Human T cell-mediated immunity to viruses in tissues and circulation

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PROJECT 1: PROJECT SUMMARY Understanding anti-viral immunity in humans requires investigating the complexity of the human immune response—sampling diverse groups of individuals, and studying immune responses where they function and are maintained in tissue sites throughout the body. T cells coordinate anti-viral adaptive immunity through their activation and differentiation in lymphoid tissues, subsequent migration to tissue sites of infection, and their long-term maintenance as virus-specific memory T cell subsets in circulation and in diverse tissue sites. The majority of memory T cells throughout the body are non-circulating, tissue-resident memory T (TRM) cells which can mediate protective immunity, as demonstrated in mouse models, and are therefore important for understanding and targeting anti-viral immunity. Studying TRM is challenging in humans where blood remains the most readily sampled and studied site. Over 10 years ago, my laboratory set up a human tissue resource to obtain multiple lymphoid and mucosal tissues from individual organ donors, and have optimized the study of immune cells from over 500 donors, revealing precise tissue-regulated compartmentalization and site-specific adaptations. In our studies under the current HIPC award, we identified how T cells-specific for ubiquitous viruses are distributed and function in tissues, with an initial focus on cytomegalovirus (CMV)--later extended to influenza-specific and more recently to SARS-CoV-2-specific immunity. Our results reveal virus-specific adaptive immune responses are controlled on multiple levels—by the virus itself, including its pathogenesis and tissue targets, the tissue site which influences T cell functionality, age which correlates with T cell differentiation and dissemination, and sex-specific variations. Our central hypothesis is that the virus, tissue, age and sex direct specific and measurable influences on the anti-viral T cell response that together influence its functionality and protective efficacy. In the proposed study, we will apply systems-wide approaches to analyze the complexity and heterogeneity of the human T cell response through a comprehensive assessment of their profiles across blood and tissues. In Aim 1 we will quantify the contribution of virus type, tissue, age, and sex in anti-viral T cell phenotypes, and understanding how these factors interact in predictive models for human T cell immunity. In aim 2, we will analyze virus-specific T cell functional states and clonal signatures across diverse tissue sites to address how virus-specific T cells integrate both site- and virus-specific features into their clonal and functional signatures. We will use combinatorial single cell profiling by CITE-Seq with determination of paired T cell receptor clone sequences of CMV-, influenza-, and SARS-CoV-2-responding CD4+ and CD8+T cells following stimulation with viral epitope pools. Functional and tissue-specific signatures will be validated by cytokine analysis and tissue imaging by the immune assay core, to identify cell-cell interactions as additional features of virus-specific T cells in tissues. Together, the proposed studies will provide a functional map of anti-viral T cell immunity across multiple tissues and virus specificities.