Gladstone Institute of Virology and Immunology, San Francisco, United States.
Department of Medicine, University of California, San Francisco, San Francisco, United States.
Elife. 2018 Apr 17;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.
我们报告组蛋白去乙酰化酶 7（HDAC7）控制自然杀伤 T（NKT）细胞的胸腺效应编程，干扰这种功能有助于组织特异性自身免疫。胸腺细胞中 HDAC7 功能的获得会阻断负选择和 NKT 细胞的发育，并将 Vα14/Jα18 TCR 转基因胸腺细胞转向 Tconv 样谱系。相反，HDAC7 的缺失会促进胸腺细胞凋亡，并导致先天效应细胞的扩增。在研究涉及的机制时，我们发现 HDAC7 与 PLZF 结合并调节 PLZF 依赖性转录。此外，HDAC7 和其许多转录靶标都是 IBD 和 PSC 的人类风险基因座，这些自身免疫性疾病与我们在小鼠中观察到的 HDAC7 功能获得性疾病非常相似。重要的是，在这些小鼠中重建 iNKT 细胞减轻了它们的疾病，这表明由于改变的 HDAC7 功能导致的负选择和 iNKT 细胞的联合缺陷可能导致组织特异性自身免疫，这一发现可能解释了 HDAC7 与肝胆自身免疫之间的关联。
