1. Immunology and Inflammation
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IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

  1. Rosanne Spolski  Is a corresponding author
  2. Erin E West
  3. Peng Li
  4. Sharon Veenbergen
  5. Sunny Yang
  6. Majid Kazemian
  7. Jangsuk Oh
  8. Zu-Xi Yu
  9. Alexandra Freeman
  10. Stephen Holland
  11. Philip M Murphy
  12. Warren J Leonard  Is a corresponding author
  1. National Heart, Lung, and Blood Institute, United States
  2. National Institute of Allergy and Infectious Diseases, Netherlands
  3. National Institute of Allergy and Infectious Diseases, United States
Research Article
  • Cited 7
  • Views 1,878
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Cite this article as: eLife 2019;8:e45501 doi: 10.7554/eLife.45501

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNb induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type-I IFN in the innate immune response to MRSA.

Data availability

All sequencing data in the final manuscript will be deposited in GEO.

The following data sets were generated

Article and author information

Author details

  1. Rosanne Spolski

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    For correspondence
    spolskir@nhlbi.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
  2. Erin E West

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peng Li

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sharon Veenbergen

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Sunny Yang

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Majid Kazemian

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7080-8820
  7. Jangsuk Oh

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Zu-Xi Yu

    The Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alexandra Freeman

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Stephen Holland

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Philip M Murphy

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Warren J Leonard

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    For correspondence
    wjl@helix.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5740-7448

Funding

National Institutes of Health (Division of Intramural Research, NHLBI)

  • Warren J Leonard

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments involving animals were performed under protocols (H-0087R4) approved by the National Heart, Lung, and Blood Institute Animal Care and Use Committee and followed National Institutes of Health guidelines for use of animals in intramural research.

Human subjects: Blood samples were obtain from normal donors from the NIH Blood Bank under a waiver from the NIH Office of Human Subjects research. Blood samples were also obtained from AD-HIES patients who had given informed consent under an NIH IRB-approved protocol.

Reviewing Editor

  1. Wayne M Yokoyama, Washington University School of Medicine, United States

Publication history

  1. Received: January 24, 2019
  2. Accepted: April 9, 2019
  3. Accepted Manuscript published: April 10, 2019 (version 1)
  4. Accepted Manuscript updated: April 16, 2019 (version 2)
  5. Version of Record published: May 7, 2019 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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Further reading

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    Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.

    1. Immunology and Inflammation
    Drew Wilfahrt et al.
    Research Article

    After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.