Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors

Quiñones-Parra, Sergio M., Gras, Stephanie, Nguyen, Thi H. O., Farenc, Carine, Szeto, Christopher, Rowntree, Louise C., Chaurasia, Priyanka, Sant, Sneha, Boon, Adrianus C.M., Jayasinghe, Dhilshan, Rimmelzwaan, Guus F., Petersen, Jan, Doherty, Peter C., Uldrich, Adam P., Littler, Dene R., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Kedzierska, Katherine 2025. Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors. Science Immunology 10 (104) , eadn3805. 10.1126/sciimmunol.adn3805

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Abstract

Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01-restricted nucleoprotein (NP) epitopes (B*35:01-NP ) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP CD8 T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP CD8 T cell responses. Six TCR-HLA-B*35:01/NP crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Association for the Advancement of Science
Last Modified:	20 Feb 2025 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/176341

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