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

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CD 8 T细胞在胸腺发育期间被删除，并且必须使逃避消除的细胞在外周中耐受以防止自身免疫损伤。然而，许多候选癌症抗原是自身抗原，并且对这些蛋白质的耐受性可阻碍抗肿瘤T细胞应答。我们最近证明，这样的自身/肿瘤抗原特异性CD 8 T细胞具有与功能性无反应性相关的耐受特异性基因程序，所述功能性无反应性反映为它们不能响应于抗原而增殖，缺乏效应子功能所需的关键转录因子和分子，并且表达与降低的免疫细胞功能相关的基因。然而，耐受性不是不可逆的固定分化状态：在体内淋巴细胞减少诱导的稳态增殖（HP）期间，耐受性基因程序可以暂时被超控，导致抗原应答性和功能的拯救。一旦HP的增殖驱动结束并且T细胞退出细胞周期，耐受性基因签名被重新激活。 无论细胞是否再次遇到耐受性自身抗原。这些发现表明，不需要持续的抗原暴露来维持耐受性，并且表明自身耐受性T细胞“记住”在与外周中的自身抗原的初始遭遇期间建立的耐受性程序。 我们的具体假设是，自我耐受性代表了一种独特的分化状态，这种状态是由“耐受性特异性”程序通过“耐受性特异性”染色质标记和调控元件表观遗传印记维持的。基因表达的表观遗传调控机制刚刚开始被理解，部分是通过最近的工作由DNA元件百科全书（ENCODE）项目，揭示染色质可及性，基因表达，DNA甲基化和调控因子占用模式之间的新关系，并确定新的顺式调控基序的转录因子。拟议的研究将确定与不同的CD 8 T细胞分化和功能状态相关的染色质状态，以确定自我耐受和功能性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干预性临床机会，而且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）通过使用ENCODE技术结合染色质状态的全面、高分辨率全基因组分析来确定与自身耐受性的建立和维持相关的细胞内在调节机制，以鉴定耐受性T细胞中唯一编码的表观遗传程序;和2）确定潜在的机制和策略，通过这些机制和策略，可以消除耐受性印记和表观遗传记忆，以实现永久性的重建。与自身/肿瘤特异性CD 8 T细胞长期拯救和分化为功能性抗原应答性T细胞相关的编程。