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）的慢性刺激驱使T细胞逐渐失去其发挥免疫调节作用的能力。 它们的效应子在一个被称为衰竭的过程中发挥作用。T细胞耗竭发生在癌症和 持续性感染导致适应性免疫应答无法控制肿瘤，或 感染CD8 T细胞耗竭最初是在慢性淋巴细胞性脉络丛脑膜炎病毒感染期间被描述的。 （LCMV）感染。然而，CD4 T细胞控制着维持效应CD8 T细胞和CD8 T细胞之间的微妙平衡。 慢性感染期间T细胞应答与CD8 T细胞耗竭的发展。尽管他们 虽然在维持抗病毒CD8 T细胞应答中起着关键作用，但对特异性信号传导的了解要少得多。 缺陷和代谢变化发生在耗尽的CD4 T细胞内。基因表达研究 LCMV特异性的CD4 T细胞已经表明，在CD4 T细胞之间有数百个基因的差异表达。 在急性与慢性LCMV感染期间分离的细胞，并且这些遗传变化与急性LCMV感染不同。 CD4 T细胞与CD8 T细胞。CD 4 T细胞中许多差异表达的基因与TCR相关 信号传导和代谢途径，但这些改变如何导致TCR信号传导的特定缺陷， 细胞代谢尚未确定。我们的长期目标是了解 慢性病毒感染和癌症进展期间的CD4 T细胞功能障碍。本申请的目的 目的是确定慢性炎症过程中CD4 T细胞信号传导和代谢途径的特定缺陷， LCMV感染。我们的中心假设是，病毒特异性CD4 T细胞在关键免疫应答中产生多种缺陷。 TCR下游的信号传导途径和代谢途径，导致免疫调节的能力受损。 CD4 T细胞介导效应活性并在慢性病毒感染期间增殖。我们的假设是基于 我们自己的初步数据，结合已发表的遗传研究，表明多个基因的表达， 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感染这项研究的基本原理是，一旦主要的信号和代谢缺陷 影响耗尽的CD4 T细胞，新的和创新的治疗方法可以针对 恢复CD4 T细胞效应活性，增强慢性病毒感染和人类癌症的清除。我们 将通过以下两个具体目标实现本提案的目标：1）审查 病毒耗竭对CD4 T细胞中早期TCR信号传导和功能的影响，以及2）研究病毒耗竭对CD4 T细胞中早期TCR信号传导和功能的影响。 消耗对CD4 T细胞代谢的影响。这些目标的完成将决定T细胞是否在 慢性病毒感染导致CD4 T细胞信号传导能力和代谢能力的内在变化， 影响效应器功能的功能。我们的研究结果将有助于深入了解分子机制， CD4 T细胞耗竭，并强调调节信号传导或代谢以增强免疫应答的潜在途径。 在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