Publication date: Dec 10, 2025
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 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.
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| Concepts | Keywords |
|---|---|
| Attractive | Coronavirus |
| Cd8 | Cov |
| Coronaviruses | Diverse |
| Immunogenic | Epitopes |
| Nucleocapsid | Hla |
| Immunodominant | |
| Lll | |
| Nucleocapsid | |
| Restricted | |
| Sars | |
| Spr | |
| Structural | |
| Tcrs | |
| Vaccine | |
| Variants |