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11 25, 2020;183 (5): 1340-1353.e16.

Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4 T Cells in COVID-19.

Benjamin J Meckiff, Ciro Ramírez-Suástegui, Vicente Fajardo, Serena J Chee, Anthony Kusnadi, Hayley Simon, Simon Eschweiler, Alba Grifoni, Emanuela Pelosi, Daniela Weiskopf, Alessandro Sette, Ferhat Ay, Grégory Seumois, Christian H Ottensmeier, Pandurangan Vijayanand
Author Information
  1. Benjamin J Meckiff: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  2. Ciro Ramírez-Suástegui: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  3. Vicente Fajardo: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  4. Serena J Chee: Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
  5. Anthony Kusnadi: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  6. Hayley Simon: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  7. Simon Eschweiler: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  8. Alba Grifoni: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  9. Emanuela Pelosi: Southampton Specialist Virology Center, University Hospitals NHS Foundation Trust, Southampton SO16 6YD, UK.
  10. Daniela Weiskopf: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  11. Alessandro Sette: La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA.
  12. Ferhat Ay: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  13. Grégory Seumois: La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  14. Christian H Ottensmeier: La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; Institute of Translational Medicine, Department of Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool L69 7ZX, UK. Electronic address: cho@soton.ac.uk.
  15. Pandurangan Vijayanand: La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: vijay@lji.org.
PMID: 33096020 DOI: 10.1016/j.cell.2020.10.001

Abstract

The contribution of CD4 T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4 T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper cells and cytotoxic T helper (T) cells (CD4-CTLs) responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (T). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic T response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T1 and T17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4 T cells compared to influenza-reactive CD4 T cells. Together, our analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4 T cells in distinct disease severities.

Keywords

ARTE CD4(+) T cells CD4-CTLs COVID-19 SARS-CoV-2 T(FH) T(REG) antigen-reactive T cell enrichment cytotoxic human scRNA-seq single-cell RNA sequencing

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Grants

  1. S10 OD025052/NIH HHS
  2. R35 GM128938/NIGMS NIH HHS
  3. S10 RR027366/NCRR NIH HHS
  4. R01 HL114093/NHLBI NIH HHS
  5. 21998/Cancer Research UK
  6. U19 AI118626/NIAID NIH HHS
  7. U19 AI142742/NIAID NIH HHS

MeSH Term

Adult
Aged
Aged, 80 and over
Antibodies, Viral
CD4 Lymphocyte Count
COVID-19
Cohort Studies
England
Female
Humans
Male
Middle Aged
Reverse Transcriptase Polymerase Chain Reaction
SARS-CoV-2
Severity of Illness Index
Single-Cell Analysis
Spike Glycoprotein, Coronavirus
T Follicular Helper Cells
T-Lymphocytes, Cytotoxic
T-Lymphocytes, Regulatory
Transcriptome

Chemicals

Antibodies, Viral
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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