Human organoids with an autologous tissueresident immune compartment

• Published in: Nature (London) Vol. 633; no. 8028; pp. 165 - 4
• Main Authors: Recaldin, Timothy, Steinacher, Linda, Gjeta, Bruno, Harter, Marius F, Adam, Lukas, Kromer, Kristina, Mendes, Marisa Pimentel, Bellavista, Marina, Nikolaev, Mikhail, Lazzaroni, Giacomo, Krese, Rok, Kilik, Umut, Popovic, Doris, Stoll, Bilgenaz, Gerard, Regine, Bscheider, Michael, Bickle, Marc, Cabon, Lauriane, Camp, J Gray, Gjorevski, Nikolche
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 05.09.2024
• Subjects: Autoimmune diseases; Biological effects; CD4 antigen; CD8 antigen; Cell culture; Cell migration; Cytokines; Cytotoxicity; Effector cells; Epithelial cells; Epithelium; Extracellular matrix; Flow cytometry; Homeostasis; Immune system; Immunological memory; Immunotherapy; Inflammation; Intestine; Lymphatic system; Lymphocytes; Lymphocytes T; Memory cells; Organoids; Perturbation; Physiology; Stem cells; T cell receptors; Target acquisition; Tissues; Transcriptomics; Tumorigenesis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-07791-5

The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer13. 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 biologies 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-l-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.