tetano
Editor, Senior Moderator
Nat Commun
. 2025 Dec 10.
doi: 10.1038/s41467-025-66322-6. Online ahead of print. Structural insights into clonal restriction and diversity in T cell recognition of two immunodominant SARS-CoV-2 nucleocapsid epitopes
Ping Yuan[SUP] #[/SUP][SUP] 1 [/SUP], Guodong Chen[SUP] #[/SUP][SUP] 1 [/SUP], Yukun Li[SUP] #[/SUP][SUP] 2 [/SUP], Xichun Liu[SUP] 3 [/SUP], Shayana Saravanakumar[SUP] 4 5 [/SUP], Jianfeng Zhao[SUP] 1 [/SUP], Qianyu Ji[SUP] 6 [/SUP], Hong Wang[SUP] 7 [/SUP], Ying-Wu Lin[SUP] 3 [/SUP], Mostafa Elbahnasawy[SUP] 8 [/SUP], Nan-Ping Weng[SUP] 8 [/SUP], Brian G Pierce[SUP] 9 10 [/SUP], Roy A Mariuzza[SUP] 11 12 [/SUP], Daichao Wu[SUP] 13 [/SUP]
Affiliations
T cells play a crucial role in clearing SARS-CoV-2 and in forming long-term memory responses to that coronavirus. The highly immunogenic nucleocapsid (N) protein of SARS-CoV-2 is much more conserved than the spike (S) protein across variants of concern, making it an attractive vaccine target for activating cytotoxic CD8[SUP]+[/SUP] T cells. Of particular interest are the immunodominant N epitopes LLL and SPR. Whereas LLL elicits a clonally restricted T cell response, the response to SPR is highly diverse. To understand the basis for this difference, here we determine structures of T cell receptors (TCRs) bound to LLL-HLA-A2 and SPR-HLA-B7, revealing the structural underpinnings of highly restricted Vα gene usage by LLL-specific TCRs, as well as multiple structural solutions to recognizing SPR and thereby generating a clonally diverse T cell response to that epitope. These structures also provide frameworks for understanding T cell recognition of SARS-CoV-2 variants and other coronaviruses. Finally, we compare the X-ray structures of TCR-LLL-HLA-A2 and TCR-SPR-HLA-B7 complexes with models predicted by multiple versions of AlphaFold, highlighting some success while showing room for improvement. Overall, our findings expand understanding of coronavirus T cell recognition, informing vaccine design and advances in computational modeling approaches.
. 2025 Dec 10.
doi: 10.1038/s41467-025-66322-6. Online ahead of print. Structural insights into clonal restriction and diversity in T cell recognition of two immunodominant SARS-CoV-2 nucleocapsid epitopes
Ping Yuan[SUP] #[/SUP][SUP] 1 [/SUP], Guodong Chen[SUP] #[/SUP][SUP] 1 [/SUP], Yukun Li[SUP] #[/SUP][SUP] 2 [/SUP], Xichun Liu[SUP] 3 [/SUP], Shayana Saravanakumar[SUP] 4 5 [/SUP], Jianfeng Zhao[SUP] 1 [/SUP], Qianyu Ji[SUP] 6 [/SUP], Hong Wang[SUP] 7 [/SUP], Ying-Wu Lin[SUP] 3 [/SUP], Mostafa Elbahnasawy[SUP] 8 [/SUP], Nan-Ping Weng[SUP] 8 [/SUP], Brian G Pierce[SUP] 9 10 [/SUP], Roy A Mariuzza[SUP] 11 12 [/SUP], Daichao Wu[SUP] 13 [/SUP]
Affiliations
- PMID: 41372155
- DOI: 10.1038/s41467-025-66322-6
T cells play a crucial role in clearing SARS-CoV-2 and in forming long-term memory responses to that coronavirus. The highly immunogenic nucleocapsid (N) protein of SARS-CoV-2 is much more conserved than the spike (S) protein across variants of concern, making it an attractive vaccine target for activating cytotoxic CD8[SUP]+[/SUP] T cells. Of particular interest are the immunodominant N epitopes LLL and SPR. Whereas LLL elicits a clonally restricted T cell response, the response to SPR is highly diverse. To understand the basis for this difference, here we determine structures of T cell receptors (TCRs) bound to LLL-HLA-A2 and SPR-HLA-B7, revealing the structural underpinnings of highly restricted Vα gene usage by LLL-specific TCRs, as well as multiple structural solutions to recognizing SPR and thereby generating a clonally diverse T cell response to that epitope. These structures also provide frameworks for understanding T cell recognition of SARS-CoV-2 variants and other coronaviruses. Finally, we compare the X-ray structures of TCR-LLL-HLA-A2 and TCR-SPR-HLA-B7 complexes with models predicted by multiple versions of AlphaFold, highlighting some success while showing room for improvement. Overall, our findings expand understanding of coronavirus T cell recognition, informing vaccine design and advances in computational modeling approaches.