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

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

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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.

项目摘要 CD8 T细胞对病毒感染和肿瘤的反应显着促进免疫复杂的人决定此类病理的临床结果。 CD8 T细胞响应的功能完整性取决于 CD8效应子（TEFF）和内存（TMEM）种群的特性特性。但是，在慢性期间病毒感染和癌症，抗原持久性而没有清除的抗原持久性，无法有效的TEFF和TMEM 开发，而是将CD8 T细胞分化偏向于表观遗传上不同的“疲惫”谱系（Tex）。 Tex裸露的进行性功能障碍和效应特性丧失，增殖能力和记忆力潜在的PD1和其他抑制性受体（IRS）的共表达持续增加。询问启动和维持Tex表观遗传状态的基本机制是中心的重要的是了解Tex生物学并确定有选择性靶向或调节Tex的策略。但是，该领域通常缺乏对Tex特异性表观遗传过程的详细机械理解。在慢性感染和功能失调的肿瘤特异性T细胞的疲惫模型，转录因子托克斯对于Tex开发的倡议至关重要，反映终端TEFF分化和潜在对Tex血统的表观遗传承诺。该建议旨在识别和审问机械细节 Tex通过TOX进行的法规，需要开始开发免疫疗法的方法表观遗传重新编程Tex并改善免疫疗法的临床结果。分子交易tox员工执行其效果仍然很大未知。了解细节 TOX活性的限制仍然受其N和C末端结构域的功能表征的限制（“ NTD” 与其HMG-box DNA结合域有关的“ CTD”）。我的初步数据证明了失去 TOX NTD或CTD都足以消除表面PD1表达的增加特征是由全长（“ FL”）托克斯驱动，这表明这些领域的作用尚不清楚。该提议的核心假设是，托克斯活性的不同特征归因于其n- 与C末端域以及NTD-或CTD特异性扰动的选择性调制 Tex对慢性病毒感染的反应。该提案通过询问TOX的特征来检验该假设 PDCD1基因座（编码PD1）处的相互作用和域级函数，通过定义在多大程度上 NTD和CTD通过定义NTD和CTD计划如何揭示其特定于Tex特定角色的全球差异通过确定哪种NTD和CTD介导的蛋白质相互作用TOX用途调节文本转录。因此，该提案将提高有关分子如何的基本知识可以操纵调节精疲力尽的过程以改善慢性病毒期间的CD8 T细胞反应感染和癌症。