Cellular Immune Responses to Respiratory Infection

对呼吸道感染的细胞免疫反应

基本信息

项目摘要

The overall goal of our work is to identify mechanisms that regulate the activation and expansion of high avidity CD8+ T cells in response to virus infection in the lung. The difficulty in the development of protective vaccines for a number of clinically relevant respiratory viruses suggests that our understanding of the parameters that promote a protective immune response in the lung is incomplete. It has been shown previously that high avidity CD8+ T cells, which recognize low levels of antigenic peptide, are very potent immune cells since they recognize target cells at earlier times after infection and lyse infected cells more rapidly than low avidity cells. Thus the presence of high avidity cells is a key component of an optimal antiviral response. Our published data indicate that at early times after infection (d3) of the respiratory tract with the paramyxovirus simian virus 5 or the poxvirus vaccinia virus, the CD8+ T cell response is almost exclusively high avidity. However, at later times after infection (d5), low avidity cells are readily detected, comprising 50-60% of the total responding cells. Analysis of the CD8+ effector cells present in the lung identified a progressive loss in the ability of high avidity cells at this site to secrete IFN?, or lyse cells in response to stimulation. Loss of function selectively in high avidity cells is a novel form of immunosuppression. In aim 1, we will determine the extent of the functional deficit in the high avidity cells and whether low avidity cells demonstrate defects consistent with the early stages of the induction of nonresponsiveness. Subsequent studies will investigate the mechanism responsible for the change in function. Finally we will test the hypothesis that changes over time in the inflammatory environment present in the lung, e.g. cytokines and nitric oxide, are responsible for the induction of nonresponsiveness in high avidity cells. The studies in aim 2 analyze the generation of the anti-viral CD8+ T cell response in the draining lymph node. We will test the hypothesis that the high avidity cells detected at early times postinfection can give rise to low avidity ceils present at later times. In addition we will test the hypothesis that the level of peptide presented or the antigen presenting cell present at various times post infection controls the selective presence of high avidity anti-viral CD8+ T cells at early times (d3) postinfection. Given the emerging threat of the aerosolized delivery of bioterrorism agents (including viruses) on the battlefield, it is of the utmost importance that we increase our understanding of the immune response elicited following respiratory infection and mechanisms by which these pathogens can suppress that response. Results from these studies should provide information that will promote development of new vaccines that will provide optimal protection against respiratory pathogens.
我们工作的总体目标是确定调节高亲和力CD8+T细胞激活和扩张的机制,以应对肺部病毒感染。为一些临床相关的呼吸道病毒开发保护性疫苗的困难表明,我们对促进肺部保护性免疫反应的参数的理解是不完整的。以往的研究表明,高亲和力CD8+T细胞识别低水平的抗原肽,是一种非常有效的免疫细胞,因为它们在感染后较早识别靶细胞,并比低亲和力细胞更快地溶解感染细胞。因此,高亲和力细胞的存在是最佳抗病毒反应的关键组成部分。我们发表的数据表明,在呼吸道感染副粘病毒猴病毒或痘病毒痘苗病毒后的早期(D3),CD8+T细胞反应几乎完全是高亲和力的。然而,在感染后的较晚时间(D5),很容易检测到低亲和力的细胞,占总反应细胞的50%-60%。对肺中存在的CD8+效应细胞的分析表明,该部位的高亲和力细胞分泌干扰素的能力逐渐丧失,或对刺激做出反应的溶解细胞。高亲和力细胞选择性丧失功能是一种新的免疫抑制形式。在目标1中,我们将确定高亲和力细胞的功能缺陷的程度,以及低亲和力细胞是否表现出与诱导无反应的早期阶段一致的缺陷。随后的研究将探讨导致功能变化的机制。最后,我们将检验这一假说,即随着时间的推移,肺部炎症环境的变化,如细胞因子和一氧化氮,是诱导高亲和力细胞无反应性的原因。目的2的研究分析引流淋巴结中抗病毒CD8+T细胞反应的产生。我们将检验这一假设,即在感染后早期检测到的高亲和力细胞可以导致稍后出现的低亲和力细胞。此外,我们还将检验这样一种假设,即感染后不同时间呈现的多肽或抗原呈递细胞控制着感染早期(D3)高亲和力抗病毒CD8+T细胞的选择性存在。鉴于战场上新出现的雾化运送生物恐怖主义制剂(包括病毒)的威胁,我们必须加深对呼吸道感染后引发的免疫反应以及这些病原体抑制这种反应的机制的了解。这些研究的结果应该提供信息,以促进新疫苗的开发,从而提供对呼吸道病原体的最佳保护。

项目成果

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Martha Ann Alexander-Miller其他文献

Martha Ann Alexander-Miller的其他文献

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{{ truncateString('Martha Ann Alexander-Miller', 18)}}的其他基金

Development of vaccine approaches to elicit broadly protective influenza-specific immune responses in infants
开发疫苗方法以在婴儿中引发广泛保护性的流感特异性免疫反应
  • 批准号:
    10229523
  • 财政年份:
    2020
  • 资助金额:
    $ 32.29万
  • 项目类别:
Development of vaccine approaches to elicit broadly protective influenza-specific immune responses in infants
开发疫苗方法以在婴儿中引发广泛保护性的流感特异性免疫反应
  • 批准号:
    10456073
  • 财政年份:
    2020
  • 资助金额:
    $ 32.29万
  • 项目类别:
Immune regulation by pneumococcus
肺炎球菌的免疫调节
  • 批准号:
    9317155
  • 财政年份:
    2017
  • 资助金额:
    $ 32.29万
  • 项目类别:
Regulation of avidity in T lymphocytes
T 淋巴细胞亲合力的调节
  • 批准号:
    9039367
  • 财政年份:
    2016
  • 资助金额:
    $ 32.29万
  • 项目类别:
Regulation of avidity in T lymphocytes
T 淋巴细胞亲合力的调节
  • 批准号:
    9199573
  • 财政年份:
    2016
  • 资助金额:
    $ 32.29万
  • 项目类别:
Vaccination strategies to overcome immune deficiencies in neonates
克服新生儿免疫缺陷的疫苗接种策略
  • 批准号:
    8840143
  • 财政年份:
    2012
  • 资助金额:
    $ 32.29万
  • 项目类别:
Vaccination strategies to overcome immune deficiencies in neonates
克服新生儿免疫缺陷的疫苗接种策略
  • 批准号:
    8477124
  • 财政年份:
    2012
  • 资助金额:
    $ 32.29万
  • 项目类别:
Vaccination strategies to overcome immune deficiencies in neonates
克服新生儿免疫缺陷的疫苗接种策略
  • 批准号:
    8668895
  • 财政年份:
    2012
  • 资助金额:
    $ 32.29万
  • 项目类别:
Vaccination strategies to overcome immune deficiencies in neonates
克服新生儿免疫缺陷的疫苗接种策略
  • 批准号:
    8319130
  • 财政年份:
    2012
  • 资助金额:
    $ 32.29万
  • 项目类别:
Cellular Immune Responses to Respiratory Infection
对呼吸道感染的细胞免疫反应
  • 批准号:
    7371984
  • 财政年份:
    2004
  • 资助金额:
    $ 32.29万
  • 项目类别:

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    2339172
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    2024
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Machine Learning of Disease Biomarkers from B and T cell Receptor Repertoires
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T 细胞受体信号传导对记忆 CD8 T 细胞干性的影响
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    10676407
  • 财政年份:
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T细胞受体交叉反应性和病毒免疫逃逸的结构基础
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