Protective CD4+ T cells

保护性 CD4 T 细胞

基本信息

  • 批准号:
    9022392
  • 负责人:
  • 金额:
    $ 38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-03-15 至 2018-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): CD4+ T cells play a major role in adaptive immune responses to intracellular and extracellular microbes by regulating the functions of B cells, CD8+ T cells, and phagocytes. However, the prevalence of phagosomal infections caused by Mycobacteria, Salmonella, and Cryptococcus in CD4+ T cell-deficient AIDS patients demonstrates that the most important function of these cells is phagocyte activation. Yet this function is poorly understood, which probably explains why no effective vaccines exist for these pathogens that kill at 2 million people every year. The size of this knowledge gap becomes clear when one considers the odd features of CD4+ T cell-dependent "concomitant immunity", which likely operates for all phagosomal infections. IFN-γ producing Th1 cells control the infection within phagocytes at the initial site of infection and prevent it from spreading to other parts of he body. Oddly, however, the Th1 cells never eliminate the microbes from the initial site. Indeed, persistent infection at the original site is required for the Th1 cells to eliminate bacteria from other body sites after a second infection. The regulatory mechanisms that allow Th1 cells to control the infection without eliminating it are not understood. In addition, it is not clear why CD4+ T cell memory is not retained if the original infection is eliminated and why persistent infection does not result in T cell exhaustion. We will use a sensitive peptide: major histocompatibility complex II (p:MHCII) tetramer- based cell enrichment method to study the endogenous CD4+ T cell response to a prototypical persistent phagosomal infection caused by ingestion of Salmonella enterica serovar Typhimuruim (ST) bacteria to gain insight into how protective CD4+ T cells are generated and function. We will test our idea that presentation of p: MHCII complexes exclusively by infected phagocytes drives the generation of IFN-γ-producing Th1 effector cells without generating B cell-dependent follicular helper T cells. We will explore the possibility that infected phagocytes at the site of initial infection produce IL-10, which limis their capacity to clear their infection and prevents terminal differentiation of the Th1 cells, locking them in a state where they retain the capacity to multiple protective phagocyte-activating cytokines. We will determine whether the persistently infected IL-10-producing phagocytes in the mesenteric lymph nodes also stimulate bursts of proliferation by Th1 memory cells that periodically circulate through this site to maintain a stable and functional protective population. Accomplishing our specific aims with a robust defined in vivo model system could guide vaccine development against this recalcitrant class of pathogens.
描述(由申请人提供):CD 4 + T细胞通过调节B细胞、CD 8 + T细胞和吞噬细胞的功能,在针对细胞内和细胞外微生物的适应性免疫应答中发挥主要作用。然而,由分枝杆菌、沙门氏菌和隐球菌引起的吞噬体感染在CD 4 + T细胞缺陷型AIDS患者中的流行表明,这些细胞的最重要功能是吞噬细胞活化。然而,人们对这种功能知之甚少,这可能解释了为什么没有针对这些每年导致200万人死亡的病原体的有效疫苗。当人们考虑到CD 4 + T细胞依赖的“伴随免疫”的奇怪特征时,这种知识差距的大小变得清晰,这可能对所有吞噬体感染都起作用。产生IFN-γ的Th 1细胞在感染的初始部位控制吞噬细胞内的感染,并防止其扩散到身体的其他部位。然而,奇怪的是,Th 1细胞从来没有从初始位置消除微生物。事实上,在第二次感染后,Th 1细胞需要在原始部位持续感染才能从其他身体部位消除细菌。允许Th 1细胞控制感染而不消除感染的调节机制尚不清楚。此外,尚不清楚为什么在消除原始感染后CD 4 + T细胞记忆没有保留,以及为什么持续感染不会导致T细胞耗竭。我们将使用基于敏感肽:主要组织相容性复合体II(p:MHCII)四聚体的细胞富集方法来研究内源性CD 4 + T细胞对由肠道沙门氏菌血清型Typhimuruim(ST)细菌摄入引起的原型持续性吞噬体感染的应答,以深入了解保护性CD 4 + T细胞如何产生和发挥功能。我们将测试我们的想法,即仅由感染的吞噬细胞呈递p:MHCII复合物驱动产生IFN-γ的Th 1效应细胞,而不产生B细胞依赖性滤泡辅助T细胞。我们将探讨感染的吞噬细胞在初始感染的网站产生IL-10,这限制了他们的能力,以清除他们的感染,并防止终端分化的Th 1细胞,锁定他们在一个状态,他们保留了多种保护性吞噬细胞激活细胞因子的能力。我们将确定肠系膜淋巴结中持续感染的产生IL-10的吞噬细胞是否也会刺激Th 1记忆细胞的爆发性增殖,Th 1记忆细胞周期性地在该部位循环,以维持稳定且功能性的保护性细胞群。 实现我们的具体目标与一个强大的定义在体内模型系统可以指导疫苗的开发,针对这类不稳定的病原体。

项目成果

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Marc Kevin Jenkins其他文献

Marc Kevin Jenkins的其他文献

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{{ truncateString('Marc Kevin Jenkins', 18)}}的其他基金

Detection and Activation of CD4+ T cells with Low Affinity TCRs
低亲和力 TCR 的 CD4 T 细胞的检测和激活
  • 批准号:
    10348758
  • 财政年份:
    2019
  • 资助金额:
    $ 38万
  • 项目类别:
Detection and Activation of CD4+ T cells with Low Affinity TCRs
低亲和力 TCR 的 CD4 T 细胞的检测和激活
  • 批准号:
    10570243
  • 财政年份:
    2019
  • 资助金额:
    $ 38万
  • 项目类别:
Protective CD4+ T Cells
保护性 CD4 T 细胞
  • 批准号:
    10349513
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Protective CD4+ T cells
保护性 CD4 T 细胞
  • 批准号:
    8430702
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Protective CD4+ T cells
保护性 CD4 T 细胞
  • 批准号:
    8810212
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Analysis of peripheral tolerance in vivo
体内外周耐受性分析
  • 批准号:
    8500973
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Protective CD4+ T cells
保护性 CD4 T 细胞
  • 批准号:
    8634713
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Protective CD4+ T cells
保护性 CD4 T 细胞
  • 批准号:
    9228319
  • 财政年份:
    2013
  • 资助金额:
    $ 38万
  • 项目类别:
Analysis of peripheral tolerance in vivo
体内外周耐受性分析
  • 批准号:
    8308579
  • 财政年份:
    2011
  • 资助金额:
    $ 38万
  • 项目类别:
Flow Cytometry Core
流式细胞术核心
  • 批准号:
    8308583
  • 财政年份:
    2011
  • 资助金额:
    $ 38万
  • 项目类别:

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