Human organoids with an autologous tissue-resident immune compartment

Timothy Recaldin, Linda Steinacher, Bruno Gjeta, Marius F. Harter, Lukas Adam, Kristina Kromer, Marisa Pimentel Mendes, Marina Bellavista, Mikhail Nikolaev, Giacomo Lazzaroni, Rok Krese, Umut Kilik, Doris Popovic, Bilgenaz Stoll, Régine Gerard, Michael Bscheider, Marc Bickle, Lauriane Cabon (), J. Gray Camp () and Nikolche Gjorevski ()
Additional contact information
Timothy Recaldin: Roche Pharma Research and Early Development
Linda Steinacher: Roche Pharma Research and Early Development
Bruno Gjeta: Roche Pharma Research and Early Development
Marius F. Harter: Roche Pharma Research and Early Development
Lukas Adam: Roche Pharma Research and Early Development
Kristina Kromer: Roche Pharma Research and Early Development
Marisa Pimentel Mendes: Roche Pharma Research and Early Development
Marina Bellavista: Roche Pharma Research and Early Development
Mikhail Nikolaev: Roche Pharma Research and Early Development
Giacomo Lazzaroni: Roche Pharma Research and Early Development
Rok Krese: Roche Pharma Research and Early Development
Umut Kilik: Roche Pharma Research and Early Development
Doris Popovic: Roche Pharma Research and Early Development
Bilgenaz Stoll: Roche Pharma Research and Early Development
Régine Gerard: Roche Pharma Research and Early Development
Michael Bscheider: Roche Pharma Research and Early Development
Marc Bickle: Roche Pharma Research and Early Development
Lauriane Cabon: Roche Pharma Research and Early Development
J. Gray Camp: Roche Pharma Research and Early Development
Nikolche Gjorevski: Roche Pharma Research and Early Development

Nature, 2024, vol. 633, issue 8028, 165-173

Abstract: Abstract The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer1–3. Whereas stem cell-derived organoids are powerful models of epithelial function4, they lack tissue-resident immune cells that are essential for capturing organ-level processes. We describe human intestinal immuno-organoids (IIOs), formed through self-organization of epithelial organoids and autologous tissue-resident memory T (TRM) cells, a portion of which integrate within the epithelium and continuously survey the barrier. TRM cell migration and interaction with epithelial cells was orchestrated by TRM cell-enriched transcriptomic programs governing cell motility and adhesion. We combined IIOs and single-cell transcriptomics to investigate intestinal inflammation triggered by cancer-targeting biologics in patients. Inflammation was associated with the emergence of an activated population of CD8+ T cells that progressively acquired intraepithelial and cytotoxic features. The appearance of this effector population was preceded and potentiated by a T helper-1-like CD4+ population, which initially produced cytokines and subsequently became cytotoxic itself. As a system amenable to direct perturbation, IIOs allowed us to identify the Rho pathway as a new target for mitigation of immunotherapy-associated intestinal inflammation. Given that they recapitulate both the phenotypic outcomes and underlying interlineage immune interactions, IIOs can be used to study tissue-resident immune responses in the context of tumorigenesis and infectious and autoimmune diseases.

Date: 2024
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DOI: 10.1038/s41586-024-07791-5

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