T cell immunity towards SARS-CoV-2 spike (S), membrane (M), and nucleocapsid (N)-proteins might define COVID-19 severity. Therefore, we compare the SARS-CoV-2-reactive T cell responses in moderate, severe, and critical COVID-19 patients and unexposed donors. Overlapping peptide pools of all three proteins induce SARS-CoV-2-reactive T cell response with dominance of CD4+ over CD8+ T cells and demonstrate interindividual immunity against the three proteins.

M-protein induces the highest frequencies of CD4+ T cells, suggesting its relevance for diagnosis and vaccination. Importantly, T cell response of critical COVID-19 patients is robust and comparable or even superior to non-critical patients. Virus clearance and COVID-19 survival are not associated with either SARS-CoV-2 T cell kinetics or magnitude of T cell responses, respectively.

Thus, our data disprove the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. Conversely, it indicates that activation of differentiated memory effector T cells could cause hyper-reactivity and immunopathogenesis in critical patients.