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

Rowntree, Louise C, Petersen, Jan, Juno, Jennifer A, Chaurasia, Priyanka, Wragg, Kathleen, Koutsakos, Marios, Hensen, Luca, Wheatley, Adam K, Kent, Stephen J, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Kedzierska, Katherine and Nguyen, Thi HO 2021. SARS-CoV-2-specific CD8+ T-cell responses and TCR signatures in the context of a prominent HLA-A*24:02 allomorph. Immunology & Cell Biology 99 (9) , pp. 990-1000. 10.1111/imcb.12482

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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.

Item Type:	Article
Date Type:	Publication
Schools:	Medicine
Publisher:	Wiley
ISSN:	0818-9641
Date of First Compliant Deposit:	8 August 2023
Date of Acceptance:	2 June 2021
Last Modified:	15 Aug 2023 10:06
URI:	https://orca.cardiff.ac.uk/id/eprint/161519

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