tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Stephanie Gras[SUP] 2 [/SUP], Thi H O Nguyen[SUP] 1 [/SUP], Carine Farenc[SUP] 2 [/SUP], Christopher Szeto[SUP] 2 [/SUP], Louise C Rowntree[SUP] 1 [/SUP], Priyanka Chaurasia[SUP] 2 [/SUP], Sneha Sant[SUP] 1 [/SUP], Adrianus C M Boon[SUP] 3 [/SUP], Dhilshan Jayasinghe[SUP] 2 [/SUP], Guus F Rimmelzwaan[SUP] 4 [/SUP], Jan Petersen[SUP] 2 [/SUP], Peter C Doherty[SUP] 1 [/SUP], Adam P Uldrich[SUP] 1 [/SUP], Dene R Littler[SUP] 2 [/SUP], Jamie Rossjohn[SUP] 2 5 [/SUP], Katherine Kedzierska[SUP] 1 [/SUP]
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)[SUB]418-426[/SUB] epitopes (B*35:01-NP[SUB]418[/SUB]) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP[SUB]418[/SUB] variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP[SUB]418[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]418[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T cell responses. Six TCR-HLA-B*35:01/NP[SUB]418[/SUB] crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP[SUB]418[/SUB] epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP[SUB]418[/SUB] 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[SUP] 1 [/SUP], Stephanie Gras[SUP] 2 [/SUP], Thi H O Nguyen[SUP] 1 [/SUP], Carine Farenc[SUP] 2 [/SUP], Christopher Szeto[SUP] 2 [/SUP], Louise C Rowntree[SUP] 1 [/SUP], Priyanka Chaurasia[SUP] 2 [/SUP], Sneha Sant[SUP] 1 [/SUP], Adrianus C M Boon[SUP] 3 [/SUP], Dhilshan Jayasinghe[SUP] 2 [/SUP], Guus F Rimmelzwaan[SUP] 4 [/SUP], Jan Petersen[SUP] 2 [/SUP], Peter C Doherty[SUP] 1 [/SUP], Adam P Uldrich[SUP] 1 [/SUP], Dene R Littler[SUP] 2 [/SUP], Jamie Rossjohn[SUP] 2 5 [/SUP], Katherine Kedzierska[SUP] 1 [/SUP]
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)[SUB]418-426[/SUB] epitopes (B*35:01-NP[SUB]418[/SUB]) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP[SUB]418[/SUB] variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP[SUB]418[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]418[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T cell responses. Six TCR-HLA-B*35:01/NP[SUB]418[/SUB] crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP[SUB]418[/SUB] epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP[SUB]418[/SUB] 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.