Adaptive immunity to human coronaviruses is widespread but low in magnitude

  1. Hyon-Xhi Tan
  2. Wen Shi Lee
  3. Kathleen M Wragg
  4. Christina Nelson
  5. Robyn Esterbauer
  6. Hannah G Kelly
  7. Thakshila Amarasena
  8. Robert Jones
  9. Graham Starkey
  10. Bao Zhong Wang
  11. Osamu Yoshino
  12. Thomas Tiang
  13. M Lindsay Grayson
  14. Helen Opdam
  15. Rohit D’Costa
  16. Angela Vago
  17. The Austin Liver Transplant Perfusionist Group
  18. Laura K Mackay
  19. Claire L Gordon
  20. Adam K Wheatley
  21. Stephen J Kent
  22. Jennifer A Juno

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Abstract

Endemic human coronaviruses (hCoV) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV-specific T cell memory in adults. We quantified CD4 T cell and antibody responses to hCoV spike antigens in 42 SARS-CoV-2 uninfected individuals. T cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS-CoV-2 cross-reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV-specific T cells exhibited a CCR6 + central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung draining lymph nodes. Overall, hCoV-specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus-specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS-CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2021.01.24.21250074: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study protocols and sample use were approved by the University of Melbourne Human Research Ethics Committee (#2056689) and all associated procedures were carried out in accordance with the approved guidelines.
    Consent: All participants provided written informed consent in accordance with the Declaration of Helsinki.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableTissues were collected from 6 donors: male, age 40-50, brain death; female, 30-40, brain death; male, 30-40, circulatory death; male, 50-60, brain death; female, 60-70, brain death; female, 50-60, brain death.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    PBMC, lung and lymph node cells were surface stained with the following monoclonal antibodies: CD14-BV510 (M5E2), CD3-BV510 (OKT3), CD8a-BV510 (3GA), CD16-BV510 (3G8), CD10-BV510 (HI10a), SA-BV510 (BD), IgG-BV786 (G18-145), IgD-Cy7PE (IA6-2), and CD19 ECD (J3-119) (Beckman).
    CD8a-BV510
    suggested: None
    IA6-2
    suggested: None
    CD19
    suggested: (Beckman Coulter Cat# A96418, RRID:AB_2728101)
    PBMC were surface stained with the following monoclonal antibodies: CD3 BUV395 (SK7), CD45RA PeCy7 (HI100), CD20 BUV805 (2H7), CD154 APC Cy-7 (TRAP-1), CCR7 Alexa Fluor 700 (150503) (BD Biosciences), CD27 BV510 (M-T271), CD4 BV605 (RPA-T4), CD8 BV650 (RPA-T8), CD25 APC (BC96), OX-40 PerCP-Cy5.5 (ACT35), CD69 FITC (FN50), CD137 BV421 (4B4-1), CXCR3 PE Dazzle (G025H7), CCR6 BV786 (G034E3) (Biolegend), and CXCR5 PE (MU5UBEE, ThermoFisher).
    CCR7
    suggested: (GenWay Biotech Inc. Cat# GWB-EA1DA7, RRID:AB_10269678)
    CD27
    suggested: (Thermo Fisher Scientific Cat# EPX140-15803-901, RRID:AB_2576106)
    CD4
    suggested: (Thermo Fisher Scientific Cat# 88-8999-40, RRID:AB_2575220)
    CXCR5
    suggested: None
    Monoclonal antibody staining for lung and lymph node cells included: CD45RA PeCy7 (HI100), CD20 BUV805 (2H7), CD154 APC Cy-7 (TRAP-1), EpCam BV711 (EBA-1), CD103 BUV395 (Ber-ACT8) (BD Biosciences), CD3 BV510 (SK7), CD4 BV605 (RPA-T4), CD8 BV650 (RPA-T8), CD25 APC (BC96), OX-40 PerCP-Cy5.5 (ACT35), CD69 FITC (FN50), PD-1 BV421 (EH12.217), CXCR3 PE Dazzle (G025H7), CCR6 BV786 (G034E3) (Biolegend), and CXCR5 PE (MU5UBEE, ThermoFisher) Cells were washed, fixed with 1% formaldehyde and acquired on a BD LSR Fortessa using BD FACS Diva.
    CD45RA
    suggested: (BD Biosciences Cat# 742020, RRID:AB_2871317)
    CD20
    suggested: (BD Biosciences Cat# 740204, RRID:AB_2739954)
    CD103
    suggested: (BD Biosciences Cat# 740238, RRID:AB_2739985)
    CD3
    suggested: None
    PD-1 BV421
    suggested: None
    CCR6
    suggested: (BD Biosciences Cat# 740840, RRID:AB_2740494)
    Experimental Models: Cell Lines
    SentencesResources
    Lenti-X 293T cells (TakaraBio) were co-transfected with a lentiviral backbone plasmid expressing Luciferase-IRES-ZsGreen (BEI Resources; NR-52948), helper plasmids encoding HIV Tat, Gag-Pol and Rev (BEI Resources; NR-52948) and a pseudotyping plasmid encoding native NL63 S protein (DQ445911.1).
    293T
    suggested: None
    Infectivity of virions was determined by titration on 293T-ACE2 cells (BEI resources; NR-52511).
    293T-ACE2
    suggested: RRID:CVCL_YZ65)
    Software and Algorithms
    SentencesResources
    Following stimulation, cells were washed, stained with Live/dead Blue viability dye (ThermoFisher), and a cocktail of monoclonal antibodies.
    ThermoFisher
    suggested: (ThermoFisher; SL 8; Centrifuge, RRID:SCR_020809)
    PBMC were surface stained with the following monoclonal antibodies: CD3 BUV395 (SK7), CD45RA PeCy7 (HI100), CD20 BUV805 (2H7), CD154 APC Cy-7 (TRAP-1), CCR7 Alexa Fluor 700 (150503) (BD Biosciences), CD27 BV510 (M-T271), CD4 BV605 (RPA-T4), CD8 BV650 (RPA-T8), CD25 APC (BC96), OX-40 PerCP-Cy5.5 (ACT35), CD69 FITC (FN50), CD137 BV421 (4B4-1), CXCR3 PE Dazzle (G025H7), CCR6 BV786 (G034E3) (Biolegend), and CXCR5 PE (MU5UBEE, ThermoFisher).
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    The half maximal inhibitory concentration for plasma (IC50) was determined using four-parameter nonlinear regression in GraphPad Prism with curve fits constrained to have a minimum of 0% and maximum of 100% neutralisation.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.01.24.21250074v1 on medRxiv
  3. Version published to 10.1002/cti2.1264