Human dendritic cell localization and anti-viral function in tissue sites

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PROJECT 2: PROJECT SUMMARY Dendritic cells (DCs) are key immune sentinels that link innate recognition to adaptive immunity against pathogens, thereby initiating T and B cell responses. The DC lineage comprises two major subsets, type I interferon-producing plasmacytoid DCs (pDCs) and antigen-presenting conventional or classical DCs (cDCs). The exact subset composition and functional state of DC populations is specific for each organ/tissue, reflecting unique local immune environments. The parameters of DC function that correlate with protective versus pathogenic responses are still poorly understood. Furthermore, the location and functionality of DC populations in tissues and lymphoid organs has not been interrogated within the entire human body. In the first cycle of the project, we found that human pDCs respond differently to free viruses and virus-infected cells; compared to the former, the response to the latter is characterized by sustained production of type I and type III interferons and diminished production of inflammatory cytokines. The overall goal of the current project is a comprehensive characterization of human DC composition and function, specifically as it relates to immune responses to antiviral vaccines. We hypothesize that the type of pDC response (interferon-focused vs inflammatory cytokine-focused) is an important parameter of anti- viral/anti-vaccine immune responses that may correlate with and/or predict protective T cell and antibody responses. To test this notion, in Aim 1 we will build a universal reference map of pDC activation and test the ability of pDCs to mount interferon-focused and polyfunctional responses in subjects undergoing vaccination against influenza or COVID-19. We further posit that DC functionality may be shaped by specific tissue environments within the same individual. To explore this, in Aim 2 we will use high-dimensional immunochemistry to identify the location and cellular interactions of DC subsets in tissues and lymphoid organs, and combine the results with single-cell transcriptomics and the analysis of cytokine responses. Collectively, these studies would yield a comprehensive view of the composition, tissue diversity and functionality of the human DC compartment. They would also provide insights into the role and mechanism of cytokine responses by DCs in protective immune responses to virus infections.