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


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
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3703-3183


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.


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)


© 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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