SARS-CoV-2-specific CD8+ T-cell responses and TCR signatures in the context of a prominent HLA-A*24:02 allomorph

In-depth understanding of human T-cell-mediated immunity in coronavirus disease 2019 (COVID-19) is needed if we are to optimize vaccine strategies and immunotherapies. Identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell epitopes and generation of peptide-human leukocyte antigen (peptide-HLA) tetramers facilitate direct ex vivo analyses of SARS-CoV-2-specific T cells and their T-cell receptor (TCR) repertoires. We utilized a combination of peptide prediction and in vitro peptide stimulation to validate novel SARS-CoV-2 epitopes restricted by HLA-A*24:02, one of the most prominent HLA class I alleles, especially in Indigenous and Asian populations. Of the peptides screened, three spike-derived peptides generated CD8(+)IFN gamma(+) responses above background, S1208-1216 (QYIKWPWYI), S448-456 (NYNYLYRLF) and S193-201 (VFKNIDGYF), with S-1208 generating immunodominant CD8(+)IFN gamma(+) responses. Using peptide-HLA-I tetramers, we performed direct ex vivo tetramer enrichment for HLA-A*24:02-restricted CD8(+) T cells in COVID-19 patients and prepandemic controls. The precursor frequencies for HLA-A*24:02-restricted epitopes were within the range previously observed for other SARS-CoV-2 epitopes for both COVID-19 patients and prepandemic individuals. Naive A24/SARS-CoV-2-specific CD8(+) T cells increased nearly 7.5-fold above the average precursor frequency during COVID-19, gaining effector and memory phenotypes. Ex vivo single-cell analyses of TCR alpha beta repertoires found that the A24/S(448)(+)CD8(+) T-cell TCR alpha beta repertoire was driven by a common TCR beta chain motif, whereas the A24/S(1208)(+)CD8(+) TCR alpha beta repertoire was diverse across COVID-19 patients. Our study provides an in depth characterization and important insights into SARS-CoV-2-specific CD8(+) T-cell responses associated with a prominent HLA-A*24:02 allomorph. This contributes to our knowledge on adaptive immune responses during primary COVID-19 and could be exploited in vaccine or immunotherapeutic approaches.

Automated summary

This study identified novel HLA-A*24:02-restricted epitopes of SARS-CoV-2 and characterized the CD8(+) T-cell responses associated with this HLA allomorph during COVID-19. The frequencies of A24/SARS-CoV-2-specific CD8(+) T cells increased substantially during COVID-19, showing effector and memory phenotypes. Ex vivo analyses of TCR alpha beta repertoires revealed distinct differences in repertoire diversity among COVID-19 patients for different epitopes.