine-producing reactivity of their CD8+ T cells. Reactive CD8+ T cells were detectable in 90% of the unexposed persons, confirming high cross-reactive immune memory in the general population. Compared to unexposed persons and MD patients, SD pa-tients had higher numbers of SARS-CoV-2 reactive CD8+ T cells with cytolytic function that can simultaneously produce inflammatory cytokines. In addition, SD patients showed higher CD8+ T cell reactivity against non-SARS-CoV-2-related viruses, which was mainly mediated by cytolytic response. Sequence alignments showed that cross-reactivities with the Spike protein could contribute to the expansion of such cells. Since insufficiently regulated cytolytic CD8+ T cells can damage peripheral and vascular tissue structures, high levels of both SARS-CoV-2-reactive and heterologously activated cytolytic CD8+ T cells could favor severe disease progression.