Molecular Mechanisms of TOX-mediated Programming of CD8 T Cell Exhaustion

TOX 介导的 CD8 T 细胞耗竭编程的分子机制

基本信息

批准号：
10606385
负责人：
Matthew Ambrose Sullivan
金额：
$ 5.27万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606385
关键词：
ATAC-seq Acceleration Acetylation Acute Adoptive Transfer Antigens Binding Binding Proteins Biology C-terminal CD8-Positive T-Lymphocytes CD8B1 gene Cell Proliferation Cell Surface Proteins Cell physiology Cells Characteristics Chromatin Chronic Clinical Coupled DNA Binding Domain Data Development Disease Enhancers Epigenetic Process Eragrostis Exhibits Flow Cytometry Functional disorder Genetic Transcription Goals HMG-Box Domains Histone H3 Immune Immune response Immunotherapy In Vitro Knowledge Length Lymphocytic choriomeningitis virus Mediating Memory Memory impairment Messenger RNA Methylation Modeling Molecular Morbidity - disease rate Mus Nuclear Protein Outcome PD-1 blockade PD-L1 blockade Pathology Patients Phenotype Play Population Process Proliferating Property Proteins Proteomics Receptor Signaling Regulation Repression Role Severity of illness Signal Pathway Surface System T cell differentiation T cell response T-Lymphocyte Testing Transcriptional Activation Transcriptional Regulation Viral Cancer Virus Virus Diseases chronic infection exhaust exhaustion experience immune checkpoint blockade improved in vivo mortality mutant novel therapeutics overexpression progenitor programmed cell death ligand 1 programmed cell death protein 1 programs protein complex protein expression receptor recruit response restraint screening synergism transcription factor transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY CD8 T cell responses to viral infections and tumors contribute significantly to the immune responses that dictate the clinical outcomes of such pathologies. The functional integrity of CD8 T cell responses depends on the characteristic properties of CD8 effector (Teff) and memory (Tmem) populations. However, during chronic viral infections and cancer, antigen persistence without clearance precludes effective Teff and Tmem development, instead biasing CD8 T cell differentiation towards an epigenetically distinct “exhausted” lineage (Tex). Tex exhibit progressive dysfunction and loss of effector properties, proliferation capacity, and memory potential, as well as a sustained increase in co-expression of PD1 and multiple other inhibitory receptors (IRs). Interrogating the fundamental mechanisms that initiate and maintain the Tex epigenetic state is of central importance to understanding Tex biology and identifying strategies to selectively target or modulate Tex. However, the field generally lacks a detailed mechanistic understanding of Tex-specific epigenetic processes. In models of exhaustion during chronic infection and of dysfunctional tumor-specific T cells, the transcription factor TOX is essential for the initiation of Tex development, repressing terminal Teff differentiation and potentiating epigenetic commitment to the Tex lineage. This proposal seeks to identify and interrogate the mechanistic details of Tex regulation by TOX that would be required to begin developing immunotherapy approaches to epigenetically reprogram Tex and improve immunotherapy clinical outcomes. The molecular transactions TOX employs to exert its effects remain largely unknown. Understanding the details of TOX activity remains limited by a lack of functional characterization of its N- and C-terminal domains (“NTD” and “CTD”) in relation to its HMG-box DNA binding domain. My preliminary data demonstrate in vitro that loss of either the TOX NTD or CTD is sufficient to abrogate the increase in surface PD1 expression that is characteristically driven by full-length (“FL”) TOX, suggesting important, as yet unknown roles for these domains. The central hypothesis of this proposal is that distinct features of TOX activity are attributable to its N- vs. C-terminal domains and that NTD- or CTD-specific perturbations will enable selective modulation of Tex responses to chronic viral infection. This proposal tests this hypothesis by interrogating features of TOX’s interactions and domain-level function at the Pdcd1 locus (encoding PD1), by defining the extent to which the NTD and CTD exhibit global differences in their Tex-specific roles, by defining how the NTD and CTD program the Tex epigenetic state, and by determining which NTD- and CTD-mediated protein interactions TOX uses to regulate Tex transcription. This proposal will thus advance fundamental knowledge of how the molecular processes regulating exhaustion may be manipulated to improve CD8 T cell responses during chronic viral infections and cancer.

项目概要 CD8 T 细胞对病毒感染和肿瘤的反应对免疫反应有显着贡献，决定此类病理的临床结果取决于 CD8 T 细胞反应的功能完整性。然而，在慢性过程中，CD8 效应子 (Teff) 和记忆 (Tmem) 群体的特征特性。病毒感染和癌症，未经清除的抗原持续存在会阻碍 Teff 和 Tmem 的有效发挥发育，而不是使 CD8 T 细胞分化偏向于表观遗传上独特的“耗尽”谱系 (Tex)。Tex 表现出进行性功能障碍以及效应器特性、增殖能力和记忆的丧失。潜力，以及 PD1 和多种其他抑制性受体 (IR) 共表达的持续增加。探究启动和维持 Tex 表观遗传状态的基本机制是至关重要的对于理解 Tex 生物学和确定选择性靶向或调节 Tex 的策略非常重要。然而，该领域普遍缺乏对 Tex 特异性表观遗传过程的详细机制理解。慢性感染期间的疲惫模型和功能失调的肿瘤特异性 T 细胞（转录因子） TOX 对于 Tex 发育的启动、抑制 Teff 终末分化和增强 Tex 发育至关重要该提案旨在识别和询问其机制细节。 TOX 的 Tex 调节需要开始开发免疫治疗方法表观遗传重新编程 Tex 并改善免疫治疗的临床结果。 TOX 用于发挥其作用的分子交易的细节仍然很大程度上未知。由于缺乏 N 端和 C 端结构域（“NTD”）的功能表征，TOX 活性的和“CTD”）与其 HMG-box DNA 结合域相关。我的初步数据证明了体外的损失。 TOX NTD 或 CTD 都足以消除表面 PD1 表达的增加，即其特征是由全长（“FL”）TOX 驱动，表明这些结构域具有重要但未知的作用。该提案的中心假设是 TOX 活性的独特特征可归因于其 N- 与 C 末端结构域相比，NTD 或 CTD 特异性扰动将能够选择性调节 Tex 对慢性病毒感染的反应通过询问 TOX 的特征来测试这一假设。通过定义 Pdcd1 位点（编码 PD1）的相互作用和域级功能 NTD 和 CTD 通过定义 NTD 和 CTD 程序的方式，在其特定于德克萨斯州的角色中表现出全球差异 Tex 表观遗传状态，并通过确定 TOX 使用哪些 NTD 和 CTD 介导的蛋白质相互作用因此，该提案将提高分子如何调节 Tex 转录的基础知识。调节疲劳的过程可能被操纵以改善慢性病毒感染期间的 CD8 T 细胞反应感染和癌症。