Histone deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T-Cells
- Gladstone Institute of Virology and Immunology, United States
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.
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Gene Regulation by Histone Deacetylase 7 During Invariant Natural Killer T Cell DevelopmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE105026).
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Multiple levels of transcriptional regulation by PLZF in NKT cell developmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE81772).
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Immunological Genome Project data Phase 1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE15907).
Article and author information
Author details
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.
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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Histone deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T-Cells
eLife 7:e32109.
https://doi.org/10.7554/eLife.32109
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