1. Immunology and Inflammation
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Histone deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T-Cells

  1. Herbert G Kasler
  2. Intelly S Lee
  3. Hyung W Lim
  4. Eric Verdin  Is a corresponding author
  1. Gladstone Institute of Virology and Immunology, United States
Research Article
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Cite this article as: eLife 2018;7:e32109 doi: 10.7554/eLife.32109

Abstract

We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, and diverts Vα14/Jα18 TCR transgenic thymocytes into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice mitigated their disease, suggesting that the combined defects in negative selection and iNKT cells due to altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

Data availability

All of the RNA-seq data associated with this manuscript have been deposited in the NCBI GEO archive, under accession number GSE105026. A full processed data matrix, with extensive annotation and aligned data from the other studies cited below is also provided as Supplementary File 1.

The following data sets were generated
The following previously published data sets were used
    1. Yang L
    (2009) Immunological Genome Project data Phase 1
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE15907).

Article and author information

Author details

  1. Herbert G Kasler

    Gladstone Institute of Virology and Immunology, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Intelly S Lee

    Gladstone Institute of Virology and Immunology, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Hyung W Lim

    Gladstone Institute of Virology and Immunology, San Francisco, United States
    Competing interests
    Hyung W Lim, is currently affiliated with Novartis Institutes for Biomedical Research (NIBR), but the research was conducted when he was at the Gladstone Institute/University of California. The author has no competing financial interests to declare.
  4. Eric Verdin

    Gladstone Institute of Virology and Immunology, San Francisco, United States
    For correspondence
    EVerdin@buckinstitute.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3703-3183

Funding

National Institutes of Health (AI117864)

  • Eric Verdin

Kurtzig and Mulholland Families

  • Eric Verdin

Gladstone Institutes

  • Eric Verdin

National Institutes of Health (DA041742)

  • Eric Verdin

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 mice were housed in specific pathogen-free barrier facilities at the Gladstone Institutes or the Buck institute. All animal care and animal experiments were carried out in compliance with NIH guidelines and IACUC-approved UCSF (AN110172) or Buck Institute (A10154) animal use protocols.

Reviewing Editor

  1. Wayne M Yokoyama, Howard Hughes Medical Institute, Washington University School of Medicine, United States

Publication history

  1. Received: September 19, 2017
  2. Accepted: April 5, 2018
  3. Accepted Manuscript published: April 17, 2018 (version 1)
  4. Version of Record published: May 9, 2018 (version 2)

Copyright

© 2018, Kasler 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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    Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.

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    The model organism Caenorhabditis elegans mounts transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, the regulation of which is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature, which was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-α, which controlled host defense cell non-autonomously. These findings reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal FMOs as important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α during S. aureus infection, with implications for host defense and inflammation in higher organisms.