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

• 成果类型: Article
• 署名作者: Rowntree, Louise C.; Allen, Lilith F.; Hagen, Ruth R.; McQuilten, Hayley A.; Quadeer, Ahmed A.; Chaurasia, Priyanka; Kaewpreedee, Prathanporn; Lee, Kelly W. K.; Cohen, Carolyn A.; Petersen, Jan; Littler, Dene R.; Habel, Jennifer R.; Zhang, Wuji; Cheng, Samuel M. S.; Chan, Ken Ka Pang; Kwok, Janette S. Y.; Leung, Kathy S. M.; Wu, Joseph T.; Lee, Cheuk-Kwong; Davies, Jane; Pannaraj, Pia S.; Allen, E. Kaity; Thomas, Paul G.; Tosif, Shidan; Crawford, Nigel W.; Lappas, Martha; Thevarajan, Irani; Lewin, Sharon R.; Kent, Stephen J.; Juno, Jennifer A.; Bond, Katherine A.; Williamson, Deborah A.; Holmes, Natasha E.; Smibert, Olivia C.; Gordon, Claire L.; Trubiano, Jason A.; Kotsimbos, Tom C.; Cheng, Allen C.; Efstathiou, Claudia; Turtle, Lance; Thwaites, Ryan S.; Brightling, Christopher E.; Rossjohn, Jamie; McKay, Matthew R.; Tian, Jinmin; Liu, William Jun; Gao, George Fu; Xu, Jianqing; Sonehara, Kyuto; Ishii, Ken J.; Namkoong, Ho; Okada, Yukinori; Peiris, Malik; Hui, David S. C.; Poon, Leo L. M.; Doherty, Peter C.; Nguyen, Thi H. O.; Valkenburg, Sophie A.; Kedzierska, Katherine
• 署名单位: University of Melbourne; Peter Doherty Institute; Hong Kong University of Science & Technology; University of Melbourne; Monash University; Monash University; University of Hong Kong; University of Hong Kong; Chinese University of Hong Kong; Prince of Wales Hospital; Chinese University of Hong Kong; University of Hong Kong; University of Hong Kong; University of Hong Kong; Charles Darwin University; Menzies School of Health Research; Children's Hospital Los Angeles; University of California System; University of California Los Angeles; St Jude Children's Research Hospital; Murdoch Children's Research Institute; University of Melbourne; Royal Children's Hospital Melbourne; Royal Children's Hospital Melbourne; University of Melbourne; University of Melbourne; Peter Doherty Institute; University of Melbourne; Peter Doherty Institute; Melbourne Health; Royal Melbourne Hospital; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; Monash University; University of Melbourne; Alfred Health; Melbourne Sexual Health Centre; Monash University; Victorian Infectious Diseases Reference Laboratory; University of Melbourne; Peter Doherty Institute; Melbourne Health; Royal Melbourne Hospital; University of St Andrews; Austin Research Institute; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; Austin Research Institute; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; University of Melbourne; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; Austin Research Institute; Peter Maccallum Cancer Center; Peter Maccallum Cancer Center; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; Florey Institute of Neuroscience & Mental Health; Howard Florey Institute Affiliates; Monash University; Monash University; Monash Health; Monash University; Monash University; Imperial College London; University of Liverpool; University of Leicester; Cardiff University; Chinese Center for Disease Control & Prevention; National Institute for Viral Disease Control & Prevention, Chinese Center for Disease Control & Prevention; Fudan University; Fudan University; University of Osaka; University of Tokyo; University of Tokyo; University of Osaka; Keio University; RIKEN; University of Osaka; Hokkaido University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8687
• DOI: 10.1073/pnas.2503145122
• 发表日期: 2025-09-09
• 关键词: magnitude; responses; memory

摘要

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 S919-927 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.