表观遗传操作恢复有缺陷的CD8 + T细胞的功能，包括慢性病毒

StephenW

Molecular Therapy (2014); 22 9, 1698–1706. doi:10.1038/mt.2014.91
Epigenetic Manipulation Restores Functions of Defective CD8+ T Cells From Chronic Viral Infection

Fuqin Zhang1,2, Xiaohui Zhou2,3, Joanna R DiSpirito2, Chuan Wang2,4, Ying Wang1 and Hao Shen1,2

    1Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China
    2Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    3Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
    4Department of Public Health Laboratory Sciences, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China

Correspondence: Hao Shen, Department of Microbiology, University of Pennsylvania Perelman School of Medicine, 3610 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA. E-mail: [email protected]

Received 4 March 2014; Accepted 8 May 2014
Accepted article preview online 27 May 2014; Advance online publication 1 July 2014
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Abstract

Functional exhaustion of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T cell dysfunction are not well understood. Epigenetics plays an important role in the control of T cell development, differentiation, and function. To examine if epigenetics also plays a role in T cell exhaustion, we analyzed chromatin remodeling in CD8+ T cells from mice with chronic lymphocytic choriomeningitis virus infection. We observed downregulation of diacetylated histone H3 in both virus-specific and total CD8+ T cells, and functional defects not only in virus-specific CD8+ T cells but also within the total CD8+ T cell population. In vitro treatment of these exhausted CD8+ T cells with histone deacetylase inhibitors restored diacetylated histone H3 levels, and improved their immune functions. Upon adoptive transfer, these treated CD8+ T cells developed into functional memory T cells in vivo that enhanced protective immunity. These results define a role of epigenetics in T cell exhaustion and suggest epigenetic manipulation as a novel molecular therapy to restore immune functions.

StephenW

分子疗法（2014年）; 229，1698至1706年。 DOI：10.1038/ mt.2014.91
表观遗传操作恢复有缺陷的CD8 + T细胞的功能，包括慢性病毒感染

抚琴Zhang1,2，小惠Zhou2,3，乔安娜řDiSpirito2，川Wang2,4，迎旺1和郝Shen1,2

    免疫1上海市研究所，上海交通大学医学院，上海，中国
    微生物学，医学佩雷尔曼学院，宾夕法尼亚大学，费城，宾夕法尼亚州，美国教研室
    3Shanghai公共卫生临床中心，复旦大学，上海，中国
    4Department公共卫生化验科学，中国西部公共卫生学院，四川大学，四川成都，中国的

函授：郝社嗯，微生物学，医学宾州佩雷尔曼学院大学，3610汉密尔顿城，费城，宾夕法尼亚州19104，美国系。电子邮箱：[email protected]

收到2014年3月4日;接受2014年5月8日
已接受的文章在网上预览2014年5月27日;提前在网上公布2014年7月1日
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摘要

抗原特异性T细胞功能衰竭是许多慢性感染的标志性特征，但T细胞功能障碍的潜在机制尚不十分清楚。表观遗传学扮演的T细胞发育，分化和功能的控制中起重要作用。为了检验是否表观遗传学也起着T细胞耗竭的作用，我们从小鼠慢性淋巴细胞性脉络丛脑膜炎病毒感染分析染色质重塑中的CD8+ T细胞。我们在两种病毒特异性和总CD8 + T细胞，和功能缺陷不仅在病毒特异性CD8 + T细胞，而且在总CD8 + T细胞群中观察到二乙酰化组蛋白H3的表达下调。在体外处理这些耗尽CD8 + T细胞与组蛋白脱乙酰酶抑制剂的还原二乙酰化组蛋白H3的水平，并提高它们的免疫功能。在过继转移，这些处理过的CD8 + T细胞发展成官能的记忆性T细胞在体内的增强的保护性免疫。这些结果确定表观遗传学在T细胞耗竭的作用，并建议后生操控作为一种新型的分子疗法，恢复免疫功能。