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

基本信息

  • 批准号:
    10359809
  • 负责人:
  • 金额:
    $ 19.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 影响因子:
    3.2
  • 作者:
    Yahashiri,Atsushi;Kaus,GabrielaM;Popham,DavidL;Houtman,JonCD;Weiss,DavidS
  • 通讯作者:
    Weiss,DavidS
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Jon C.D. Houtman其他文献

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:
    10.1101/2022.07.01.498525
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Atsushi Yahashiri;Gabriela M. Kaus;D. Popham;Jon C.D. Houtman;David S. Weiss
  • 通讯作者:
    David S. Weiss

Jon C.D. Houtman的其他文献

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{{ truncateString('Jon C.D. Houtman', 18)}}的其他基金

R25 YES: Cancer Research Opportunities at Iowa
R25 是:爱荷华州的癌症研究机会
  • 批准号:
    10712349
  • 财政年份:
    2023
  • 资助金额:
    $ 19.31万
  • 项目类别:
MMP-9 based immune-driven mechanisms of neovascular AMD
基于MMP-9的新生血管性AMD的免疫驱动机制
  • 批准号:
    10719958
  • 财政年份:
    2023
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8220881
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8530594
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8795270
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8606956
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8610251
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    7883144
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8068032
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:
Cooperative SH2 and SH3 domain-mediated interactions at the adaptor protein Grb2
SH2 和 SH3 结构域介导的接头蛋白 Grb2 上的协同相互作用
  • 批准号:
    8447598
  • 财政年份:
    2010
  • 资助金额:
    $ 19.31万
  • 项目类别:

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