1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion

  1. Katherine A Smith  Is a corresponding author
  2. Stephan Löser
  3. Fumi Varyani
  4. Yvonne Harcus
  5. Henry J McSorley
  6. Andrew NJ McKenzie
  7. Rick M Maizels  Is a corresponding author
  1. Cardiff University, United Kingdom
  2. University of Glasgow, United Kingdom
  3. University of Edinburgh, United Kingdom
  4. MRC Laboratory of Molecular Biology, United Kingdom
Research Article
  • Cited 13
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Cite this article as: eLife 2018;7:e38269 doi: 10.7554/eLife.38269

Abstract

Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type 2 immune response to helminth parasites. However its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14-17) drove immunity. Moreover when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Katherine A Smith

    Cardiff Institute of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    For correspondence
    SmithK28@Cardiff.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8150-5702
  2. Stephan Löser

    Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Fumi Varyani

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Yvonne Harcus

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Henry J McSorley

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrew NJ McKenzie

    Protein and Nucleic Acid Chemistry Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Rick M Maizels

    Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    For correspondence
    rick.maizels@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3216-1944

Funding

Wellcome (106122)

  • Rick M Maizels

Wellcome (90281)

  • Rick M Maizels

European Commission (657639)

  • Katherine A Smith

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 animal protocols adhered to the guidelines of the UK home office and complied with the Animals (Scientific Procedures) Act 1986. The protocols were approved by the Ethical Review Committees of the University of Edinburgh (UK Home Office Project number 60/4105) and the University of Glasgow (Project number 70/8384).

Reviewing Editor

  1. Andrew J MacPherson, University of Bern, Switzerland

Publication history

  1. Received: May 10, 2018
  2. Accepted: September 21, 2018
  3. Accepted Manuscript published: September 21, 2018 (version 1)
  4. Version of Record published: October 5, 2018 (version 2)

Copyright

© 2018, Smith 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.

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Further reading

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    Marie Ghraichy et al.
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    Several human B-cell subpopulations are recognized in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. Using advanced bioinformatic analysis and machine learning, we show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.

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    Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNF,α MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffc of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell traffcking and cytokine expression.