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: 8568389
• 负责人: PHILIP D GREENBERG
• 金额: $ 18.15万
• 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/8568389
• 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; 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CD8 T细胞在胸腺发育过程中被删除了自我抗原的反应，并且必须在外围耐受的逃避消除的细胞以防止自身免疫性损伤。但是，许多候选癌症是自我抗原，对这些蛋白质的耐受性会阻碍抗肿瘤T细胞反应。我们最近证明，这种自我/肿瘤抗原特异性CD8 T细胞具有耐受性 - 特异性基因程序，与功能性无响应性相关，因为它们无法响应抗原而增殖，缺乏关键转录因子和效应子功能所需的分子，以及与免疫细胞功能降低相关的效应基因。但是，耐受性不是不可逆转的固定分化状态：在体内淋巴细胞减少诱导的稳态增殖（HP）期间，可以暂时覆盖耐受性生长程序，从而导致抗原反应性和功能。一旦HP末端的增殖驱动驱动和T细胞退出细胞周期，耐受性基因的信号即可得到。 不管细胞是否重新遇到耐受性自我抗原。这些发现表明，不需要连续的抗原暴露才能保持耐受性，并表明自耐T细胞“记住”在最初遇到时与外围自我抗原建立的耐受性计划。 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“耐受性特异性”染色质标记和调节元素表观遗传的“宽容特异性”程序维持。基因表达的表观遗传调节机制刚刚开始被理解，部分是通过DNA元素百科全书（编码）项目的最新工作，揭示了染色质可及性，基因表达，DNA-甲基化和调节因子占用模式之间的新关系，并鉴定出新的CIS调控基序的转递因子。拟议的研究将确定与不同的CD8 T细胞分化和功能状态相关的染色质状态，以定义承诺命运的表观遗传基础以及自耐和功能性T细胞的可塑性。阐明染色质状态如何编码和维持耐受状态的状态不仅可以识别出癌症免疫疗法的介入临床机会，而且还提出了减轻自身免疫和移植排斥的危险的策略。 具体目的是：1）定义与建立和维持自耐建立和维持自我耐受的细胞内部调节机制，并使用编码技术和全面的，高分辨率的全基因组对染色质状态的分析来识别具有耐受性T细胞的表观遗传程序唯一编码的表观遗传程序； 2）确定可以删除耐受性和表观遗传记忆的潜在机制和策略，以实现与长期营救和自我/肿瘤特异性CD8 T细胞分化为功能性抗原反应性T细胞相关的永久性重新编程。