Robust T Cell Response Toward Spike, Membrane, and Nucleocapsid SARS-CoV-2 Proteins Is Not Associated with Recovery in Critical COVID-19 Patients.

T cell immunity toward SARS-CoV-2 spike (S-), membrane (M-), and nucleocapsid (N-) proteins may 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. The 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 do not support 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 hyperreactivity and immunopathogenesis in critical patients.

Heightened Circulating Interferon-Inducible Chemokines, and Activated Pro-Cytolytic Th1-Cell Phenotype Features Covid-19 Aggravation in the Second Week of Illness.

Covid-19 features a delayed onset of critical illness occurring approximately one week from the beginning of symptoms, which corresponds to the bridging of innate and adaptive immunity. We reasoned that the immune events occurring at the turning point of disease might mark the direction toward pathogenic versus protective inflammatory responses. Subjects with either severe (s; PaO2/FiO2 ratio <200) or mild (m; PaO2/FiO2 ratio>300) Covid-19 were enrolled. A range of chemokines and cytokines as well as reactive oxygen species (ROS) were measured in plasma. Dendritic and NK cell frequency, monocyte and B-/T-cell phenotype and SARS-CoV-2-specific T-cell responses were assessed in PBMC. Twenty mCovid-19 and 20 sCovid-19 individuals were studied. sCovid-19 patients displayed higher non-classical monocytes, plasma chemokines (CXCL8, CXCL9, CXCL10), cytokines (IL-6, IL-10), and ROS versus mCovid-19. sCovid-19 also showed significantly increased activated CD38+HLA-DR+ T-lymphocyte, and granzyme-B+/perforin+ pro-cytolytic T-cells. All Covid-19 patients showed SARS-CoV-2 specific-T-cell response with a predominance of Th1 bi- or trifunctional IFN-γ/IL-2/TNF-α-expressing CD4+, while no difference according to disease severity was observed. Severe Covid-19 features heightened circulating IFN-inducible chemokines and activated pro-cytolytic Th1 cell phenotype in the second week of illness, yet SARS-CoV-2-specific responses are similar to that of mild illness. Altogether, our observations suggest Th1 polarization coupled to higher cytolytic profile in sCovid-19 as correlate of disease pathogenesis and as potential targets to be investigated in the roadmap to therapy and vaccine development.