Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19

Abstract

OVID-19 is caused by the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the majority of COVID-19 infections are relatively mild, with recovery typically within 2-3 weeks 1,2 , a significant number of patients develop severe illness, which is postulated to be related to both an overactive immune response and viral-induced pathology 3,4. The role of T cell immune responses in disease pathogenesis and longer-term protective immunity is currently poorly defined, but essential to understand in order to inform therapeutic interventions and vaccine design. Currently, there are many ongoing vaccine trials, but it is unknown whether they will provide long-lasting protective immunity. Most vaccines are designed to induce antibodies to the SARS-CoV-2 spike protein, but it is not yet known if this will be sufficient to induce full protective immunity to SARS-CoV-2 (refs. 5-8). Studying natural immunity to the virus, including the role of SARS-CoV-2specific T cells, is critical to fill the current knowledge gaps for improved vaccine design. For many primary virus infections, it typically takes 7-10 d to prime and expand adaptive T cell immune responses in order to control the virus 9. This coincides with the typical time it takes for patients with COVID-19 to either recover or develop severe illness. There is an incubation time of 4-7 d before symptom onset and a further 7-10 d before individuals progress to severe disease 10 .

CD8+ T cell responses in convalescent COVID-19 individuals target epitopes from the entire SARS-CoV-2 proteome and show kinetics of early differentiation

“…In addition to the detection of epitopes previously described by others, over a third (i.e. 35%) of the antigen-specific T cells identified here have not been previously reported (Table S6), thereby highlighting the sensitivity of the adopted screening approach 8,9,22–27 . However, given the low frequencies of many of these CD8 T+ cells, it is possible that these were below the detection threshold since T cell counts are very low in acutely infected patient samples 28 .…”

“…A mass cytometry based peptide-MHC-tetramer staining strategy 17 was applied, whereby 408 SARS-CoV-2 candidate epitopes were screened spanning 6 different HLA alleles. This enabled an ex vivo identification and true phenotypic characterization of virus-specific T cells in COVID-19 convalescent individuals without an in-vitro culture or stimulation bias which could affect the cellular phenotype, in contrast to prior studies using overlapping peptide pools 6–8 . The high detection rate of SARS-CoV-2-specific CD8+ T cells across these COVID-19 convalescent donors is consistent with previous reports 6–8 .…”

“…A study by Peng et al . indicated that the majority of those who recover from COVID-19 exhibit robust and broad SARS-CoV-2 specific T cell responses 8 . Further, those who manifest mild symptoms displayed a greater proportion of polyfunctional CD8+ T cell responses compared with severely diseased cases, suggesting a role of CD8+ T cells in ameliorating disease severity.…”

SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike

“…CD4 T cells are critical for driving antibody responses by mediating germinal center selection of antigen specific B cells. Notably, CD4 T cells targeting multiple SARS-CoV-2 antigens and the magnitude of the CD4 T cell response positively correlate with SARS-CoV-2 specific antibody responses22,23 . Moreover, subjects with more severe disease demonstrate an increased breadth andMethodsStudy cohortsAll studies were performed with the approval of the Universityof Chicago institutional review board and University of Chicago and University of Wisconsin-Madison institutional biosafety committees.…”

Distinct B cell subsets give rise to antigen-specific antibody responses against SARS-CoV-2

“…Mechanistically, these observations may be explained by reduced adaptability of B cells or increased reliance on CD4 T cell help for B cell activation, which have been observed in aged individuals upon viral infections 27,28 . Furthermore, T cell responses to SARS-CoV-2 ORF proteins are prevalent in convalescent COVID-19 patients, and recent studies suggest impaired T cell responses in aged COVID-19 patients impact antibody responses 10,29,30,42 . More research is warranted to definitively determine whether B cell targeting of distinct SARS-CoV-2 antigens correlates with age and disease severity.…”