Mechanisms to diversify repertoire and modify T cell activity after infection

感染后 T 细胞活性多样化和改变的机制

• 批准号: 8709989
• 负责人: Paul G. Thomas
• 金额: $ 45.54万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709989
• 关键词: Acute; Age; Alleles; Animals; Antiviral Agents; Autoimmunity; B-Lymphocytes; Bar Codes; Biological; CD3 Antigens; Cell Culture Techniques; Cell Cycle; Cell Lineage; Cells; Chronic; DNA Sequence Rearrangement; Data; Development; Event; Generations; Genetic Transcription; Host Defense; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Inflammation; Influenza; Maintenance; Mature T-Lymphocyte; Measures; Memory; Messenger RNA; Methods; Modeling; Mus; Peripheral; Plastics; Play; Receptor Signaling; Regulation; Reporting; Role; Sampling; Signal Transduction; Stimulus; T cell response; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Thymus Gland; Transgenic Organisms; Viral; Virus; Virus Diseases; adaptive immunity; aged; base; in vivo; in vivo Model; innovation; novel; pathogen; public health relevance; receptor; response; theories

DESCRIPTION (provided by applicant): In contrast to B cells, the T cell receptor repertoire is generally considered fixed once fully mature T cells exit the thymus. We recently developed the technology to detect and sequence the message of paired ¿¿ T cell receptors from single cells in mice and humans. This approach permitted two important observations: 1) the proportion of cells transcribing message for two Tcra chains varies dramatically over the course of acute and memory immune responses and 2) clonal lineages of T cells in vivo demonstrate evidence of receptor revision in the periphery. Using innovative in vitro single cell culture platforms, unique in vivo models including conditional RAG-deficient mice, and a valuable panel of longitudinal human samples, we propose to extend these observations to assess the hypothesis that optimal T cell responses to viral infections require an inherently plastic peripheral repertoire. Our three aims test the specific hypotheses that 1) Dual TCR¿ allele expression regulates TCR signal strength and functional T cell activity by interfering with in frame allele transcription and/or TCR:CD3 assembly, 2) Peripheral TCR revision is induced in most na¿ve T cells by strong TCR signaling and 3) Both dual allele expression and revision are required for optimal T cell activity in acute and chronic infections (influenza and mCMV). These studies combine a suite of novel in vitro technology and in vivo models that will result in a new understanding of how optimal antiviral T cell responses are generated and regulated, with broad implications for our understanding of adaptive immunity.

描述（由适用提供）：与B细胞相比，一旦完全成熟的T细胞退出胸腺，T细胞受体库通常被认为是固定的。我们最近开发了该技术来检测和测序来自小鼠和人类中单细胞的配对„ T细胞受体的信息。这种方法允许两个重要的观察结果：1）在急性和记忆免疫调查的过程中，对两个TCRA链转录信息的细胞比例发生了巨大变化，而2）T细胞在体内的克隆谱系，证明了外周的受体翻修证据。使用创新的体外单细胞培养平台，独特 体内模型，包括条件抹布缺陷的小鼠以及一大批纵向人类样品，我们建议扩展这些观察结果，以评估以下假设：最佳的T细胞对病毒感染的反应需要固有的塑料外周曲线。我们的三个 目的测试特定的假设，即1）双重TCR等位基因表达来调节TCR信号强度和功能性T细胞活性，通过干扰框架等位基因转录和/或TCR：CD3组装，2）在大多数NATCR细胞中诱导了TCR和3个细胞的最佳表达和3），并且在大多数Diual Enlele表达中诱导了外围TCR修订，并且在大多数Diual等位基因表达中都需要进行二重性等位基因的表达（3）均具有。 MCMV）。这些研究结合了一套新型的体外技术和体内模型，这将使​​人们对最佳抗病毒药T细胞反应的产生和调节有了新的了解，这对我们对适应性免疫组织化学的理解产生了广泛的影响。