PT  - JOURNAL ARTICLE
AU  - Dannielle Wellington
AU  - Zixi Yin
AU  - Zhanru Yu
AU  - Raphael Heilig
AU  - Simon Davis
AU  - Roman Fischer
AU  - Suet Ling Felce
AU  - Philip Hublitz
AU  - Ryan Beveridge
AU  - Danning Dong
AU  - Guihai Liu
AU  - Xuan Yao
AU  - Yanchun Peng
AU  - Benedikt M Kessler
AU  - Tao Dong
TI  - SARS-CoV-2 mutations affect proteasome processing to alter CD8<sup>+</sup> T cell responses
AID  - 10.1101/2022.04.08.487623
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.08.487623
4099  - http://biorxiv.org/content/early/2022/04/08/2022.04.08.487623.short
4100  - http://biorxiv.org/content/early/2022/04/08/2022.04.08.487623.full
AB  - Viral CD8+ epitopes are generated by the cellular turnover of viral proteins, predominantly by the proteasome. Mutations located within viral epitopes can result in escape from memory T cells but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two of the most dominant SARS-CoV-2 nucleoprotein CD8+ epitopes, we identified mutations in epitope flanking regions and investigated the contribution of these mutations to antigen processing and T cell activation using SARS-CoV-2 nucleoprotein transduced B cell lines and in vitro proteasomal processing of peptides. We found that decreased NP9-17-B*27:05 CD8+ T cell responses to the NP-Q7K mutation correlated with lower epitope surface expression, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-B*07:02 epitopes, respectively, increased CD8+ T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on antigen processing and presentation, thereby contributing to escape from immunodominant T cell responses. Alternatively, mutations could enhance antigen processing and efficacy of T cell recognition, opening new avenues for improving future vaccine designs.One Sentence Summary Natural mutations in the flanking regions of known immunodominant SARS-CoV-2 nucleoprotein epitopes can decrease CD8+ T cell responses leading to partial escape.Competing Interest StatementThe authors have declared no competing interest.