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.

项目总结： 通过T细胞受体(TCR)的慢性刺激促使T细胞逐渐失去发挥作用的能力 它们的效应器在一个称为耗竭的过程中发挥作用。在癌症和癌症期间，T细胞耗尽 持续性感染导致适应性免疫反应不能控制肿瘤或 感染。CD8 T细胞耗竭最初是在慢性淋巴细胞性脉络膜脑膜炎病毒期间被描述的 (LCMV)感染。然而，CD4T细胞控制着维持效应器CD8的微妙平衡 慢性感染时T细胞应答与CD8 T细胞耗竭的关系尽管他们 在维持抗病毒CD8 T细胞反应中的关键作用，对特定的信号转导知之甚少 在耗尽的CD4T细胞内发生的缺陷和代谢变化。基因表达研究检查 LCMV特异性的CD4T细胞已经表明，数百个基因在CD4T之间存在差异表达 在急性和慢性LCMV感染期间分离的细胞，并且这些基因变化对于 CD4T细胞与CD8T细胞的比较。CD4T细胞中的许多差异表达基因与TCR有关 信号和代谢途径，但这些变化如何导致TCR信号和代谢的特定缺陷 细胞新陈代谢还没有定义。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的CD4T细胞功能障碍。本应用程序的目标是 目的是确定慢性阻塞性肺疾病发展过程中CD4T细胞信号和代谢途径的具体缺陷 巨细胞病毒感染。我们的中心假设是，病毒特异性的CD4T细胞在危重疾病中会出现多种缺陷 TCR下游的信号通路和代谢通路，导致细胞功能受损 CD4T细胞在慢性病毒感染期间介导效应器活动和增殖。我们的假设是基于 我们自己的初步数据，结合已发表的基因研究，表明多种基因的表达 LCMV持续克隆后病毒特异性CD4T细胞中信号和代谢蛋白的减少 13感染。这项拟议研究的基本原理是，一旦主要的信号和代谢缺陷 影响耗尽的CD4T细胞被识别，新的和创新的治疗方法可以有针对性地 恢复CD4T细胞效应器活性，增强对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)审查 病毒衰竭对CD4T细胞早期TCR信号和功能的影响2)研究病毒的影响 疲劳对CD4T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CD4T细胞信号传递能力和代谢的内在变化 会影响效应器功能的功能。我们的研究结果将为我们深入了解人类免疫缺陷的分子机制。 CD4T细胞耗竭和强调潜在的途径来调节信号或代谢以增强 慢性病毒感染或癌症免疫治疗过程中耗尽的CD4T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