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Publications

Journal Article Ppublish

PubMed: 40892914 DOI: 10.1073/pnas.2503145122

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

Proc Natl Acad Sci U S A 122(36):e2503145122

Authors: Louise C Rowntree, Lilith F Allen, Ruth R Hagen, Hayley A McQuilten, Ahmed A Quadeer, Priyanka Chaurasia, Prathanporn Kaewpreedee, Kelly W K Lee, Carolyn A Cohen, Jan Petersen, Dene R Littler, Jennifer R Habel, Wuji Zhang, Samuel M S Cheng, Ken Ka Pang Chan, Janette S Y Kwok, Kathy S M Leung, Joseph T Wu, Cheuk-Kwong Lee, Jane Davies, Pia S Pannaraj, E Kaity Allen, Paul G Thomas, Shidan Tosif, Nigel W Crawford, Martha Lappas, Irani Thevarajan, Sharon R Lewin, Stephen J Kent, Jennifer A Juno, Katherine A Bond, Deborah A Williamson, Natasha E Holmes, Olivia C Smibert, Claire L Gordon, Jason A Trubiano, Tom C Kotsimbos, Allen C Cheng, Claudia Efstathiou, Lance Turtle, Ryan S Thwaites, Christopher E Brightling, Jamie Rossjohn, Matthew R McKay, Jinmin Tian, William Jun Liu, George Fu Gao, Jianqing Xu, Kyuto Sonehara, Ken J Ishii … and 9 other authors

Affiliations

  • Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
  • Department of Electronic and Computer Engineering, School of Engineering, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, Hong Kong, China.
  • Department of Electrical and Electronic Engineering, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
  • HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
  • Division of Public Health Laboratory Sciences, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
  • Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
  • Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
  • Division of Transplantation and Immunogenetics, Department of Pathology, Queen Mary Hospital, Hong Kong Special Administrative Region, Hong Kong, China.
  • The Hong Kong Jockey Club Global Health Institute, Hong Kong Special Administrative Region, Hong Kong, China.
  • WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
  • Laboratory of Data Discovery for Health, Hong Kong Science Park, Hong Kong Special Administrative Region, Hong Kong, China.
  • The University of Hong Kong - Shenzhen Hospital, Shenzhen 518009, China.
  • Menzies School of Health Research, Darwin, NT 0810, Australia.
  • Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027.
  • Department of Pediatrics, Molecular Microbiology and Immunology, Keck School of Medicine, The University of California, Los Angeles, CA 90033.
  • Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
  • Infection and Immunity, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
  • Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Department of General Medicine, Royal Children's Hospital Melbourne, Melbourne, VIC 3052, Australia.
  • Royal Children's Hospital Melbourne, Immunisation Service, Melbourne, VIC 3052, Australia.
  • Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
  • Victorian Infectious Diseases Service, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
  • Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia.
  • ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Melbourne Sexual Health Centre, Infectious Diseases Department, Alfred Health, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
  • Victorian Infectious Diseases Reference Laboratory, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
  • Department of Microbiology, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.
  • School of Medicine, University of St Andrews, Scotland KY16 9TF, United Kingdom.
  • Department of Infectious Diseases and Immunology, Austin Health, Heidelberg, VIC 3084, Australia.
  • Data Analytics Research and Evaluation Centre, Austin Health and University of Melbourne, Heidelberg, VIC 3084, Australia.
  • Department of Infectious Diseases, Centre for Antibiotic Allergy and Research, Austin Health, Heidelberg, VIC 3084, Australia.
  • Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • National Centre for Infections in Cancer, Peter McCallum Cancer Centre, Melbourne, VIC 3000, Australia.
  • Department of Respiratory Medicine, The Alfred Hospital, Melbourne, VIC 3004, Australia.
  • Department of Medicine, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, VIC 3004, Australia.
  • School of Public Health and Preventive Medicine, Monash University, Clayton, VIC 3004, Australia.
  • Monash Infectious Diseases, Monash Health and School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.
  • National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
  • Institute of Infection, Ecological and Veterinary Sciences, University of Liverpool & Liverpool University Hospital National Health Service Foundation Trust, Wirral CH64 7TE, United Kingdom.
  • Institute for Lung Health, Leicester NIHR BRC, University of Leicester, Leicester LE1 7RH, United Kingdom.
  • Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
  • National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.
  • Shanghai Public Health Clinical Centre and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, Shanghai 201508, China.
  • Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
  • Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8654, Japan.
  • Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Saito Asagi, Ibaraki 567-0085, Osaka, Japan.
  • Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
  • Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.

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 + T-cells directed against HLA-B*15:01-restricted Spike-derived S 919-927 peptide (B15/S 919 +CD8 + T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8 + T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S 919 +CD8 + 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 919 +CD8 + 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 919 +CD8 + T-cell responses lacking a highly expanded key public B15/S 919 +CD8 + T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S 919 +CD8 + 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 919 +CD8 + T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S 919 +CD8 + T-cells did not differ across disease severity. Moreover, B15/S 919 +CD8 + 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.

MeSH

Cells, Covid-19, Hla-B Antigens, T-Lymphocytes, Infections