HLA-B*15:01-positive severe COVID-19 patients lack CD8 <sup>+</sup> T cell pools with highly expanded public clonotypes
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (59)
Louise C. Rowntree
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Lilith F. Allen
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Ruth R. Hagen
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Hayley A. McQuilten
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Ahmed A. Quadeer
Department of Electronic and Computer Engineering, School of Engineering, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region
Priyanka Chaurasia
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University
Prathanporn Kaewpreedee
HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region
Kelly W. K. Lee
HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region
Carolyn A. Cohen
HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region
Jan Petersen
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University
Dene R. Littler
Jennifer R. Habel
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Wuji Zhang
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Samuel M. S. Cheng
Division of Public Health Laboratory Sciences, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region
Ken Ka Pang Chan
Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong
Janette S. Y. Kwok
Division of Transplantation and Immunogenetics, Department of Pathology, Queen Mary Hospital, Hong Kong Special Administrative Region
Kathy S. M. Leung
The Hong Kong Jockey Club Global Health Institute, Hong Kong Special Administrative Region
Joseph T. Wu
The Hong Kong Jockey Club Global Health Institute, Hong Kong Special Administrative Region
Cheuk-Kwong Lee
The Hong Kong Jockey Club Global Health Institute, Hong Kong Special Administrative Region
Jane Davies
Menzies School of Health Research
Pia S. Pannaraj
Division of Infectious Diseases, Children’s Hospital Los Angeles
E. Kaity Allen
Department of Immunology, St. Jude Children’s Research Hospital
Paul G. Thomas
Shidan Tosif
Infection and Immunity, Murdoch Children’s Research Institute
Nigel W. Crawford
Infection and Immunity, Murdoch Children’s Research Institute
Martha Lappas
Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne
Irani Thevarajan
Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Sharon R. Lewin
Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Stephen J. Kent
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Jennifer A. Juno
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Katherine A. Bond
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Deborah A. Williamson
Victorian Infectious Diseases Service, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity
Natasha E. Holmes
Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Olivia C. Smibert
Department of Infectious Diseases and Immunology, Austin Health
Claire L. Gordon
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Jason A. Trubiano
Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Tom C. Kotsimbos
Department of Respiratory Medicine, The Alfred Hospital
Allen C. Cheng
School of Public Health and Preventive Medicine, Monash University
Claudia Efstathiou
National Heart and Lung Institute, Imperial College London
Lance Turtle
Institute of Infection, Ecological and Veterinary Sciences, University of Liverpool & Liverpool University Hospital National Health Service Foundation Trust
Ryan S. Thwaites
National Heart and Lung Institute, Imperial College London
Christopher E. Brightling
Institute for Lung Health, Leicester NIHR BRC, University of Leicester
Jamie Rossjohn
Matthew R. McKay
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Jinmin Tian
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention
William Jun Liu
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention
George Fu Gao
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention
Jianqing Xu
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
Kyuto Sonehara
Ken J. Ishii
Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Saito Asagi
Ho Namkoong
Yukinori Okada
Malik Peiris
HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region
David S. C. Hui
Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong
Leo L. M. Poon
HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region
Peter C. Doherty
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Thi H. O. Nguyen
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Sophie A. Valkenburg
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Katherine Kedzierska
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity