Chromatin states encoding fate commitment and plasticity of tolerant CD8 T cells

染色质状态编码耐受 CD8 T 细胞的命运承诺和可塑性

• 批准号: 8667993
• 负责人: PHILIP D GREENBERG
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667993
• 关键词: Antigen Presentation; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beryllium; CD8B1 gene; Cell Cycle; Cell physiology; Cells; Chromatin; Clinical; Complex; Cues; DNA; DNA Methylation; DNA Modification Process; DNA Sequence; Development; Encyclopedia of DNA Elements; Enhancers; Environment; Epigenetic Process; Exhibits; Failure; Functional RNA; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Graft Rejection; Immune; Immunotherapeutic agent; Individual; Inflammatory; Injury; Lead; Left; Listeriosis; Lymphopenia; Maintenance; Malignant Neoplasms; Mediating; Memory; Methods; MicroRNAs; Nature; Nucleosomes; Organism; Pattern; Phenotype; Prevention; Proliferating; Promoter Regions; Proteins; Regulatory Element; Resolution; Role; Science; Self Tolerance; Signal Pathway; Signal Transduction; Stimulus; T cell differentiation; T cell response; T-Lymphocyte; Technology; Therapeutic; Tolerogen; Transcript; Transplantation; Transplanted tissue; Tumor Antigens; Work; cancer immunotherapy; chromatin modification; epigenome; genome-wide analysis; histone modification; imprint; in vivo; novel; prevent; programs; public health relevance; response; transcription factor; tumor

DESCRIPTION (provided by applicant): Most CD8 T cells reactive with self-antigens are deleted during thymic development, and the cells that evade elimination must be rendered tolerant in the periphery to prevent autoimmune injury. However, many candidate cancer antigens are self-antigens, and tolerance to these proteins can impede anti-tumor T cell responses. We recently demonstrated that such self/tumor-antigen specific CD8 T cells harbor a tolerance- specific gene program associated with functional unresponsiveness reflected by their inability to proliferate in response to antigen, lack key transcription factors and molecules needed for effector function(s), and express genes associated with reduced immune cell function. However, tolerance is not an irreversible, fixed differentiation state: the tolerance gen program can be temporarily overridden during periods of lymphopenia- induced homeostatic proliferation (HP) in vivo, resulting in rescue of antigen responsiveness and function. Once the proliferative drive of HP ends and T cells exit the cell cycle, the tolerance gene signature is re- imposed regardless of whether the cells re-encounter the tolerizing self-antigen. These findings demonstrate that continuous antigen exposure is not required to maintain tolerance, and suggest that self-tolerant T cells "remember" the tolerance program established during the initial encounter(s) with self-antigen in the periphery. Our specific hypothesis is that self-tolerance represents a unique differentiation state that is maintained by a "tolerance-specific" program epigenetically imprinted through "tolerance-specific" chromatin marks and regulatory elements. Epigenetic regulatory mechanisms of gene expression are just beginning to be understood, in part through recent work by The Encyclopedia of DNA elements (ENCODE) project, revealing new relationships between chromatin accessibility, gene expression, DNA-methylation and regulatory factor occupancy patterns, and identifying novel cis-regulatory motifs of transcription factor. The proposed studies will determine the chromatin states associated with distinct CD8 T cell differentiation and functional states to define the epigenetic underpinnings of commitment fate and plasticity of self-tolerant and functional T cells. Elucidating how chromatin states encode and maintain the tolerant state may not only identify interventional clinical opportunities for cancer immunotherapy, but also suggest strategies for mitigating the dangers of autoimmunity and transplant rejection. The Specific Aims are to: 1) Define the cell-intrinsic regulatory mechanism(s) associated with the establishment and maintenance of self-tolerance by using ENCODE technologies with comprehensive, high- resolution genome-wide analysis of chromatin states to identify the epigenetic program uniquely encoded in tolerant T cells; and 2) Determine the underlying mechanism(s) and strategies by which tolerance imprinting and epigenetic memory can be erased to achieve permanent re-programming associated with long-term rescue and differentiation of self/tumor-specific CD8 T cells into functional antigen-responsive T cells.

描述（由申请人提供）：大多数与自身抗原反应的 CD8 T 细胞在胸腺发育过程中被删除，并且必须使逃避消除的细胞在外周具有耐受性，以防止自身免疫损伤。然而，许多候选癌症抗原是自身抗原，对这些蛋白质的耐受会阻碍抗肿瘤 T 细胞反应。我们最近证明，这种自身/肿瘤抗原特异性CD8 T细胞具有与功能无反应相关的耐受特异性基因程序，反映为它们无法响应抗原而增殖，缺乏效应功能所需的关键转录因子和分子，并表达与免疫细胞功能降低相关的基因。然而，耐受性并不是一种不可逆的、固定的分化状态：在体内淋巴细胞减少诱导的稳态增殖（HP）期间，耐受性基因程序可以暂时被覆盖，从而挽救抗原反应性和功能。一旦 HP 的增殖驱动结束并且 T 细胞退出细胞周期，耐受基因特征就会重新出现。 无论细胞是否再次遇到耐受性自身抗原，都施加。这些发现表明，维持耐受性不需要持续的抗原暴露，并且表明自我耐受的 T 细胞“记住”在外周初次遇到自身抗原时建立的耐受程序。 我们的具体假设是，自我耐受代表了一种独特的分化状态，该状态由通过“耐受特异性”染色质标记和调控元件进行表观遗传印记的“耐受特异性”程序维持。基因表达的表观遗传调控机制刚刚开始被人们所理解，部分是通过 DNA 元件百科全书 (ENCODE) 项目最近的工作，揭示了染色质可及性、基因表达、DNA 甲基化和调控因子占据模式之间的新关系，并鉴定了转录因子的新顺式调控基序。拟议的研究将确定与不同 CD8 T 细胞分化和功能状态相关的染色质状态，以定义自我耐受和功能性 T 细胞的定型命运和可塑性的表观遗传基础。阐明染色质状态如何编码和维持耐受状态不仅可以确定癌症免疫治疗的介入临床机会，还可以提出减轻自身免疫和移植排斥危险的策略。 具体目标是： 1) 使用 ENCODE 技术，对染色质状态进行全面、高分辨率的全基因组分析，确定与自我耐受的建立和维持相关的细胞内在调节机制，以确定耐受 T 细胞中独特编码的表观遗传程序； 2) 确定潜在的机制和策略，通过这些机制和策略可以消除耐受印记和表观遗传记忆，以实现与自身/肿瘤特异性 CD8 T 细胞长期拯救和分化为功能性抗原反应性 T 细胞相关的永久重编程。

项目成果

Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.

• DOI: 10.1016/j.immuni.2016.07.011
• 发表时间: 2016-08-16
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Schietinger, Andrea;Philip, Mary;Krisnawan, Varintra E.;Chiu, Edison Y.;Delrow, Jeffrey J.;Basom, Ryan S.;Lauer, Peter;Brockstedt, Dirk G.;Knoblaugh, Sue E.;Haemmerling, Guenter J.;Schell, Todd D.;Garbi, Natalio;Greenberg, Philip D.
• 通讯作者: Greenberg, Philip D.