@article{18e32cce135d4d88acae14d492849e92,
title = "HLA-B*15:01-positive severe COVID-19 patients lack CD8+ 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 S919-927 peptide (B15/S919+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/S919+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/S919+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/S919+CD8+ T-cell responses lacking a highly expanded key public B15/S919+CD8+ T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S919+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/S919+CD8+ T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S919+CD8+ T-cells did not differ across disease severity. Moreover, B15/S919+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.",
keywords = "HLA-B*15:01, COVID-19, T cell receptors, Middle aged, Aged, CD8+ T cells, CD8-positive T-lymphocytes - immunology, Severe disease, Male, SARS-CoV-2 - immunology, Adult, Humans, Female, COVID-19 - immunology - genetics, Spike glycoprotein, Coronavirus - immunology",
author = "Rowntree, \{Louise C.\} and Allen, \{Lilith F.\} and Hagen, \{Ruth R.\} and McQuilten, \{Hayley A.\} and Quadeer, \{Ahmed A.\} and Priyanka Chaurasia and Prathanporn Kaewpreedee and Lee, \{Kelly W. K.\} and Cohen, \{Carolyn A.\} and Jan Petersen and Littler, \{Dene R.\} and Habel, \{Jennifer R.\} and Wuji Zhang and Cheng, \{Samuel M. S.\} and Chan, \{Ken Ka Pang\} and Kwok, \{Janette S. Y.\} and Leung, \{Kathy S. M.\} and Wu, \{Joseph T.\} and Cheuk-Kwong Lee and Jane Davies and Pannaraj, \{Pia S.\} and \{Kaity Allen\}, E. and Thomas, \{Paul G.\} and Shidan Tosif and Crawford, \{Nigel W.\} and Martha Lappas and Irani Thevarajan and Lewin, \{Sharon R.\} and Kent, \{Stephen J.\} and Juno, \{Jennifer A.\} and Bond, \{Katherine A.\} and Williamson, \{Deborah A.\} and Holmes, \{Natasha E.\} and Smibert, \{Olivia C.\} and Gordon, \{Claire L.\} and Trubiano, \{Jason A.\} and Kotsimbos, \{Tom C.\} and Cheng, \{Allen C.\} and Claudia Efstathiou and Lance Turtle and Thwaites, \{Ryan S.\} and Brightling, \{Christopher E.\} and Jamie Rossjohn and McKay, \{Matthew R.\} and Jinmin Tian and Liu, \{William Jun\} and Gao, \{George Fu\} and Jianqing Xu and Kyuto Sonehara and Ishii, \{Ken J.\} and Ho Namkoong and Yukinori Okada and Malik Peiris and Hui, \{David S. C.\} and Poon, \{Leo L. M.\} and Doherty, \{Peter C.\} and Nguyen, \{Thi H. O.\} and Valkenburg, \{Sophie A.\} and Katherine Kedzierska",
note = "Funding: This research was funded in whole or part by the National Health and Medical Research Council (NHMRC). This work was supported by NHMRC L1 to K.K. (\#1173871), NHMRC EL1 to L.C.R. (\#2026357) and T.H.O.N. (\#1194036), NHMRC EL2 to D.A.W. (\#1174555), J.A.J. (\#2009308), and S.A.V. (\#2007929). NHMRC Early Career Fellowships to C.L.G. (\#1160963) and J.A.T. (\#1139902). S.J.K. is supported by a NHMRC Senior Principal Research Fellowship (\#1136322). J.R. is supported by a NHMRC Investigator Award. J.A.J. is funded by the Charles and Sylvia Viertel Charitable Foundation. W.Z. and J.R.H. are supported by the Melbourne Research Scholarship from University of Melbourne. This work was supported by Theme-based Research Scheme of the Research Grants Council of the Hong Kong Special Administrative Region (HKSAR), China (\#T11-712/19-N) to K.K., Theme-based Research Scheme of the Research Grants Council of HKSAR (\#T11-705/21-N) to A.A.Q., M.R.M., M.P., L.L.M.P., and S.A.V., Health and Medical Research Fund (\#1903003) to D.S.C.H., Medical Research Future Fund (MRFF) Award (\#1202445) to K.K., MRFF Award (\#2005544) to S.J.K., J.A.J., D.A.W., A.C.C., and K.K., MRFF Award (\#2016062) to L.C.R., S.J.K., J.A.J., J.A.T., J.R., T.H.O.N., and K.K., NHMRC Program Grant (\#1149990) to S.J.K., Australian Research Council (ARC) Discovery Project (\#DP230102850) to A.A.Q. and M.R.M., and NIH contract CIVC-HRP (HHS-NIH-NIAID-BAA2018) to P.G.T. and K.K. This work was supported by the National Institute of Allergy and Infectious Diseases UO1 grant 1U01AI144616-01 “Dissection of Influenza Vaccination and Infection for Childhood Immunity” to P.S.P., P.G.T., and K.K. K.S.M.L. and J.T.W. were supported by Health and Medical Research Fund (\#21200122, COVID190126 and CID-HKU2) and AIR@InnoHK administered by Innovation and Technology Commission of The Government of the HKSAR. M.P. and L.L.M.P. were supported by InnoHK, an initiative of the Innovation and Technology Commission, the Government of the HKSAR. S.T. is supported by a Murdoch Children{\textquoteright}s Research Institute Clinician Scientist Fellowship. M.R.M. is supported by an ARC Future Fellowship (\#FT200100928). This project is partly supported by the Japan Agency for Medical Research and Development under Grants number \#JP243fa627005. We thank Eunice Shui, Karen YS Yui, Fionn Ma, and Alan Cheung for Hong Kong patient sample coordination. Samples from the PHOSP-COVID study were collected as independent research jointly funded by the National Institute for Health and Care Research (NIHR) and UK Research and Innovation (UKRI) Coronavirus Immunology Consortium (UK-CIC) [PHOSP COVID, UK-CIC grant references: MR/V027859/1, COV0319 and MR/V028448/1]. L.T. is supported by the US Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085 and National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership the UK Health Security Agency, in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.",
year = "2025",
month = sep,
day = "9",
doi = "10.1073/pnas.2503145122",
language = "English",
volume = "122",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "36",
}