1. Immunology and Inflammation

Critical role of WNK1 in MYC-dependent early mouse thymocyte development

  1. Robert Köchl  Is a corresponding author
  2. Lesley Vanes
  3. Miriam Llorian Sopena
  4. Probir Chakravarty
  5. Harald Hartweger
  6. Kathryn Fountain
  7. Andrea White
  8. Jennifer Cowan
  9. Graham Anderson
  10. Victor LJ Tybulewicz  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. University of Birmingham, United Kingdom
https://doi.org/10.7554/eLife.56934
Share this article
Cite this article
  1. Robert Köchl
  2. Lesley Vanes
  3. Miriam Llorian Sopena
  4. Probir Chakravarty
  5. Harald Hartweger
  6. Kathryn Fountain
  7. Andrea White
  8. Jennifer Cowan
  9. Graham Anderson
  10. Victor LJ Tybulewicz
(2020)
Critical role of WNK1 in MYC-dependent early mouse thymocyte development
eLife 9:e56934.
https://doi.org/10.7554/eLife.56934
  2. Download BibTeX
  3. Download .RIS

Abstract

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in mouse thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the b-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.

Data availability

RNAseq data have been deposited in GEO under accession number GSE136210.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Robert Köchl

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Robert.Koechl@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

  2. Lesley Vanes

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Miriam Llorian Sopena

    Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Probir Chakravarty

    Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Harald Hartweger

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Kathryn Fountain

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Andrea White

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  8. Jennifer Cowan

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  9. Graham Anderson

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  10. Victor LJ Tybulewicz

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Victor.T@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2439-0798

Funding

Medical Research Council (U117527252)

  • Victor LJ Tybulewicz

Francis Crick Institute (FC001194)

  • Victor LJ Tybulewicz

Medical Research Council (FC001194)

  • Victor LJ Tybulewicz

Wellcome Trust (FC001194)

  • Victor LJ Tybulewicz

Cancer Research UK (FC001194)

  • Victor LJ Tybulewicz

Biotechnology and Biological Sciences Research Council (BB/L00805X/1)

  • Victor LJ Tybulewicz

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

Reviewing Editor

  1. Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, France

Ethics

Animal experimentation: All experiments were carried out under the authority of a Project Licence granted by the UK Home Office (PPL70/8843).

Version history

  1. Received: March 15, 2020
  2. Accepted: October 13, 2020
  3. Accepted Manuscript published: October 14, 2020 (version 1)
  4. Version of Record published: October 27, 2020 (version 2)

Copyright

© 2020, Köchl 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

  • 1,660
    views
  • 175
    downloads
  • 11
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Robert Köchl
  2. Lesley Vanes
  3. Miriam Llorian Sopena
  4. Probir Chakravarty
  5. Harald Hartweger
  6. Kathryn Fountain
  7. Andrea White
  8. Jennifer Cowan
  9. Graham Anderson
  10. Victor LJ Tybulewicz
(2020)
Critical role of WNK1 in MYC-dependent early mouse thymocyte development
eLife 9:e56934.
https://doi.org/10.7554/eLife.56934

Share this article

https://doi.org/10.7554/eLife.56934

Categories and tags

Research organism

Further reading

    1. Immunology and Inflammation

    Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response

    Harshavardhan Lingegowda, Katherine B Zutautas ... Chandrakant Tayade
    Research Article

    Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.

    1. Immunology and Inflammation
    2. Neuroscience

    Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice

    Nicolas Aubert, Madeleine Purcarea ... Gilles Marodon
    Research Article

    CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.

    1. Immunology and Inflammation

    Amphibian mast cells serve as barriers to chytrid fungus infections

    Kelsey A Hauser, Christina N Garvey ... Leon Grayfer
    Research Article

    Global amphibian declines are compounded by deadly disease outbreaks caused by the chytrid fungus, Batrachochytrium dendrobatidis (Bd). Much has been learned about the roles of amphibian skin-produced antimicrobial components and microbiomes in controlling Bd, yet almost nothing is known about the roles of skin-resident immune cells in anti-Bd defenses. Mammalian mast cells reside within and serve as key immune sentinels in barrier tissues like skin. Accordingly, we investigated the roles of Xenopus laevis frog mast cells during Bd infections. Our findings indicate that enrichment of X. laevis skin mast cells confers anti-Bd protection and ameliorates the inflammation-associated skin damage caused by Bd infection. This includes a significant reduction in infiltration of Bd-infected skin by neutrophils, promoting mucin content within cutaneous mucus glands, and preventing Bd-mediated changes to skin microbiomes. Mammalian mast cells are known for their production of the pleiotropic interleukin-4 (IL4) cytokine and our findings suggest that the X. laevis IL4 plays a key role in manifesting the effects seen following cutaneous mast cell enrichment. Together, this work underscores the importance of amphibian skin-resident immune cells in anti-Bd defenses and illuminates a novel avenue for investigating amphibian host–chytrid pathogen interactions.