Treating chronic viral infection by epigenetic reprogramming of exhausted CD8 T cells

通过对耗尽的 CD8 T 细胞进行表观遗传重编程来治疗慢性病毒感染

基本信息

批准号：
10242714
负责人：
Michael C. Abt
金额：
$ 52.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242714
关键词：
Address Adoptive Transfer Antigens Back CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell physiology Cells Characteristics Chromatin Structure Chronic DNA Methylation Defect Enhancers Environment Epigenetic Process Exhibits FDA approved Failure Functional disorder Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Transcription HDAC4 gene Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Histones Immune In Vitro Infection Inflammatory Interferon Type II Interleukin-10 Lead Lymphocytic Choriomeningitis Lymphocytic choriomeningitis virus Maps Memory Methylation Molecular Morbidity - disease rate Mus PD-1 blockade PD-L1 blockade Pathway interactions Pharmaceutical Preparations Play Production Proliferating Regulatory T-Lymphocyte Role Signal Transduction T memory cell T-Cell Development T-Lymphocyte Testing Therapeutic Time Translating Up-Regulation Valproic Acid Viral Virus Virus Diseases Work anti-PD-L1 therapy chromatin remodeling chronic infection cytokine effector T cell exhaust exhaustion functional restoration imprint improved improved functioning in vivo insight mortality mouse model optimal treatments prevent programmed cell death ligand 1 programs promoter receptor repaired response transcriptome

项目摘要

During many chronic viral infections, virus-specific CD8 T cells become exhausted as a result of prolonged antigenic and inflammatory stimulation. Exhausted CD8 T cells are characterized by a progressive loss of the ability to produce effector cytokines and kill target cells, poor proliferative capacity, and increased expression of multiple inhibitory receptors. T cell exhaustion was first characterized in the murine model of lymphocytic choriomeningitis virus (LCMV) infection. Considerable effort has been focused on elucidating the mechanisms that regulate T cell exhaustion, with multiple factors and pathways implicated. Blockade of the PD-1:PD-L1 inhibitory pathway early during infection can prevent progression of CD8 T cell exhaustion and, if given at later time points, can partially rescue the function of exhausted CD8 T cells. Recent results show that PD-L1 blockade does not reinvigorate all exhausted CD8 T cells but selectively expands a subset of exhausted CD8 T cells into effectors that function only temporarily, reverting back to the exhausted state. Even when removed from the chronic infection environment, exhausted CD8 T cells are unable to differentiate into functional memory, indicating that the functional defects are molecularly imprinted within exhausted T cells. Our recent work has shown that progressive loss of CD8 T cell functionality during chronic LCMV infection is associated with decreased diacetylated histone H3 (diAcH3) levels globally and at specific loci encoding effector cytokines, indicating a loss of open chromatin structure at these loci. In vitro treatment of exhausted T cells with valproic acid (VPA), a histone deacetylase inhibitor (HDACi), restores diAcH3 levels and effector cytokine production. Remarkably, when adoptively transferred into naïve hosts, VPA-treated “exhausted” CD8 T cells exhibit improved functionality for an extended period of time and differentiate into functional memory T cells with enhanced recall responses. Together, these results show that epigenetics plays a crucial role in regulating T cell exhaustion and may hold the key to reprogramming exhausted T cells into functional effectors capable of clear chronic infection. In this application, we will test 1) if adoptive transfer of exhausted CD8 T cells that have been rescued by in vitro HDACi treatment will work in vivo to clear an established chronic LCMV infection, and 2) if direct treatment of chronically infected mice with HDACi in vivo can rejuvenate exhausted CD8 T cell and allow for viral clearance. We will examine how exhausted T cells are reprogrammed epigenetically and transcriptionally by HDAC inhibition to understand the mechanisms of HDACi in rescuing exhaustion. We will test whether HDACi can reprogram and rescue subsets of exhausted CD8 T cells that fail to respond to PD-L1 blockade. We will examine if combining PD-L1 blockade with epigenetic manipulation synergizes to restore the functionality of all exhausted CD8 T cells and achieve faster viral clearance. Through these studies, we hope to gain a better understanding of the molecular mechanisms underlying T cell exhaustion and to develop an optimal strategy for enhancing immune control and clearance of chronic viral infection.

在许多慢性病毒感染期间，病毒特异性 CD8 T 细胞由于长期感染而耗尽。抗原和炎症刺激耗尽的特点是 CD8 T 细胞逐渐丧失。产生效应细胞因子并杀死靶细胞的能力，增殖能力差，表达增加多种抑制性 T 细胞耗竭的研究首次在小鼠淋巴细胞模型中得到表征。脉络膜脑膜炎病毒（LCMV）感染的机制已得到大量研究。调节 T 细胞耗竭，涉及多种因素和通路的 PD-1:PD-L1 阻断。感染早期的抑制途径可以防止 CD8 T 细胞耗竭的进展，如果稍后给予时间点，可以部分挽救耗尽的CD8 T细胞的功能。最近的结果表明，PD-L1。封锁不会使所有耗尽的 CD8 T 细胞重新焕发活力，但会选择性地扩增耗尽的 CD8 T 细胞的子集细胞变成仅暂时起作用的效应器，即使被移除也会恢复到耗尽状态。由于慢性感染环境，耗尽的 CD8 T 细胞无法分化为功能性 T 细胞。记忆，表明功能缺陷被分子印记在耗尽的 T 细胞内。研究表明，慢性 LCMV 感染期间 CD8 T 细胞功能的逐渐丧失与全局和特定位点编码效应子的二乙酰化组蛋白 H3 (diAcH3) 水平降低细胞因子，表明这些位点的开放染色质结构丧失。体外处理耗尽的 T 细胞。含有组蛋白脱乙酰酶抑制剂 (HDACi) 丙戊酸 (VPA)，可恢复 diAcH3 水平和效应细胞因子值得注意的是，当过继转移到幼稚宿主中时，经 VPA 处理的 CD8 T 细胞“耗尽”。在较长时间内表现出改进的功能并分化为功能性记忆 T 细胞这些结果共同表明表观遗传学在调节中发挥着至关重要的作用。 T 细胞耗竭，可能是将耗竭的 T 细胞重新编程为功能效应器的关键，该效应器能够在此应用中，我们将测试 1) 是否过继转移已耗尽的 CD8 T 细胞。通过体外 HDACi 治疗获救的患者将在体内发挥作用，清除已确定的慢性 LCMV 感染，并且 2) 体内直接用 HDACi 治疗慢性感染小鼠是否可以使耗尽的 CD8 T 细胞恢复活力，并且我们将研究耗尽的 T 细胞如何进行表观遗传重新编程并进行病毒清除。我们将通过 HDAC 抑制转录来了解 HDACi 拯救衰竭的机制。测试 HDACi 是否可以重新编程并拯救无法响应 PD-L1 的耗尽 CD8 T 细胞子集我们将研究 PD-L1 阻断与表观遗传操作相结合是否可以协同恢复。通过这些研究，我们可以提高所有耗尽的 CD8 T 细胞的功能并实现更快的病毒清除。希望更好地了解 T 细胞耗竭的分子机制并开发增强免疫控制和清除慢性病毒感染的最佳策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antigen-specific memory Th17 cells promote cross-protection against nontypeable Haemophilus influenzae after mild influenza A virus infection.

DOI：
10.1016/j.mucimm.2023.01.007
发表时间：
2023-04
期刊：
MUCOSAL IMMUNOLOGY
影响因子：
8
作者：
Zhang, Xinyun;Yang, Ying;Chen, ShengSen;Li, Wenchao;Li, Yong;Akerley, Brian J.;Shao, Linyun;Zhang, Wenhong;Shen, Hao;Abt, Michael C.
通讯作者：
Abt, Michael C.

Next steps in the identification of gene targets for type 1 diabetes.

DOI：
10.1007/s00125-020-05248-8
发表时间：
2020-11
期刊：
Diabetologia
影响因子：
8.2
作者：
Grant SFA;Wells AD;Rich SS
通讯作者：
Rich SS

Immunological consequences of microbiome-based therapeutics.

DOI：
10.3389/fimmu.2022.1046472
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

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Michael C. Abt其他文献

Monocyte Reconstitution and Gut Microbiota Composition after Hematopoietic Stem Cell Transplantation

造血干细胞移植后的单核细胞重建和肠道菌群组成

DOI：
10.1101/777268
发表时间：
2019
期刊：
Clinical Hematology International
影响因子：
0
作者：
S. Morjaria;Allen W. Zhang;Sohn G. Kim;J. Peled;Simone Becattini;E. Littmann;E. Pamer;M. Perales;Michael C. Abt
通讯作者：
Michael C. Abt