Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aimee L. Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Hélène Ruffieux, Aloka De Sa, Oisín Huhn, Michael D. Morgan, Pehuén Pereyra Gerber, Mark R. Wills, Stephen Baker, Fernando J. Calero-Nieto, Rainer Doffinger, Gordon Dougan, Anne Elmer, Ian G. Goodfellow, Ravindra K. Gupta, Myra HosmilloKelvin Hunter, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Jeremy K. Nicholson, Anna M. Petrunkina, Sylvia Richardson, Caroline Saunders, James E.D. Thaventhiran, Erik J.M. Toonen, Michael P. Weekes, Berthold Göttgens, Mark Toshner, Christoph Hess, John R. Bradley, Paul A. Lyons* (Corresponding Author), Kenneth G.C. Smith* (Corresponding Author), Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) Covid BioResource Collaboration

*Corresponding author for this work

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The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.
Original languageEnglish
Pages (from-to)1257-1275.e8
Number of pages28
Issue number6
Early online date16 May 2021
Publication statusPublished - 8 Jun 2021

Bibliographical note

We thank all the patients and health care workers who consented to take part in this study. We are grateful to CVC Capital Partners, the Evelyn Trust (20/75), Addenbrooke's Charitable Trust, Cambridge University Hospitals (12/20A), the NIHR Cambridge Biomedical Research Centre, and the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC) for their financial support. Further support: K.G.C.S.: Wellcome Investigator Award (200871/Z/16/Z); M.P.W.: Wellcome Senior Clinical Research Fellowship (108070/Z/15/Z); C.H.: Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M.: MRC (CSF MR/P008801/1), NHSBT (WPA15-02), and Addenbrooke's Charitable Trust, (grant ref. to 900239 NJM); I.G.G.: Wellcome Senior Fellowship and Wellcome grant (Ref: 207498/Z/17/Z); P.J.L.: Wellcome Trust Principal Research Fellowship (084957/Z/08/Z) and MRC (MR/V011561/1); J.K.N.: The Spinnaker Healthcare Research Trust and the McCusker Foundation as part of Australian National Phenome Centre. P.K. is the recipient of a Jacquot Research Entry Scholarship of the Royal Australasian College of Physicians Foundation. We would like to thank the NIHR Cambridge Clinical Research Facility outreach team for enrollment of patients; the NIHR Cambridge Biomedical Research Centre Cell Phenotyping Hub and the CRUK Cambridge Institute flow cytometry core facility for flow and mass cytometry; and the Cambridge NIHR BRC Stratified Medicine Core Laboratory NGS Hub (supported by an MRC Clinical Infrastructure Award) for RNA sequencing.

Data Availability Statement

The datasets generated during this study are available at NIHR CITIID COVID-19 Cohort (https://www.covid19cellatlas.org/patient/citiid/). In addition, whole blood RNA-seq data are available at European Genome phenome Archive (EGA, ID:EGAS00001005332), and flow cytometry data are available at FLOW Repository (IDs: FR-FCM-Z3XQ, FR-FCM-Z3SR, FR-FCM-Z3ST, FR-FCM-Z3SS). CITE-seq processed data are available to download from Array Express using accession number E-MTAB-10026.


  • SARS-CoV-2
  • COVID-19
  • bystander CD8+ T cell
  • recovery
  • immune pathology
  • systemic inflammation
  • complement
  • TNF-α
  • interferon


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