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.