Human anti-viral immune responses in tissues and circulation

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OVERALL: PROGRAM SUMMARY Human immune responses to viral infection and vaccination engage a complex, multi-scale system involving numerous diverse cellular populations residing in and circulating between tissues. The Columbia HIPC Center has established a framework for human immunology studies that includes a unique tissue resource where lymphoid, mucosal and peripheral tissue are obtained from individual organ donors, vaccine cohorts treated with immunomodulatory therapies, and technology for single-cell genomics, imaging, and computational biology. The overall goal of the Center is to obtain in-depth profiles of human innate and adaptive immune cells in response to viral pathogens (including influenza, CMV, and SARS-CoV-2) and vaccine antigens in both tissues and circulation, to provide a comprehensive assessment of the human immune response across the body and over age. In Project 1 (PI: D. Farber), we will quantitatively analyze the contributions of virus type, tissue, age, and sex on human anti-viral T cell immunity and define the functional states and clonal signatures of T cells in diverse tissue sites with single-cell resolution. Project 2 (PI: B. Reizis) will produce a comprehensive characterization of human dendritic cell composition and function in tissues and circulation in the context of anti-viral immune responses and vaccination. In Project 3 (PI: P. De Jager), we will leverage a cohort of multiple sclerosis patients treated with molecularly targeted drugs that selectively perturb immune populations in a compartment-specific fashion. By following this cohort longitudinally through multiple cycles of vaccination with sophisticated molecular profiling and single-cell analysis, we will answer fundamental questions about the role of circulating and tissue-resident lymphocytes in maintaining T cell function and responses to vaccines. All of these projects will be supported by five cores. The Administrative Core will coordinate inter- and intra-center communication and collaboration, while managing financial aspects of the Center. The Single Cell Core will provide state-of-the-art protocols and technologies for single-cell genomics, including CITE-seq, scTCR-seq, scPLATE-seq, and a new technique for linking antigen-specificity with CITE- seq and scTCR-seq of individual T cells called TetTCR-seqHD. The Immune Assay and Imaging Core will provide quantitative analysis of antibodies and high-dimensional imaging technologies for spatial analysis of gene signatures and cell-cell interactions in situ. The Clinical Core will organize tissue and patient cohort resources, distributing tissue specimens and blood to project investigators. Finally, the Data Management and Analysis Core (DMAC) will offer innovative computational tools for systems-level and single-cell analysis; infrastructure for computing, data storage, and data curation; and tools for data sharing to ensure the long-term impact of the Center’s efforts. Together, the Columbia HIPC will uncover new insights into human immunity and produce valuable data resources and reference maps for defining human immune responses across the body and the human population.