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Human immune organoids: a tool to study vaccine responses

Nature Reviews Immunology volume 23, page 699 (2023)Cite this article

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Technological advances have markedly improved our ability to quantify and understand human immune responses to vaccines and pathogens. Sampling peripheral blood is both informative and practical, and by far the most common source of human immunology data. However, several central processes that initiate and regulate adaptive immunity are restricted to lymphoid tissue sites, such as the lymph nodes, tonsils and spleen. Animal models provide a solid foundational understanding of these events, but pre-clinical studies continue to poorly predict the magnitude and quality of vaccine responses in humans. A better understanding of human lymphoid tissue biology and the inner workings of the responding cells during a productive adaptive immune response will be crucial to inform rational vaccine and adjuvant design. To work towards this goal, we developed an in vitro immune organoid system, derived from readily available primary human lymphoid tissues (tonsils), that recapitulates several essential features of the adaptive immune response.

The preparation of immune organoids is relatively straightforward for scientists skilled in primary cell culture. Single-cell suspensions are made from dissociated lymphoid tissues. Conveniently, the suspensions can be cryopreserved with limited effects on cell composition. Cells are plated at high density in a low-attachment device to encourage cell-to-cell interactions and then treated with antigens to initiate the adaptive immune response. Over the first few days, cell reaggregation occurs and anecdotally, we observe more intense and rapid cell clustering with robust responses. Using a series of standard immunological assays (flow cytometry, single-cell RNA sequencing with immune repertoire analysis, ELISA and microneutralization), we showed that organoids supported affinity maturation, the production of virus-specific neutralizing antibodies, and antigen-specific T cell expansion to influenza vaccines and viruses1. Importantly, the established system is amenable to manipulation using routine methods such as cell sorting. Using depletion experiments, we determined the relative roles of individual cell types (including plasmacytoid dendritic cells, naive and memory B and T cells) in the specific antibody response and our findings closely matched our current understanding of their defined functions.

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  1. Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021)

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  2. Kastenschmidt, J. M. et al. Influenza vaccine format mediates distinct cellular and antibody responses in human immune organoids. Immunity 56, 1910–1926.e7 (2023)

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Authors and Affiliations

  1. Department of Physiology & Biophysics, University of California Irvine, Irvine, CA, USA

    Lisa E. Wagar

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  1. Lisa E. Wagar
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Correspondence to Lisa E. Wagar.

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Competing interests

L.E.W. is a co-inventor on a US patent (US-20230235284-A1) describing the immune organoid technology.

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Wagar, L.E. Human immune organoids: a tool to study vaccine responses. Nat Rev Immunol 23, 699 (2023). https://doi.org/10.1038/s41577-023-00956-9

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  • DOI: https://doi.org/10.1038/s41577-023-00956-9

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