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: 9319117
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319117
• 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; Data; Development; Event; Generations; Genetic Transcription; Host Defense; Human; Immune response; Immune system; Immunity; Immunologic Memory; In Vitro; Individual; Infection; Inflammation; Influenza; Maintenance; Mature T-Lymphocyte; Measures; Messenger RNA; Methods; Modeling; Mus; Peripheral; Plasticizers; 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; immune function; 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（由申请方提供）：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。我们最近开发了一种技术，可以检测和测序来自小鼠和人类单细胞的配对T细胞受体的信息。该方法允许两个重要的观察结果：1）转录两个Tcra链的信息的细胞的比例在急性和记忆免疫应答的过程中显著变化，和2）体内T细胞的克隆谱系证明了外周中受体修正的证据。采用创新的体外单细胞培养平台， 在包括条件性RAG缺陷小鼠的体内模型和一组有价值的纵向人类样本中，我们建议扩展这些观察以评估对病毒感染的最佳T细胞应答需要固有的可塑性外周库的假设。我们的三 目的是测试以下特定假设：1）双TCR等位基因表达通过干扰框内等位基因转录和/或TCR：CD 3组装来调节TCR信号强度和功能性T细胞活性，2）外周TCR修订在大多数幼稚T细胞中由强TCR信号传导诱导，3）双重等位基因表达和修订都是急性和慢性感染（流感和mCMV）中最佳T细胞活性所需的。这些研究结合了联合收割机一套新的体外技术和体内模型，将导致对最佳抗病毒T细胞应答如何产生和调节的新理解，对我们理解适应性免疫具有广泛的意义。

项目成果

Past Life and Future Effects-How Heterologous Infections Alter Immunity to Influenza Viruses.

• DOI: 10.3389/fimmu.2018.01071
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Souquette A;Thomas PG
• 通讯作者: Thomas PG

Diverse heterologous primary infections radically alter immunodominance hierarchies and clinical outcomes following H7N9 influenza challenge in mice.

• DOI: 10.1371/journal.ppat.1004642
• 发表时间: 2015-02
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Duan S;Meliopoulos VA;McClaren JL;Guo XZ;Sanders CJ;Smallwood HS;Webby RJ;Schultz-Cherry SL;Doherty PC;Thomas PG
• 通讯作者: Thomas PG

Hitting the Target: How T Cells Detect and Eliminate Tumors.

• DOI: 10.4049/jimmunol.1701413
• 发表时间: 2018-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zamora AE;Crawford JC;Thomas PG
• 通讯作者: Thomas PG

Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8⁺ T cells.

严重 H7N9 疾病的恢复与 CD8 T 细胞主导的多种反应机制有关

• DOI: 10.1038/ncomms7833
• 发表时间: 2015-05-13
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Wang, Zhongfang;Wan, Yanmin;Qiu, Chenli;Quinones-Parra, Sergio;Zhu, Zhaoqin;Loh, Liyen;Tian, Di;Ren, Yanqin;Hu, Yunwen;Zhang, Xiaoyan;Thomas, Paul G.;Inouye, Michael;Doherty, Peter C.;Kedzierska, Katherine;Xu, Jianqing
• 通讯作者: Xu, Jianqing

Balancing Immune Protection and Immune Pathology by CD8(+) T-Cell Responses to Influenza Infection.

• DOI: 10.3389/fimmu.2016.00025
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Duan S;Thomas PG
• 通讯作者: Thomas PG