Histone Deacetylase 7 Mediates Tissue-Specific Autoimmunity via Control of Innate Effector Function in Invariant Natural Killer T-Cells

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, diverting these cells into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes aberrant 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 abrogated their disease, suggesting that interaction between the defects in negative selection and iNKT cells caused by altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.