SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8+ T cell responses

Dannielle Wellington; Zixi Yin; Zhanru Yu; Raphael Heilig; Simon Davis; Roman Fischer; Suet Ling Felce; Elie Antoun; Philip Hublitz; Ryan Beveridge; Danning Dong; Guihai Liu; Xuan Yao; Yanchun Peng; Benedikt M Kessler; Tao Dong

doi:10.1016/j.heliyon.2023.e20076

SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8⁺ T cell responses

Heliyon. 2023 Sep 14;9(10):e20076. doi: 10.1016/j.heliyon.2023.e20076. eCollection 2023 Oct.

Authors

Dannielle Wellington^{1

2}, Zixi Yin^{1

2}, Zhanru Yu^{1

3}, Raphael Heilig³, Simon Davis^{1

3}, Roman Fischer^{1

3}, Suet Ling Felce^{1

4}, Elie Antoun^{1

4}, Philip Hublitz⁵, Ryan Beveridge⁶, Danning Dong^{1

2}, Guihai Liu^{1

2}, Xuan Yao^{1

2}, Yanchun Peng^{1

2}, Benedikt M Kessler^{1

3}, Tao Dong^{1

2}

Affiliations

¹ Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK.
² MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK.
³ Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK.
⁴ Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁵ Genome Engineering Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK.
⁶ Virus Screening Facility, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.

Abstract

Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two SARS-CoV-2 nucleoprotein CD8⁺ epitopes, we investigated the contribution of these flanking mutations to proteasomal processing and T cell activation. We found decreased NP_9-17-B*27:05 CD8⁺ T cell responses to the NP-Q7K mutation, 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-D103 N/Y mutations flanking the NP_9-17-B*27:05 and NP_105-113-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 proteasomal processing, either contributing to T cell escape or enhancement that may be exploited for future vaccine design.

Grants and funding

G0501068/MRC_/Medical Research Council/United Kingdom