CD4 T cell intrinsic signaling defects during viral exhaustion

病毒耗竭期间 CD4 T 细胞内在信号传导缺陷

• 批准号: 10359809
• 负责人: Jon C.D. Houtman
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-25 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359809
• 关键词: Acute; Address; Affect; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cellular Metabolic Process; Chronic; Collaborations; Complex; Data; Defect; Development; Distal; Equilibrium; Exhibits; Exploratory/Developmental Grant; Failure; Functional disorder; Gene Expression; Generations; Genes; Genetic study; Goals; Human; Immune System Diseases; Immune response; Impairment; Infection; Investigation; Laboratories; Lead; Lymphocytic choriomeningitis virus; Maintenance; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mission; Mitochondria; Modeling; Molecular; Mus; Mutation; Oxidative Phosphorylation; Pathogenesis; Play; Process; Proliferating; Proteins; Public Health; Publishing; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Stimulus; T Cell Receptor Signaling Pathway; T cell response; T-Cell Receptor; T-Lymphocyte; Therapeutic; Time; United States National Institutes of Health; Viral; Viral Cancer; Virus; Virus Diseases; Work; adaptive immune response; base; burden of illness; cancer cell; cancer immunotherapy; chronic infection; differential expression; effector T cell; exhaust; exhaustion; experience; innovation; insight; mouse model; novel; novel therapeutic intervention; prevent; receptor function; response; tumor; tumor progression

Project Summary: Chronic stimulation through the T cell receptor (TCR) drives T cells to progressively lose their ability to exert their effector functions in a process termed exhaustion. T cell exhaustion occurs during both cancer and persistent infections contributing to the failure of the adaptive immune response to control the tumor or infection. CD8 T cell exhaustion was initially described during chronic lymphocytic choriomeningitis virus (LCMV) infection. However, CD4 T cells control the delicate balance between the maintenance of effector CD8 T cell responses versus the development of CD8 T cell exhaustion during chronic infection. Despite their critical role in maintaining the antiviral CD8 T cell response, much less is known about the specific signaling defects and metabolic changes that occur within exhausted CD4 T cells. Gene expression studies examining LCMV-specific CD4 T cells have indicated that hundreds of genes are differentially expressed between CD4 T cells isolated during an acute versus chronic LCMV infection and that these genetic changes are different for CD4 T cells versus CD8 T cells. Many of the differentially expressed genes in CD4 T cells are related to TCR signaling and metabolic pathways, but how these alterations lead to specific defects in TCR signaling and cellular metabolism has not been defined. Our long-term goal is to understand the mechanisms that mediate CD4 T cell dysfunction during chronic viral infections and cancer progression. The objective of this application is to determine the specific defects in CD4 T cell signaling and metabolic pathways that develop during chronic LCMV infection. Our central hypothesis is that virus-specific CD4 T cells develop multiple defects in critical signaling pathways downstream of the TCR and metabolic pathways, resulting in the impaired ability of the CD4 T cell to mediate effector activity and proliferate during a chronic viral infection. Our hypothesis is based our own preliminary data, in conjunction with published genetic studies, indicating that expression of multiple signaling and metabolic proteins are reduced in virus-specific CD4 T cells following a persistent LCMV Clone 13 infection. The rationale for the proposed research is that, once the principal signaling and metabolic defects affecting exhausted CD4 T cells are identified, new and innovative therapeutic approaches can be targeted to restore CD4 T cell effector activity and enhance clearance of chronic viral infections and human cancers. We will achieve the goals of this proposal by pursuing the following two specific aims: 1) Examine the effects of viral exhaustion on early TCR signaling and function in CD4 T cells and 2) Investigate the impact of viral exhaustion on metabolism in CD4 T cells. The completion of these aims will determine if T cell exhaustion after infection with a chronic virus results in CD4 T cell intrinsic changes in the signaling capacity and metabolic function that would impact effector functions. Our results will provide insight into the molecular mechanism of CD4 T cell exhaustion and highlight potential avenues to modulate either signaling or metabolism to enhance the function of exhausted CD4 T cells during either chronic viral infection or cancer immunotherapy.

项目概要： 通过 T 细胞受体 (TCR) 的慢性刺激会促使 T 细胞逐渐丧失发挥作用的能力 它们的效应器在一个称为耗尽的过程中发挥作用。 T 细胞耗竭发生在癌症和 持续感染导致适应性免疫反应无法控制肿瘤或 感染。 CD8 T 细胞耗竭最初是在慢性淋巴细胞脉络膜脑膜炎病毒期间描述的 （LCMV）感染。然而，CD4 T 细胞控制着维持效应 CD8 之间的微妙平衡。 慢性感染期间 T 细胞反应与 CD8 T 细胞耗竭的发展。尽管他们的 在维持抗病毒 CD8 T 细胞反应中发挥关键作用，但对具体信号传导知之甚少 耗尽的 CD4 T 细胞内发生的缺陷和代谢变化。基因表达研究检查 LCMV 特异性 CD4 T 细胞表明，CD4 T 细胞之间有数百个基因差异表达 在急性和慢性 LCMV 感染过程中分离出的细胞，这些基因变化对于 CD4 T 细胞与 CD8 T 细胞。 CD4 T细胞中许多差异表达的基因与TCR有关 信号和代谢途径，但这些改变如何导致 TCR 信号和代谢途径的特定缺陷 细胞代谢尚未定义。我们的长期目标是了解调解机制 慢性病毒感染和癌症进展期间 CD4 T 细胞功能障碍。此应用程序的目的 是为了确定 CD4 T 细胞信号传导和慢性疾病过程中产生的代谢途径的具体缺陷 巨细胞病毒感染。我们的中心假设是，病毒特异性 CD4 T 细胞在关键部位会产生多种缺陷。 TCR 和代谢途径下游的信号通路，导致 TCR 的能力受损 CD4 T 细胞在慢性病毒感染期间介导效应活性和增殖。我们的假设基于 我们自己的初步数据，结合已发表的遗传学研究，表明多种表达 持续 LCMV 克隆后，病毒特异性 CD4 T 细胞中的信号传导和代谢蛋白减少 13 感染。拟议研究的基本原理是，一旦主要信号传导和代谢缺陷 确定了对耗尽的 CD4 T 细胞的影响，可以针对新的和创新的治疗方法 恢复 CD4 T 细胞效应活性并增强慢性病毒感染和人类癌症的清除。我们 将通过追求以下两个具体目标来实现本提案的目标： 1）检查 病毒耗竭对 CD4 T 细胞早期 TCR 信号传导和功能的影响；2) 研究病毒耗竭的影响 CD4 T 细胞代谢衰竭。这些目标的完成将决定 T 细胞是否会耗尽 慢性病毒感染导致 CD4 T 细胞信号传导能力和代谢能力发生内在变化 会影响效应器功能的功能。我们的结果将提供对分子机制的深入了解 CD4 T 细胞耗竭并强调调节信号或代谢以增强的潜在途径 慢性病毒感染或癌症免疫治疗期间耗尽的 CD4 T 细胞的功能。

项目成果

Comparative Study of Bacterial SPOR Domains Identifies Functionally Important Differences in Glycan Binding Affinity.

细菌 SPOR 结构域的比较研究确定了聚糖结合亲和力的重要功能差异。

• DOI: 10.1128/jb.00252-22
• 发表时间: 2022
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Yahashiri,Atsushi;Kaus,GabrielaM;Popham,DavidL;Houtman,JonCD;Weiss,DavidS
• 通讯作者: Weiss,DavidS