Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell epitope mapping

Abstract

The current COVID-19 pandemic represents a global challenge. A better understanding of the immune response against SARS-CoV-2 is key to unveil the differences in disease severity and to develop future vaccines targeting novel SARS-CoV-2 variants. Feature barcode technology combined with CITE-seq antibodies and DNA-barcoded peptide-MHC I Dextramer reagents enabled us to identify relevant SARS-CoV-2-derived epitopes and compare epitope-specific CD8+ T cell populations between mild and severe COVID-19. We identified a strong CD8+ T cell response against an S protein-derived epitope. CD8+ effector cells in severe COVID-19 displayed hyperactivation, T cell exhaustion and were missing characteristics of long-lived memory T cells. We identify A*0101 WTAGAAAYY as an immunogenic CD8+ T cell epitope with the ability to drive clonal expansion. We provide an in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection which will be relevant for the development of molecular and targeted therapies and potential adjustments of vaccination strategies.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells

“…Thus, the appearance of this cluster was not connected to disease severity or the nature of the antigenic stimulus (vaccine or virus). In concordance with previous reports (Schreibing et al 2021;Kusnadi et al 2021), this cluster was composed of highly expanded clones (Fig. S10), with more than 87% of the cluster repertoire occupied by just 10 clones (Fig.…”

“…Staining with MHC-multimers loaded with individual peptides is an alternative approach, which requires pre-selection of immunogenic peptides. Several SARS-CoV-2 epitopes presented by common HLA alleles were discovered in the past two years, permitting the tracking of epitopespecific T cell responses in infected [13][14][15][16][17][18][19][20][21][22][23][24][25][26] and vaccinated individuals 9,12 using MHC-multimers.…”

“…Staining with MHCmultimers loaded with individual peptides is an alternative approach, but it requires pre-selection of immunogenic peptides. Several immunodominant SARS-CoV-2 epitopes presented by common HLA alleles were discovered in the past year, permitting the tracking of epitope-specific T cell response in infected (Francis et al 2021;Gangaev et al 2021;Schreibing et al 2021;Shomuradova et al 2020;Kared et al 2021;Saini et al 2021;Ferretti et al 2020;Nielsen et al 2021;Peng, Yanchun et al 2020;Rha et al 2021;Sekine et al 2020;Schulien et al 2021;Habel et al 2020;Nguyen et al 2021) and vaccinated (Thimme et al 2021;Sahin et al 2021) individuals using MHC-multimers. Although at the peak of the infection response reports have described more than 10% of CD8+ T cells specific to a single SARS-CoV-2 epitope (Saini et al 2021;Gangaev et al 2021), a month after infection the frequency of most epitope-specific T cell populations is typically less than 1% (Ferretti et al 2020;Peng, Yanchun et al 2020;Kared et al 2021;Rha et al 2021).…”

Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm

“…A number of CD8 T cell epitopes (n=133), presented to CD8 T cells by different HLA class I alleles, has been reported to be located within unmutated spike regions (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74). They are characterized by different levels of immunodominance and endowed with different CD8 T cell stimulatory capacities, as deduced from the intensity of CD8 responses measured by functional assays [e.g., TCR-dependent Activation Induced FIGURE 1 | SARS-CoV-2 spike mutation and deletion map of the prominent circulating VoC/VoI and SARS-Cov-2-specific CD8 T cell epitopes containing mutations.…”

“…Marker (AIM) and Elispot assays] and through the assessment of the frequency of circulating, multimer-positive SARS-Cov-2 specific CD8 T cells (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74). In particular, 85 of these epitopes are recognized by CD8 T cells in association with the most highly represented HLA-class I alleles (frequency > 5%, as calculated by their median expression value in the world population), 2A).…”