Systematic Examination of Antigen-Specific Recall T Cell Responses to SARS-CoV-2 versus Influenza Virus Reveals a Distinct Inflammatory Profile

Abstract

There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. In this study, we investigated human T cell recall responses to fully glycosylated spike trimer, recombinant N protein, as well as to S, N, M, and E peptide pools in the early convalescent phase and compared them with influenza-specific memory responses from the same donors. All subjects showed SARS-CoV-2–specific T cell responses to at least one Ag. Both SARS-CoV-2–specific and influenza-specific CD4+ T cell responses were predominantly of the central memory phenotype; however SARS-CoV-2–specific CD4+ T cells exhibited a lower IFN-γ to TNF ratio compared with influenza-specific memory responses from the same donors, independent of disease severity. SARS-CoV-2–specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. Most SARS-CoV-2–convalescent subjects also produced IFN-γ in response to seasonal OC43 S protein. We observed granzyme B+/IFN-γ+, CD4+, and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ T cell responses predominating over CD8+ T cell responses. Peripheral T follicular helper (pTfh) responses to S or N strongly correlated with serum neutralization assays as well as receptor binding domain–specific IgA; however, the frequency of pTfh responses to SARS-CoV-2 was lower than the frequency of pTfh responses to influenza virus. Overall, T cell responses to SARS-CoV-2 are robust; however, CD4+ Th1 responses predominate over CD8+ T cell responses, have a more inflammatory profile, and have a weaker pTfh response than the response to influenza virus within the same donors, potentially contributing to COVID-19 disease.

Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8+ T cell repertoire upon viral exposure

“…Another interesting observation from this work, as noted by others ( 48 ), is that even at the height of infection or shortly after viral clearance, the cumulative anti-SARS-CoV-2 CD8 + T cell response barely reached the frequency of anti-influenza memory responses and was well below the frequencies that could be achieved by CMV-specific cells in the same individuals ( Fig. S2 ).…”

Preclinical evaluation of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B

“…These results contrast the T cell responses identified in COVID-19 patients, where CD4 + T cell responses against SARS-CoV-2 outweigh CD8 + T cells (44)(45)(46)(47)(48).…”

Immune profiling of COVID-19: preliminary findings and implications for the pandemic

“… 37 80 81 85 87 94 These tend to show a robust and highly functional T cell response, with a Th1 phenotype and good proliferative potential, following mild to moderate disease. 85 87 While severe disease can be associated with a higher proportion of SARS-CoV-2-specific T cells, 80 they may have a more exhausted phenotype, 82 with less functionality and a lower IFNγ/TNFα ratio compared with influenza-specific T cells.…”