Histone Deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T Cells

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Date: Apr. 17, 2018
From: eLife(Vol. 7)
Publisher: eLife Science Publications, Ltd.
Document Type: Report
Length: 22,288 words
Lexile Measure: 1660L

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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 V[alpha]14/J[alpha]18 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. eLife digest To protect us, our immune system must walk a narrow line: while it eliminates all external threats, it also has to refrain from attacking the healthy tissues of our body. When such misdirected attacks do take place, they can result in life-threatening autoimmune diseases. T cells are a highly diverse population of immune cells that can recognize and orchestrate the body's response against infected or 'abnormal' cells. Early in the development of most types of T cells, the body normally weeds out the ones that target healthy tissues. A gene known as Histone Deacetylase 7 (HDAC7) regulates this process. However, when HDAC7 carries a specific mutation called HDAC7-[DELTA]P, dangerous T cells that can attack healthy tissues 'escape' this selection. The HDAC7-[DELTA]P mutation allows T cells that react to many different tissues to survive. However, in mice with this genetic change, only the liver, the digestive system and the pancreas are actually damaged by the immune system and show signs of autoimmune diseases. Why are these organs affected, and not the others? Here, Kasler, Lee et al. find that HDAC7 also helps another type of T cell to develop. Known as invariant natural killer T -- or iNKT -- cells, these cells specialize in defending the gut, liver and pancreas against bacteria. Mice with the HDAC7-[DELTA]P mutation can no longer produce iNKT cells. Remarkably, restoring normal levels of these cells in the HDAC7-[DELTA]P animals reduces the symptoms of their autoimmune diseases, even though the mice are still carrying the T cells that have escaped selection and can attack healthy tissues. Taken together, these results explain why a mutation in HDAC7 can create problems only for specific organs in the body. However, it is still not clear exactly why losing iNKT cells increases autoimmune attacks of the tissues they normally occupy. One possibility is that these cells limit access to the organs by other immune cells that could cause damage. Another option is that, when iNKT cells are absent, gut bacteria can attack and create an inflammation. This recruits T cells to the site, including the ones that can attack healthy organs. In humans, mutations in HDAC7, as well as in other genes that regulate it, are also associated with autoimmune disorders of the digestive tract and liver. These include inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. Ultimately the findings presented by Kasler, Lee et al. could be a starting point for finding new treatments for these illnesses.

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Gale Document Number: GALE|A564313501