T cells play a vital role in combatting SARS-CoV-2 and forming long-term memory responses to this coronavirus. Previous studies of T cell responses to SARS-CoV-2 have focused on epitopes derived from the spike (S) protein. Much less is known about T cell responses to nucleocapsid (N) epitopes. The Mariuzza and Weng groups identified the N(222-230) peptide as a dominant epitope in COVID-19 convalescent patients that is highly conserved in SARS-CoV-2 variants. A remarkable feature of T cell receptors (TCRs) specific for N(222-230) is the almost exclusive use of the TRAV12-2 Vα gene. The crystal structure of a TCR-N(222-230)-HLA-A2 complex revealed the basis for highly restricted Vα gene usage with limited complementarity determining region 3 (CDR3α) motifs. As shown in the figure, Vα mediates the bulk (74%) of contacts between TCR and the N(222-230) peptide. This Vα dominance allows pairing with multiple Vβ chains, which make comparatively few interactions with the peptide or HLA-A2. In addition, a structure-based machine learning prediction model was developed capable of accurately predicting N(222-230)-reactive TCRs. This study provides important information for prospective efforts to rationally design T cell vaccines capable of eliciting broad and long-lasting immunity against coronaviruses.
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Figure: (a) Structure of TCR-N(222-230)-HLA-A2 complex. (b) Footprint of TCR on N(222-230)-HLA-A2. HLA-A2 is depicted as a gray surface. The SARS-CoV-2 N(222-230) peptide is drawn in stick representation. The areas contacted by individual CDR loops of the TCR are colored. (c) Pie chart showing percentage distribution of TCR contacts to the N(222-230) peptide according to CDR. |
Citation: Choy, C, Chen, J, Li, J, Gallagher, DT, Lu, J, Wu, D, Zou, A, Hemani, H, Baptiste, BA, Wichmann, E, Yang, Q, Ciffelo, J, Yin, R, McKelvy, J, Melvin, D, Wallace, T, Dunn, C, Nguyen, C, Chia, CW, Fan, J, Ruffolo, J, Zukley, L, Shi, G, Amano, T, An, Y, Meirelles, O, Wu, WW, Chou, CK, Shen, RF, Willis, RA, Ko, MSH, Liu, YT, De, S, Pierce, BG, Ferrucci, L, Egan, J, Mariuzza, R, Weng, NP. "SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors." Nat. Commun. 14, 6725 (2023). DOI:10.1038/s41467-023-42430-z.
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