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（由申请人提供）：与 B 细胞相反，一旦完全成熟的 T 细胞离开胸腺，T 细胞受体库通常被认为是固定的。我们最近开发了检测和测序配对信息的技术。 ¿这种方法获得了两个重要的观察结果：1）在急性和记忆免疫反应过程中，转录两条 Tcra 链信息的细胞比例发生显着变化；2）T 细胞的克隆谱系。使用创新的体外单细胞培养平台，证明了外周受体修复的证据。 体内模型，包括条件性 RAG 缺陷小鼠和一组有价值的纵向人类样本，我们建议扩展这些观察结果，以评估以下假设：对病毒感染的最佳 T 细胞反应需要固有的可塑性外周库。 旨在测试以下具体假设：1) 双 TCR¿等位基因表达通过干扰框内等位基因转录和/或 TCR:CD3 组装来调节 TCR 信号强度和功能性 T 细胞活性，2) 在大多数情况下诱导外周 TCR 修正3) 在急性和慢性感染（流感和 mCMV）中，双等位基因表达和修正都是最佳 T 细胞活性所必需的，这些结合了一系列新颖的体外技术和体内模型的研究。导致人们对最佳抗病毒 T 细胞反应如何产生和调节有了新的认识，这对我们对适应性免疫的理解具有广泛的影响。