The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer^1,2,3. 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 (T_RM) cells, a portion of which integrate within the epithelium and continuously survey the barrier. T_RM cell migration and interaction with epithelial cells was orchestrated by T_RM 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.

上皮细胞和免疫系统之间的密切关系对于维持组织稳态至关重要，其中的扰动与自身免疫性疾病和癌症有关^1,2,3 。尽管干细胞衍生的类器官是上皮功能的强大模型⁴ ，但它们缺乏捕获器官水平过程所必需的组织驻留免疫细胞。我们描述了人类肠道免疫类器官（IIO），它是通过上皮类器官和自体组织驻留记忆 T（ _TRM ）细胞的自组织形成的，其中一部分整合在上皮内并持续调查屏障。 T _RM细胞迁移以及与上皮细胞的相互作用是由控制细胞运动和粘附的 T _RM细胞富集转录组程序精心策划的。我们结合 IIO 和单细胞转录组学来研究患者癌症靶向生物制剂引发的肠道炎症。炎症与激活的 CD8 ⁺ T 细胞群的出现有关，这些细胞逐渐获得上皮内和细胞毒性特征。该效应细胞群体的出现先于辅助性 T 1 样 CD4 ⁺群体出现并得到增强，该群体最初产生细胞因子，随后自身产生细胞毒性。作为一个易于直接扰动的系统，IIO 使我们能够将 Rho 通路确定为减轻免疫治疗相关肠道炎症的新靶标。鉴于它们概括了表型结果和潜在的谱系间免疫相互作用，IIO 可用于研究肿瘤发生、传染性和自身免疫性疾病背景下的组织驻留免疫反应。