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

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:
    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:
    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:
    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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