Abstract

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describe Toxoplasma gondii infection converts NK cells into ILC1-like cells that are distinct from both steady-state NK cells and ILC1s in uninfected mice. These cells were Eomes-dependent, indicating that NK cells can give rise to Eomes- Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

Data availability

GEO accession numbers are noted in Materials and Methods. Accession numbers: GSE124313 (RNA-seq, ATAC-seq) and GSE124577 (scRNA-seq).

The following data sets were generated

Article and author information

Author details

  1. Eugene Park

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2617-7571
  2. Swapneel Patel

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Qiuling Wang

    Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Prabhakar Andhey

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Konstantin Zaitsev

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sophia Porter

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Maxwell Hershey

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael Bern

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Beatrice Plougastel-Douglas

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Patrick Collins

    Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Marco Colonna

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5222-4987
  12. Kenneth M Murphy

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Eugene Oltz

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Maxim Artyomov

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. L David Sibley

    Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Wayne M Yokoyama

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    For correspondence
    yokoyama@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0566-7264

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (F30DK108472)

  • Eugene Park

National Institute of Allergy and Infectious Diseases (AI128845)

  • Wayne M Yokoyama

National Institute of Allergy and Infectious Diseases (AI120606)

  • Eugene Oltz

National Institute of Allergy and Infectious Diseases (AI134035)

  • Eugene Oltz

National Institute of Allergy and Infectious Diseases (AI134035)

  • Marco Colonna

National Institute of Allergy and Infectious Diseases (AI11852)

  • Eugene Oltz

National Cancer Institute (CA188286)

  • Eugene Oltz

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

Ethics

Animal experimentation: All protocols were approved by the Institutional Animal Care and Uses Committee(Washington University School of Medicine, St. Louis, MO) under animal protocol number 20160002.

Reviewing Editor

  1. Alan Sher, NIH, NIAID, United States

Version history

  1. Received: April 11, 2019
  2. Accepted: August 8, 2019
  3. Accepted Manuscript published: August 8, 2019 (version 1)
  4. Version of Record published: August 21, 2019 (version 2)

Copyright

© 2019, Park et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,552
    Page views
  • 552
    Downloads
  • 74
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Eugene Park
  2. Swapneel Patel
  3. Qiuling Wang
  4. Prabhakar Andhey
  5. Konstantin Zaitsev
  6. Sophia Porter
  7. Maxwell Hershey
  8. Michael Bern
  9. Beatrice Plougastel-Douglas
  10. Patrick Collins
  11. Marco Colonna
  12. Kenneth M Murphy
  13. Eugene Oltz
  14. Maxim Artyomov
  15. L David Sibley
  16. Wayne M Yokoyama
(2019)
Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells
eLife 8:e47605.
https://doi.org/10.7554/eLife.47605

Further reading

    1. Immunology and Inflammation
    Atomu Yamaguchi, Noriaki Maeshige ... Hidemi Fujino
    Research Article

    The regulation of inflammatory responses is an important intervention in biological function and macrophages play an essential role during inflammation. Skeletal muscle is the largest organ in the human body and releases various factors which mediate anti-inflammatory/immune modulatory effects. Recently, the roles of extracellular vesicles (EVs) from a large variety of cells are reported. In particular, EVs released from skeletal muscle are attracting attention due to their therapeutic effects on dysfunctional organs and tissues. Also, ultrasound (US) promotes release of EVs from skeletal muscle. In this study, we investigated the output parameters and mechanisms of US-induced EV release enhancement and the potential of US-treated skeletal muscle-derived EVs in the regulation of inflammatory responses in macrophages. High-intensity US (3.0 W/cm2) irradiation increased EV secretion from C2C12 murine muscle cells via elevating intracellular Ca2+ level without negative effects. Moreover, US-induced EVs suppressed expression levels of pro-inflammatory factors in macrophages. miRNA sequencing analysis revealed that miR-206-3p and miR-378a-3p were especially abundant in skeletal myotube-derived EVs. In this study we demonstrated that high-intensity US promotes the release of anti-inflammatory EVs from skeletal myotubes and exert anti-inflammatory effects on macrophages.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Huiyun Lyu, Guohua Yuan ... Yan Shi
    Research Article

    Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.