Project 3: T Cells

项目3：总结 新冠肺炎目前是一种全球大流行，但人类T细胞反应有助于提高肺炎的数量和质量 SARS-CoV-2特异性抗体，或通过细胞毒机制作用于受感染的细胞，仍然知之甚少。 在这个U54项目中，我们将研究血液和呼吸道粘膜中的病毒特异性T细胞免疫 病毒可能引发感染的组织。我们还将比较对自然感染的反应与 在早期临床试验中由多肽疫苗产生的疫苗，以及在此5-5期间批准的其他疫苗- 一年的学习。我们的团队之前开发了一套创新的、高通量的技术和 能够分析TCRα-β序列、转录图谱和 人类样本中原始T细胞的表观遗传状态，提供了T细胞特异性的全面视图 和分子表型。我们假设对SARS-CoV-2免疫的一个关键成分是抗原- T细胞反应的特异性、表型和表观遗传持久性，本研究的目的是测量 这些组件使用高通量基因组工具来告知临床保护性免疫和 设计有效的疫苗接种策略。在第一个目标中，我们将建立一个全面的TCR数据库 SARS-CoV-2及其变种的特异性，以识别与疾病相关的私有和共享TCR特异性 反应和豁免权。在第二个目标中，我们将TCR的特异性与转录和表观遗传配对 SARS-CoV-2特异性T细胞表型以确定病毒特异性T细胞反应的免疫类型。在 第三个目的，我们将研究由X染色体失活引起的淋巴细胞表观遗传学变化在 新冠肺炎免疫中的性别偏见。我们将在几个大的患者队列的背景下实现这些目标 由临床病毒学中心开发的新冠肺炎患者、恢复期捐赠者和健康受试者，以及所有 将与项目1合作，将T细胞反应数据与血清学和B细胞测量相结合 总而言之，我们的研究将指导我们努力理解：(1)抗原特异性的多样性和特异性 新冠肺炎患者的T细胞反应，(2)恢复期T细胞记忆的表型和持久性 个人，(3)T和B细胞对SARS-CoV-2的反应之间的关系，以及(4)T细胞反应 与自然感染相比，接种疫苗会产生刺激作用。

PROJECT 3: SUMMARY COVID-19 is currently a global pandemic, but human T cell responses contributing to the quantity and quality of SARS-CoV-2 specific antibodies, or acting by cytotoxic mechanisms on infected cells, remain poorly understood. In this U54 Project, we will study virus-specific T cell immunity in the blood as well as the respiratory mucosal tissues where the virus is likely to initiate infection. We will also compare responses to natural infection with those generated by a peptide-based vaccine in early clinical trials, and in other vaccines approved during this 5- year study. Our groups have previously developed a suite of innovative, high-throughput technologies and computational algorithms to enable the analysis of TCR alpha beta sequences, transcriptional profiles, and epigenetic states in primary T cells from human samples, providing a comprehensive view of T cell specificity and molecular phenotype. We hypothesize that a critical component of immunity to SARS-CoV-2 is the antigen- specificity, phenotype, and epigenetic durability of the T cell response, and the goal of this study is to measure these components using high-throughput genomic tools to inform clinical profiles of protective immunity and the design of effective vaccination strategies. In the first aim, we will build a comprehensive database of  TCRs specific for SARS-CoV-2 and its variants to identify private and shared TCR specificities associated with disease response and immunity. In the second aim, we will pair TCR specificities with transcriptional and epigenetic phenotypes in SARS-CoV-2-specific T cells to identify immunotypes of the virus-specific T cell response. In the third aim, we will investigate the role of epigenetic changes due to X chromosome inactivation in lymphocytes in sex bias in COVID-19 immunity. We will pursue these aims in the context of several large patient cohorts of COVID-19 patients, convalescent donors, and healthy subjects developed by the Clinical Virology Core, and all T cell response data will be integrated with serology and B cell measurements in collaboration with Projects 1 and 2. Altogether, our studies will guide efforts to understand: (1) the diversity and specificity of antigen-specific T cell responses in COVID-19 patients, (2) the phenotypes and durability of T cell memory in recovered individuals, (3) relationships between T and B cell responses to SARS-CoV-2, and (4) T cell responses stimulated by vaccination compared to natural infection.