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(+)IFNγ(+) responses above background, S(1208–1216) (QYIKWPWYI), S(448–456) (NYNYLYRLF) and S(193–201) (VFKNIDGYF), with S(1208) generating immunodominant CD8(+)IFNγ(+) 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. Naïve 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 TCRαβ repertoires found that the A24/S(448) (+)CD8(+) T‐cell TCRαβ repertoire was driven by a common TCRβ chain motif, whereas the A24/S(1208) (+)CD8(+) TCRαβ 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.