title: Epigenetic manipulation restores functions of defective CD8⁺ T cells from chronic viral infection.
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.
authors.affiliation: 1] Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Fuqin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA [2] Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: DiSpirito
authors.affiliation: 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA [2] Department of Public Health Laboratory Sciences, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D042002:Chromatin Assembly and Disassembly; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones