Low-dose IL-2 reduces IL-21 + T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients

  1. Jia-Yuan Zhang
  2. Fiona Hamey
  3. Dominik Trzupek
  4. Marius Mickunas
  5. Mercede Lee
  6. Leila Godfrey
  7. Jennie H.M. Yang
  8. Marcin L Pekalski
  9. Jane Kennet
  10. Frank Waldron-Lynch
  11. Mark L. Evans
  12. Timothy I. M. Tree
  13. Linda S. Wicker
  14. John A. Todd
  15. Ricardo C. Ferreira

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Abstract

Despite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here, we examined the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) using high-resolution, single-cell multiomics and flow cytometry. We confirmed that iLD-IL-2 selectively expands thymic-derived FOXP3 + HELIOS + Tregs and CD56 br NK cells, and showed that treatment reduced the frequency of IL-21-producing CD4 + T cells and of two subsets of innate-like CD8 + T cells, mucosal-associated invariant T cells and V γ9 V δ2 T cells. The cellular changes induced by LD-IL-2 were associated with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. The anti-inflammatory nature of this gene expression signature was supported by the observation that the same genes were also modulated in COVID-19 patients, but in the opposite direction. These findings warrant continued investigations of the potential clinical benefits of iLD-IL-2 in immunotherapy and further understanding of the development of long-term sequelae in convalescent COVID-19 patients.

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  1. Version published to 10.1101/2022.04.05.22273167v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2022.04.05.22273167: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationSingle-cell proliferation scores: Single-cell proliferation scores were calculated using a previously described approach58, which is based on the average normalised expression levels of a pre-selected set of 11 mRNA features related to cell cycle (AURKB, HMGB2, HMMR, MCM4, MKI67, PCLAF, PCNA, TK1, TOP2A, TYMS, and UBE2C), subtracted by the aggregated expression of a control set of 50 randomly selected mRNA features.
    Blindingnot detected.
    Power AnalysisThis led to a significant reduction in the number of CD56br cells analysed and a concomitant reduction in statistical power to identify IL-2-induced alterations.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Red blood cells were then lysed (BD FACS Lysing solution) and immunostained samples were acquired on a BD Fortessa (BD Biosciences) flow cytometer with FACSDiva software (BD Biosciences) and analysed using FlowJo (Tree Star, Inc.).
    FACSDiva
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Validation of Day 55 signature in the COMBAT dataset: To confirm the differential expression of Day 55 signature genes after COVID-19 infection, we applied DESeq2 to pseudo-bulk RNAseq data from the COMBAT dataset, comparing 13 community COVID-19 patients with 10 healthy controls.
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    COMBAT
    suggested: (ComBat, RRID:SCR_010974)

    Results from OddPub: Thank you for sharing your data.

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT02265809CompletedAdaptive Study of IL-2 Dose Frequency on Regulatory T Cells …
    ISRCTN40319192NANA

    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.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2022.04.05.22273167v1 on medRxiv