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
Affiliations
Dannielle Wellington
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK; Corresponding author. Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford OX3 7FZ, UK.
Zixi Yin
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
Zhanru Yu
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK
Raphael Heilig
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK
Simon Davis
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK
Roman Fischer
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK
Suet Ling Felce
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
Elie Antoun
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
Philip Hublitz
Genome Engineering Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
Ryan Beveridge
Virus Screening Facility, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
Danning Dong
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
Guihai Liu
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
Xuan Yao
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
Yanchun Peng
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
Benedikt M. Kessler
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK
Tao Dong
Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK; Corresponding author. Chinese Academy of Medical Sciences (CAMS) Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, OX3 7FZ, UK.
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 NP9-17-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 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 proteasomal processing, either contributing to T cell escape or enhancement that may be exploited for future vaccine design.
