Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T cell memory formation after mild COVID-19 infection

Abstract

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cell response is a critical part of both individual and herd immunity to SARS-CoV-2 and the efficacy of developed vaccines. However neither the dynamics and cross-reactivity of the SARS-CoV-2specific T cell response nor the diversity of resulting immune memory are well understood. In this study we use longitudinal high-throughput T cell receptor sequencing to track changes in the T cell repertoire following two mild cases of COVID-19 infection. In both donors we identified SARS-CoV-2-responding CD4+ and CD8+ T cell clones. We describe characteristic motifs in TCR sequences of COVID-19-reactive clones, suggesting the existence of immunodominant epitopes. We show that in both donors the majority of infection-reactive clonotypes acquire memory phenotypes. Certain CD4+ clones were detected in the memory fraction at the pre-infection timepoint, suggesting participation of pre-existing cross-reactive memory T cells in the immune response to SARS-CoV-2.

SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential

“…Limited phenotyping based on CD45RA and CCR7 suggested SARS-CoV-2-specific CD4+ T cells to be more of the T central memory (Tcm) phenotype, while SARS-CoV-2-specific CD8+ T cells were biased towards terminally-differentiated effector cells (Temra) (Weiskopf et al, 2020). These results are consistent with longitudinal analysis of two COVID-19 individuals by bulk TCR sequencing where clonal TCR sequences (assumed to be SARS-CoV-2 specific) were prevalent among Tcm for CD4+ T cells, and Temra for CD8+ T cells (Minervina et al, 2020). However, the phenotypic features of SARS-CoV-2-specific CD4+ and CD8+ T cells have not been systematically investigated, and therefore little is actually known about the functional properties of these cells and their ability to persist long-term in convalescent individuals.…”

SARS-CoV-2 reactive T cells in uninfected individuals are likely expanded by beta-coronaviruses

“…There is mounting evidence for preformed immunity against the novel coronavirus SARS-CoV-2 (13)(14)(15)(16)(17) . Reports on memory T cell response to the endemic coronaviruses are lacking, but since antibody titers appear short-lived and frequent re-infections cannot be excluded (19)(20)(21)(22) , it is probable that the endemic coronaviruses with low virulence do not create lasting immunity.…”

“…The SARS-CoV-2 virus elicits a T cells response during the infection (13) . However, mounting evidence suggests that also uninfected individuals are capable of responding to peptides derived from the S-protein of the SARS-CoV-2 virus (13)(14)(15)(16)(17) , indicating a pre-existing immunity to the SARS-CoV-2 S protein. A single influenza epitope has been identified by comparison of T cell receptors (18) , but the original pathogenic source of this pre-formed T cell memory is generally unclear.…”

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential

“… 14 These results are consistent with longitudinal analysis of two individuals with COVID-19 by bulk TCR sequencing, where clonal TCR sequences (assumed to be SARS-CoV-2 specific) were prevalent among Tcm cells for CD4+ T cells and Temra cells for CD8+ T cells. 18 However, the phenotypic features of SARS-CoV-2-specific CD4+ and CD8+ T cells have not been investigated systematically, and little is actually known about the functional properties of these cells and their ability to persist long term in convalescent individuals.…”