Project 3: T Cells

项目3：概要 COVID-19目前是一种全球性大流行病，但人类T细胞反应有助于提高免疫应答的数量和质量。 SARS-CoV-2特异性抗体，或通过细胞毒性机制作用于感染细胞，仍然知之甚少。 在这个U 54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， 在早期临床试验中由基于肽的疫苗产生的那些，以及在这5年期间批准的其他疫苗中产生的那些， 年研究。我们的团队以前开发了一套创新的高通量技术， 计算算法，使分析TCR α β序列，转录谱， 来自人类样本的原代T细胞中的表观遗传状态，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免疫的关键成分是抗原- 特异性、表型和T细胞反应的表观遗传持久性，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保护性免疫的临床概况， 制定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乳腺癌TCR数据库 特异于SARS-CoV-2及其变体，以识别与疾病相关的私有和共享TCR特异性 反应和免疫力。在第二个目标中，我们将TCR特异性与转录和表观遗传配对， SARS-CoV-2特异性T细胞中的表型，以鉴定病毒特异性T细胞应答的免疫型。在 第三个目的，我们将研究由于X染色体失活在淋巴细胞中引起的表观遗传变化在 COVID-19免疫力的性别偏见。我们将在几个大型患者队列的背景下追求这些目标， 由临床病毒学核心开发的COVID-19患者、康复期供体和健康受试者，以及所有 T细胞应答数据将与血清学和B细胞测量结合，与项目1合作 和2.总之，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 COVID-19患者的T细胞反应，（2）恢复期患者T细胞记忆的表型和持久性 个体，（3）T和B细胞对SARS-CoV-2应答之间的关系，以及（4）T细胞应答 与自然感染相比，接种疫苗刺激。

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.