PD-1 high CXCR5 – CD4 + Peripheral Helper T (Tph) cells Promote Tissue-Homing Plasmablasts in COVID-19

  1. Hiromitsu Asashima
  2. Subhasis Mohanty
  3. Michela Comi
  4. William E. Ruff
  5. Kenneth B. Hoehn
  6. Patrick Wong
  7. Inessa Cohen
  8. Sarah Coffey
  9. Khadir Raddassi
  10. Omkar Chaudhary
  11. Avraham Unterman
  12. Brinda Emu
  13. Steven H. Kleinstein
  14. Ruth R. Montgomery
  15. Akiko Iwasaki
  16. Charles S. Dela Cruz
  17. Naftali Kaminski
  18. Albert C. Shaw
  19. David A. Hafler
  20. Tomokazu S. Sumida

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Abstract

A dysregulated immune response against coronavirus-2 (SARS-CoV-2) plays a critical role in the outcome of patients with coronavirus disease 2019 (COVID-19). A significant increase in circulating plasmablasts is characteristic of COVID-19 though the underlying mechanisms and its prognostic implications are not known. Here, we demonstrate that in the acute phase of COVID-19, activated PD-1 high CXCR5 − CD4 + T cells, peripheral helper T cells, (Tph) are significantly increased and promote inflammatory tissue-homing plasmablasts in patients with stable but not severe COVID-19. Analysis of scRNA-seq data revealed that plasmablasts in stable patients express higher levels of tissue-homing receptors including CXCR3 . The increased Tph cells exhibited “B cell help” signatures similar to that of circulating T follicular helper (cTfh) cells and promoted B cell differentiation in vitro . Compared with cTfh cells, Tph cells produced more IFNγ, inducing tissue-homing chemokine receptors on plasmablasts. Finally, expansion of activated Tph cells was correlated with the frequency of CXCR3 + plasmablasts in the acute phase of patients with stable disease. Our results demonstrate a novel role for Tph cells in acute viral immunity by inducing ectopic, antibody secreting plasmablasts.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.13.21253527: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethics Statement: This study was approved by the Institutional Review Board at the Yale School of Medicine (2000027291REG and FWA00002571, Protocol ID. 2000027690).
    Consent: Informed consent was obtained from all enrolled patients, healthcare workers and healthy donors.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-CD3 (UCHT1)
    Anti-CD3
    suggested: None
    Software and Algorithms
    SentencesResources
    Briefly, V(D)J genes aligned to the IMGT/GENE-DB v3.1.2651 germline reference database using IgBLAST v.1.15.052.
    IMGT/GENE-DB
    suggested: (IMGT/GENE-DB, RRID:SCR_006964)
    IgBLAST
    suggested: (IgBLAST, RRID:SCR_002873)
    Somatic hypermutation frequency was calculated using SHazaM v1.0.2.99954 as the frequency of non-ambiguous nucleotide differences along the IGHV gene segment (IMGT positions 1-312) between each sequence and its inferred germline ancestor.
    SHazaM
    suggested: None

    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 10.1101/2021.03.13.21253527v1 on medRxiv