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

Louise C. Rowntree, Jan Petersen, Jennifer A. Juno, Priyanka Chaurasia, Kathleen Wragg, Marios Koutsakos, Luca Hensen, Adam K. Wheatley, Stephen J. Kent, Jamie Rossjohn, Katherine Kedzierska, Thi H.O. Nguyen

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

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, S1208–1216 (QYIKWPWYI), S448–456 (NYNYLYRLF) and S193–201 (VFKNIDGYF), with S1208 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/S448+CD8+ T-cell TCRαβ repertoire was driven by a common TCRβ chain motif, whereas the A24/S1208+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.

Original languageEnglish
Pages (from-to)990-1000
Number of pages11
JournalImmunology and Cell Biology
Volume99
Issue number9
DOIs
Publication statusPublished - Oct 2021

Keywords

  • CD8 T cells
  • COVID-19
  • HLA-A*24:02
  • SARS-CoV-2 epitopes
  • T-cell receptor

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