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

Abstract

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.

SARS-CoV-2-specific T cell memory is long-lasting in the majority of convalsecent COVID-19 individuals

“…During the acute phase of COVID-19, T cell responses positively correlated with the magnitude of antibody responses 5,7,8 . However, to our knowledge it is not clear whether this association is maintained during the long-term convalescence.…”

“…While antibody-based immunity is relatively well-studied, increasing evidences suggest that T cells may play a fundamental role in the resolution of COVID-19 1,2 . The current dogma is that SARS-CoV-2-specific CD4 and CD8 T cell responses, responding at variably high frequencies recognizing multiple epitopes across the viral proteome, can be detected in most individuals both during acute COVID-19 and convalescence afterwards 3–8 . The magnitude of SARS-CoV-2-specific T cell responses during the early phase is assumed to correlate with the magnitude of antibody responses, and more severe and protracted disease usually drives a more vigorous and, in terms of epitope coverage, broader T cell response 5,7,8 .…”

“…The current dogma is that SARS-CoV-2-specific CD4 and CD8 T cell responses, responding at variably high frequencies recognizing multiple epitopes across the viral proteome, can be detected in most individuals both during acute COVID-19 and convalescence afterwards 3–8 . The magnitude of SARS-CoV-2-specific T cell responses during the early phase is assumed to correlate with the magnitude of antibody responses, and more severe and protracted disease usually drives a more vigorous and, in terms of epitope coverage, broader T cell response 5,7,8 . However, it has also been observed that cellular and humoral immune responses can become uncoupled in some SARS-CoV-2-exposed individuals, who showed strong specific T cell immunity but lack detectable antibody responses 9 .…”

Illuminating the immunopathology of SARS‐CoV‐2

“…The quality of the antigen‐specific immune response has also been investigated. It was recently reported that patients with critical COVID‐19 demonstrated equal, or even slightly higher, frequencies of polyfunctional SARS‐CoV‐2‐specific CD4 + and CD8 + T cells compared to (non‐critical) patients with moderate disease (Thieme et al, 2020). Moreover, no association was observed between the kinetics and magnitude of SARS‐CoV‐2‐specific T cell responses and viral clearance or COVID‐19 survival.…”

“…Despite the significant T cell loss, highly activated peripheral T cells were found in a subgroup of hospitalized COVID‐19 patients, and T cell activation was associated with more severe disease and organ failure (Mathew et al, 2020). There is also evidence for polyfunctional SARS‐CoV‐2‐specific CD4 + and CD8 + T cells with an effector/memory phenotype exacerbating the immunopathology in critical COVID‐19 cases (Thieme et al, 2020). Other unusual features of COVID‐19 include presence of long‐lived antibody‐secreting plasmablasts (Kuri‐Cervantes et al, 2020; Laing et al, 2020; Mathew et al, 2020), high levels of anti‐SARS‐CoV‐2 antibodies in the blood of COVID‐19 patients (Kuri‐Cervantes et al, 2020; Laing et al, 2020; Mathew et al, 2020; Rydyznski Moderbacher et al, 2020), as well as loss of Bcl‐6‐expressing T FH cells and germinal centers (potentially due to high levels of certain cytokines or defects in antigen presenting cells that help drive the response) (Kaneko et al, 2020).…”