Position-5-driven reorientation of an immunodominant HLA-A*24:02 SARS-CoV-2 epitope drives universal T-cell escape

Nakama, Takeshi, Wall, Aaron, Dolton, Garry, Tan, Li-Rong, Thomas, Hannah and Rizkallah, Pierre J. ORCID: https://orcid.org/0000-0002-9290-0369 2026. Position-5-driven reorientation of an immunodominant HLA-A*24:02 SARS-CoV-2 epitope drives universal T-cell escape. JCI Insight 10.1172/jci.insight.202235

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Abstract

Cytotoxic T lymphocytes form a critical component of SARS-CoV-2 immunity by recognizing viral peptides bound to HLA class I molecules. Here, we identified the Spike-derived peptide NYNYLYRLF448-456 (NF9) as the immunodominant HLA-A*24:02-restricted epitope in both convalescent and vaccinated donors. Across cohorts, A24/NF9-specific responses were dominated by public TCR motifs featuring TRAV12-1 (or TRAV6-1) paired with TRBJ2-7 and a conserved CDR3β sequence (CASSXXXGYEQYF). Using a panel of thirteen TCRs, we mapped recognition of single amino acid substitutions within NF9 and identified residue 5 (L452) as the principal determinant of escape. The L452R substitution, characteristic of the Delta variant, abolished recognition across all tested TCRs despite preserved HLA binding. Crystallography of a representative public TCR (P1-15) revealed that mutation at position 5 reoriented the peptide within HLA-A*24:02, flipping the adjacent Y453 side chain into the peptide-binding groove and eliminating the dominant TCR contact. This position-5-driven conformational switch provided a structural mechanism for universal loss of NF9 recognition by HLA-A*24:02-restricted T-cells. Consistent with this, Delta-infected convalescents failed to mount de novo NF9-5R-specific responses while retaining responses to the conserved A24/QI9 Spike epitope. Together, these findings defined the basis of A24/NF9 recognition and showed how one mutation remodelled peptide presentation to abrogate TCR responses.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Full author list available at DOI link
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of First Compliant Deposit:	23 March 2026
Last Modified:	23 Mar 2026 14:32
URI:	https://orca.cardiff.ac.uk/id/eprint/185960

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