Distinct lung-homing receptor expression and activation profiles on NK cell and T cell subsets in COVID-19 and influenza

  1. Demi Brownlie
  2. Inga Rødahl
  3. Renata Varnaite
  4. Hilmir Asgeirsson
  5. Hedvig Glans
  6. Sara Falck-Jones
  7. Sindhu Vangeti
  8. Marcus Buggert
  9. Hans-Gustaf Ljunggren
  10. Jakob Michaëlsson
  11. Sara Gredmark-Russ
  12. Anna Smed-Sörensen
  13. Nicole Marquardt

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Abstract

Respiratory viral infections with SARS-CoV-2 or influenza viruses commonly induce a strong infiltration of immune cells into the lung, with potential detrimental effects on the integrity of the lung tissue. Despite comprising the largest fractions of circulating lymphocytes in the lung, little is known about how blood natural killer (NK) cells and T cell subsets are equipped for lung-homing in COVID-19 and influenza. Using 28-colour flow cytometry and re-analysis of published RNA-seq datasets, we provide a detailed comparative analysis of NK cells and T cells in peripheral blood from moderately sick COVID-19 and influenza patients, focusing on the expression of chemokine receptors known to be involved in leukocyte recruitment to the lung. The results reveal a predominant role for CXCR3, CXCR6, and CCR5 in COVID-19 and influenza patients, mirrored by scRNA-seq signatures in peripheral blood and bronchoalveolar lavage from publicly available datasets. NK cells and T cells expressing lung-homing receptors displayed stronger phenotypic signs of activation as compared to cells lacking lung-homing receptors, and activation was overall stronger in influenza as compared to COVID-19. Together, our results indicate migration of functionally competent CXCR3 + , CXCR6 + , and/or CCR5 + NK cells and T cells to the lungs in moderate COVID-19 and influenza patients, identifying potential common targets for future therapeutic interventions in respiratory viral infections.

Author summary

The composition of in particular CXCR3 + and/or CXCR6 + NK cells and T cells is altered in peripheral blood upon infection with SARS-CoV-2 or influenza virus in patients with moderate disease. Lung-homing receptor-expression is biased towards phenotypically activated NK cells and T cells, suggesting a functional role for these cells co-expressing in particular CXCR3 and/or CXCR6 upon homing towards the lung.

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    SciScore for 10.1101/2021.01.13.426553: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the Regional Ethical Review Board in Stockholm, Sweden, and by the Swedish Ethical Review Authority.
    Consent: All donors provided informed written consent prior to blood sampling.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablePatients and processing of peripheral blood: We enrolled a total of 10 hospitalized patients (four females and six males; age range 24-70; average age 55.3) who were diagnosed with COVID-19 by RT-qPCR for SARS-CoV-2 in respiratory samples.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Degranulation assay: Cells were co-cultured in R10 medium alone or in presence of K562 cells for 6 hours in the presence of anti-human CD107a (H4A3, FITC, BD Biosciences).
    K562
    suggested: None
    Software and Algorithms
    SentencesResources
    Samples were analyzed on a BD LSR Fortessa equipped with four lasers (BD Biosciences), and data were analyzed using FlowJo version 9.5.2 and version 10.7.1 (Tree Star Inc).
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Principal component analysis: Analyses were performed using GraphPad Prism 9 (GraphPad Software).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Statistical analyses: GraphPad Prism 8 and 9 (GraphPad Software) was used for statistical analyses.
    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.01.13.426553v1 on bioRxiv