Tweet
Sci Immunol
. 2025 Feb 7;10(104):eadn3805.
doi: 10.1126/sciimmunol.adn3805. Epub 2025 Feb 7. Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors
Sergio M Quiñones-Parra 1 , Stephanie Gras 2 , Thi H O Nguyen 1 , Carine Farenc 2 , Christopher Szeto 2 , Louise C Rowntree 1 , Priyanka Chaurasia 2 , Sneha Sant 1 , Adrianus C M Boon 3 , Dhilshan Jayasinghe 2 , Guus F Rimmelzwaan 4 , Jan Petersen 2 , Peter C Doherty 1 , Adam P Uldrich 1 , Dene R Littler 2 , Jamie Rossjohn 2 5 , Katherine Kedzierska 1
Affiliations
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)418-426 epitopes (B*35:01-NP418) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP418 variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP418+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-NP418+CD8+ T cell responses. Six TCR-HLA-B*35:01/NP418 crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP418 epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP418 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.
. 2025 Feb 7;10(104):eadn3805.
doi: 10.1126/sciimmunol.adn3805. Epub 2025 Feb 7. Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors
Sergio M Quiñones-Parra 1 , Stephanie Gras 2 , Thi H O Nguyen 1 , Carine Farenc 2 , Christopher Szeto 2 , Louise C Rowntree 1 , Priyanka Chaurasia 2 , Sneha Sant 1 , Adrianus C M Boon 3 , Dhilshan Jayasinghe 2 , Guus F Rimmelzwaan 4 , Jan Petersen 2 , Peter C Doherty 1 , Adam P Uldrich 1 , Dene R Littler 2 , Jamie Rossjohn 2 5 , Katherine Kedzierska 1
Affiliations
- PMID: 39919196
- DOI: 10.1126/sciimmunol.adn3805
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)418-426 epitopes (B*35:01-NP418) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP418 variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP418+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-NP418+CD8+ T cell responses. Six TCR-HLA-B*35:01/NP418 crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP418 epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP418 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.