HLA-B*15:01-positive severe COVID-19 patients lack CD8 <sup>+</sup> T cell pools with highly expanded public clonotypes

Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8<sup>+</sup> T-cells directed against HLA-B*15:01-restricted Spike-derived S<sub>919-927</sub> peptide (B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8<sup>+</sup> T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell responses lacking a highly expanded key public B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells did not differ across disease severity. Moreover, B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-09-02
DOI
https://doi.org/10.1073/pnas.2503145122
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
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article

HLA-B*15:01-positive severe COVID-19 patients lack CD8 + T cell pools with highly expanded public clonotypes

Prathanporn Kaewpreedee, Jianqing Xu, Ahmed Abdul Quadeer, Paul Glyndwr Thomas et al.
Proceedings of the National Academy of Sciences
SARS-CoV-2 and COVID-19 Research
article

HLA-B*15:01-positive severe COVID-19 patients lack CD8 + T cell pools with highly expanded public clonotypes

Prathanporn Kaewpreedee, Jianqing Xu, Ahmed Abdul Quadeer, Paul Glyndwr Thomas, Katherine Kedzierska, Malik Peiris, Samuel M. S. Cheng, Jennifer R. Habel, Shidan Tosif, Jan Petersen, George F. Gao, Nigel W. Crawford, Priyanka Chaurasia, Thi H. O. Nguyen, Olivia Catherine Smibert, Carolyn A. Cohen, Kathy Leung, Claudia Efstathiou, Allen Cheng, Deborah Anne Williamson, Leo L. M. Poon, Katherine A. Bond, Jason A. Trubiano, Hayley A. McQuilten, Christopher Edward Brightling, Jennifer A. Juno, Yukinori Okada, Louise C. Rowntree, Stephen John Kent, Sophie A. Valkenburg, Janette Kwok, Ryan S. Thwaites, Claire L. Gordon, Sharon R. Lewin, Ken J. Ishii, William Jun Liu, Joseph T. Wu, Ho Namkoong, Dene R. Littler, Peter C. Doherty, Wuji Zhang, Natasha E. Holmes, Pia S. Pannaraj, Jinmin Tian, Jamie Rossjohn, Ruth R. Hagen, Lance C. W. Turtle, David S.C. Hui, Kyuto Sonehara, Matthew R. McKay, Jane Davies, Ka Pang Chan, Martha Lappas, Irani Thevarajan, Tom Kotsimbos, E. Kaity Allen, Kelly W. K. Lee, Cheuk‐Kwong Lee, Lilith F. Allen
article en

Abstract

Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8<sup>+</sup> T-cells directed against HLA-B*15:01-restricted Spike-derived S<sub>919-927</sub> peptide (B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8<sup>+</sup> T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell responses lacking a highly expanded key public B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells did not differ across disease severity. Moreover, B15/S<sub>919</sub><sup>+</sup>CD8<sup>+</sup> T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.

Proceedings of the National Academy of SciencesVol. 122(36)
University of Southern California (US), St. Jude Children's Research Hospital (US), The Royal Melbourne Hospital (AU), Royal Children's Hospital (AU), Department of Health (CN), Children's Hospital of Los Angeles (US), Shanghai Medical College of Fudan University (CN), University of Liverpool (GB), University of California, Los Angeles (US), The University of Melbourne (AU), University of St Andrews (GB), Chinese University of Hong Kong (HK), University of California, San Francisco (US), Hong Kong University of Science and Technology (HK), Keio University (JP), Hokkaido University (JP), Aintree University Hospitals NHS Foundation Trust (GB), Discovery Institute (US), Peter MacCallum Cancer Centre (AU), Queen Mary Hospital (CN), Hong Kong Science and Technology Parks Corporation (HK), Australian Regenerative Medicine Institute (AU), The Alfred Hospital (AU), Menzies School of Health Research (AU), National Institute of Biomedical Innovation, Health and Nutrition (JP), National Cancer Centre Japan (JP), Monash Alfred Psychiatry Research centre (AU), Melbourne Sexual Health Centre (AU), Hong Kong Jockey Club (HK), Lung Institute (US), Peter Doherty Institute (AU), Prince of Wales Hospital (CN), Institut de Recherche Vaccinale (FR), Monash Health (AU), Taiwan Centers for Disease Control (TW), National Institute for Viral Disease Control and Prevention (CN), University of Hong Kong - Shenzhen Hospital (CN), HKU-Pasteur Research Pole (HK), Murdoch Children's Research Institute (AU), RIKEN Center for Integrative Medical Sciences (JP), Melbourne Health (AU), Alfred Health (AU), Austin Health (AU), Institute of Infection and Immunity (CA), NIHR Leicester Biomedical Research Centre (GB), Imperial College London (GB), Monash University (AU), The University of Tokyo (JP), Cardiff University (GB), University of Hong Kong (HK), The University of Osaka (JP)
Children's Hospital Los Angeles, St. Jude Children's Research Hospital, Queen Mary University of London, Children’s Hospital of Wisconsin Research Institute, Menzies School of Health Research, UK Research and Innovation, Murdoch Children's Research Institute, National Institute for Health Research Health Protection Research Unit, National Institute for Health and Care Research, Department of Health and Social Care, University of Oxford, Monash University, Innovation and Technology Commission, University of Hong Kong, Chinese University of Hong Kong, UK Coronavirus Immunology Consortium, National Institutes of Health, University of California, Los Angeles, Medical Research Council, National Health and Medical Research Council, Health and Medical Research Fund, Monash Biomedicine Discovery Institute, Monash University, National Institute of Allergy and Infectious Diseases, Institute of Infection and Immunity, ARC Centre for Excellence in Convergent Bio-Nano Science and Technology
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SARS-CoV-2 and COVID-19 Research
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