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中文摘要
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T细胞通过其T细胞受体(TCR)识别抗原是诱导免疫应答中的重要事件。 适应性免疫反应TCR识别抗原表面上的外源肽/MHC复合物 然而,自身肽/MHC复合物也起关键作用。这些自身pMHC相互作用 是胸腺中T细胞产生MHC限制性库的阳性选择所需的,而阴性选择是必需的。 选择以清除自身反应性T细胞的库。在外周T细胞中,TCR:自身-pMHC相互作用是 对于生存、设定信号阈值和对外来抗原的反应至关重要。的TCR 自身-pMHC复合物的识别本质上是弱的,但仍然导致T细胞中的信号传导事件。的APC 例如树突状细胞在其表面上表达数千种不同的自身pMHC复合物, 研究T细胞中刺激信号的性质。我们的新方法利用TCR, 对自身pMHC的独特亲和力,这将使我们能够鉴定出增强T细胞运动性的自身pMHC, 体内反应。具体地,我们已经产生了两个TCR转基因小鼠,LLO 56和LLO 118,它们都 识别免疫显性李斯特菌表位(LLO)。研究这两种T细胞的优势在于, 对李斯特菌感染有不同的体内反应。此外,这个中心点 LLO 118和LLO 56的固有敏感性由自身pMHC设定和维持, LL 056 T细胞具有更强的自身pMHC相互作用。我们最初的体内实验表明, 它们在淋巴组织中的转运时间的差异,指出自我肽的识别是主要的 T细胞运动性的决定因素。这个提议测试的假设是,有一组自我pMHC显示, 在APC上,其在体内与LLO 56和LLO 118 T细胞产生特异性但弱的相互作用。这些 这种相互作用设定了信号传导阈值,并且对于T细胞功能和存活至关重要。为了验证这一 假设,提出了两个具体目标。在目标1中,我们提出鉴定增强T:DC的自身pMHCs 在没有抗原的情况下相互作用。我们已经开发了一种新的迷你自我pMHC库系统, 我们可以在DC上表达3至9个确定的共价连接的自身pMHC作为仅有的II类分子。我们将 使用双光子显微镜测试一系列(多达30个)自体pMHC在体内减缓 LL 0 56或LL 0 118 T细胞。在目标2中,我们将确定的特异性和在体内的功能后果, 自身pMHC:T细胞相互作用。将分析目标1中鉴定的活性自身pMHC如何特异性地 它们被T细胞识别。然后将研究活性自身pMHC增强免疫调节的能力。 对外来抗原的体内应答。通过识别一个活跃的自身pMHC,在未来的研究中,使用这种定义的 系统,这些自我pMHC诱导的T细胞的信号通路可以阐明。知道这些 通路以及它们是如何被激活的,可能会导致T 细胞存活和功能。
英文摘要
The recognition of antigen by a T cell through its T cell receptor (TCR) is a seminal event in the induction of an adaptive immune response. The TCR recognizes a foreign peptide/MHC complex on the surface of an antigen presenting cell; however, self-peptide/MHC complexes also play a critical role. These self-pMHC interactions are needed for positive selection of T cells in the thymus to generate a MHC restricted repertoire and negative selection to purge the repertoire of self-reactive T cells. In peripheral T cells TCR:self-pMHC interactions are critical for survival, for setting signaling thresholds, and for responses to foreign antigens. The TCR recognition of self-pMHC complexes is weak in nature, but still results in signaling events in the T cell. An APC such as a dendritic cell expresses thousands of different self-pMHC complexes on its surface, complicating the investigation of the nature of the signals stimulated in the T cell. Our novel approaches leverage TCRs with distinct affinities for a self-pMHC, which will allow us to identify a self-pMHC that augments T cell motility and responses in vivo. Specifically, we have generated two TCR transgenic mice, LLO56 and LLO118, which both recognize the immunodominant Listeria epitope (LLO). The advantage of studying these two T cells is that they have distinct in vivo behaviors in response to Listeria infection. Moreover, and a central point for this application, is that the intrinsic sensitivity of LLO118 and LLO56 is set and maintained by self pMHC, with the LLO56 T cells having stronger self-pMHC interactions. Our initial in vivo experiments indicate marked differences in their transit times in lymphoid tissues, pointing to the recognition of self peptides as a major determinant of T cell motilities. The hypothesis this proposal tests is that there is a set of self-pMHC displayed on an APC, which make specific, but weak, interactions with LLO56 and LLO118 T cells in vivo. These interactions set the signaling threshold and are essential for T cell function and survival. To test this hypothesis, two specific aims are proposed. In aim 1, we propose to Identify self-pMHCs that potentiate T:DC interactions in the absence of antigen. We have developed a novel mini-self-pMHC repertoire system in which we can express 3 to 9 defined covalently linkered self-pMHC as the only class II molecules on a DC. We will test a series (up to 30) of self-pMHC in vivo using 2-photon microscopy for their abilities to slow the motility of LLO56 or LLO118 T cells. In Aim 2, we will determine the specificity and in vivo functional consequences of self-pMHC:T cell interactions. The active self-pMHC identified in Aim 1, will be analyzed for how specifically they are recognized by the T cells. The active self-pMHC will then be studied for their ability to augment an in vivo response to foreign antigen. By identifying an active self-pMHC, in future studies using this defined system, the signaling pathways in T cells induced by these self-pMHC can be elucidated. Knowing these pathways and how they are activated, could lead to the development of pharmacological enhancements for T cell survival and function.
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DEFINING HOST-MICROBIAL INTERACTIONS THAT TRIGGER INFLAMMATORY BOWEL DISEASE
  • 批准号:
    8579066
  • 项目类别:
  • 资助金额:
    $40.03万
  • 财政年份:
    2013
  • 负责人:
    PAUL M ALLEN
  • 依托单位:
DEFINING HOST-MICROBIAL INTERACTIONS THAT TRIGGER INFLAMMATORY BOWEL DISEASE
  • 批准号:
    8874214
  • 项目类别:
  • 资助金额:
    $50.66万
  • 财政年份:
    2013
  • 负责人:
    PAUL M ALLEN
  • 依托单位:
DEFINING HOST-MICROBIAL INTERACTIONS THAT TRIGGER INFLAMMATORY BOWEL DISEASE
  • 批准号:
    8688237
  • 项目类别:
  • 资助金额:
    $38.69万
  • 财政年份:
    2013
  • 负责人:
    PAUL M ALLEN
  • 依托单位:
SPECIFIC RECOGNITION BY CLASS II ALLOREACTIVE T CELLS
  • 批准号:
    8361360
  • 项目类别:
  • 资助金额:
    $2.68万
  • 财政年份:
    2011
  • 负责人:
    PAUL M ALLEN
  • 依托单位:
海外基金