AbstractThe intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer1,2,3. 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.

摘要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，但它们缺乏对捕获器官水平过程至关重要的组织驻留免疫细胞。

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.

我们描述了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人类肠道免疫类器官（IIO），其中一部分整合在上皮内并不断调查屏障。TRM细胞迁移和与上皮细胞的相互作用是由控制细胞运动和粘附的富含TRM细胞的转录组程序协调的。

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.

我们结合IIOs和单细胞转录组学来研究癌症靶向生物制剂引发的肠道炎症。炎症与CD8+T细胞活化群体的出现有关，CD8+T细胞逐渐获得上皮内和细胞毒性特征。这种效应群体的出现先于T辅助细胞-1样CD4+群体，并得到加强，该群体最初产生细胞因子，随后自身产生细胞毒性。

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..

作为一个适合直接扰动的系统，IIOs使我们能够将Rho途径鉴定为缓解免疫治疗相关肠道炎症的新靶点。鉴于它们概括了表型结果和潜在的系间免疫相互作用，IIO可用于研究肿瘤发生以及传染性和自身免疫性疾病背景下的组织驻留免疫反应。。

MainOrganoids originating from adult stem cells model important aspects of human physiology and have applications in research related to genetic disorders, infectious disease, cancer, regenerative medicine and drug discovery4. However, they are epithelial-only structures, whereas native organs comprise multiple other compartments, including specialized immune cells that have essential roles in homeostasis and disease5,6.

源自成体干细胞的主要类器官模拟了人类生理学的重要方面，并在与遗传疾病，传染病，癌症，再生医学和药物发现相关的研究中有应用4。然而，它们是仅上皮结构，而天然器官包含多个其他区室，包括在体内平衡和疾病中具有重要作用的特殊免疫细胞5,6。

For example, the intestinal mucosal immune system—the largest pool of immune cells in the human body7—ensures homeostasis by perpetual policing of the interface between the intestinal barrier and luminal contents. Disruption of intestinal immune function can lead to various pathologies, including persistent infections and autoimmune and even malignant disease1,2,3,8.

例如，肠粘膜免疫系统是人体内最大的免疫细胞库7，通过永久维持肠屏障和腔内内容物之间的界面来确保体内平衡。肠道免疫功能的破坏可导致各种病理，包括持续感染和自身免疫甚至恶性疾病1,2,3,8。

Whereas intestinal organoids can accurately model the differentiation and function of epithelial cell types9,10,11, they fall short in capturing key aspects of intestinal (patho)physiology owing to the absence of a tissue-specific immune compartment12.To address these shortcomings, adult or induced pluripotent stem cell-derived organoids have been co-cultured with blood-derived innate or adaptive immune cells13,14,15.

虽然肠道类器官可以准确地模拟上皮细胞类型的分化和功能9,10,11，但由于缺乏组织特异性免疫区12，它们在捕获肠道（病理）生理学的关键方面存在不足。为了解决这些缺点，成人或诱导多能干细胞衍生的类器官已经与血源性先天性或适应性免疫细胞共培养13,14,15。

However, the incorporation of a mucosal lymphocyte compartment has proven elusive. One recent study described the generation of gut-associated lymphoid tissue in induced pluripotent stem cell-derived human intestinal organoids following transplantation in humanized mice16. Although representing an important advance, the in vivo formation of immune tissue removes the advantage of organoids as being controllable in vitro systems.

然而，粘膜淋巴细胞区室的掺入已被证明是难以捉摸的。最近的一项研究描述了在人源化小鼠中移植后诱导多能干细胞衍生的人肠道类器官中肠道相关淋巴组织的产生16。。

Similarly, fetal intestinal organoids have been co-cultured with effector memory T cells but no model exists that includes a true adult tissue-resident.

类似地，胎儿肠道类器官已经与效应记忆T细胞共培养，但不存在包括真正的成人组织驻留的模型。

Data availability

数据可用性

Sequencing files in FASTQ format supporting single-cell transcriptomic analysis of homeostasis conditions, as well as EpCAM TCB treatment, have been deposited in ArrayExpress and are accessible at E-MTAB-14171 and E-MTAB-14170, respectively. Raw count matrices, together with metadata information, for all scRNA-seq samples discussed in this study have been deposited in Mendeley and are available at https://data.mendeley.com/datasets/5h3ym82bnb/1.

支持稳态条件的单细胞转录组分析以及EpCAM TCB治疗的FASTQ格式的测序文件已保存在ArrayExpress中，可分别在E-MTAB-14171和E-MTAB-14170上访问。本研究中讨论的所有scRNA-seq样本的原始计数矩阵以及元数据信息已保存在Mendeley，可在https://data.mendeley.com/datasets/5h3ym82bnb/1.

Source data underlying all graphical representations used in the figures are provided as Supplementary Information. Source data are provided with this paper..

图中使用的所有图形表示的基础源数据作为补充信息提供。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank R. Sriram for supporting us with the establishment and oversight of the research agreements governing access to human intestinal specimens. We acknowledge the support of the non-profit foundation HTCR, which holds human tissue on trust, making it broadly available for research on an ethical and legal basis.Author informationAuthor notesThese authors contributed equally: Timothy Recaldin, Linda Steinacher, Bruno Gjeta, Marius F.

下载参考文献致谢我们感谢R.Sriram支持我们建立和监督管理人类肠道标本获取的研究协议。我们感谢非营利基金会HTCR的支持，该基金会以信托形式持有人体组织，使其在伦理和法律基础上广泛用于研究。作者信息作者注意到这些作者做出了同样的贡献：蒂莫西·雷科尔丁，琳达·施泰纳彻，布鲁诺·吉塔，马吕斯·F。

HarterAuthors and AffiliationsRoche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, SwitzerlandTimothy Recaldin, Linda Steinacher, Marisa Pimentel Mendes, Giacomo Lazzaroni & Michael BscheiderInstitute of Human Biology (IHB), Roche Pharma Research and Early Development, Basel, SwitzerlandLinda Steinacher, Bruno Gjeta, Marius F.

HarterAuthors及其附属机构罗氏创新中心巴塞尔，罗氏制药研究与早期发展，巴塞尔，瑞士蒂莫西·雷科尔丁，琳达·施泰纳彻，玛丽莎·皮门特尔·门德斯，贾科莫·拉扎罗尼和迈克尔·贝歇德人类生物学研究所（IHB），罗氏制药研究与早期发展，巴塞尔，瑞士林达·施泰纳彻，布鲁诺·吉塔，马吕斯·F。

Harter, Lukas Adam, Kristina Kromer, Marina Bellavista, Mikhail Nikolaev, Rok Krese, Umut Kilik, Doris Popovic, Bilgenaz Stoll, Régine Gerard, Marc Bickle, Lauriane Cabon, J. Gray Camp & Nikolche GjorevskiHannover Medical School, Institute of Immunology, Hannover, GermanyLinda SteinacherUniversity of Basel, Basel, SwitzerlandBruno Gjeta & Umut KilikGustave Roussy Cancer Campus, University Paris-Saclay, Paris, FranceMarius F.

哈特（Harter）、卢卡斯·亚当（LukasAdam）、克里斯蒂娜·克罗默（KristinaKromer）、玛丽娜·贝拉维斯塔（MarinaBellavista）、米哈伊尔·尼古拉耶夫（MikhailNikolaev）、罗克·克雷斯（RokKrese）、乌穆特·基利克（UmutKilik）、多丽丝·波波维奇（DorisPopovic）、比尔根茨·斯托尔（Bilg。格雷·坎普（Gray Camp＆Nikolche GjorevskiHannover）医学院，汉诺威免疫学研究所，德国巴塞尔大学琳达·施泰纳彻大学（Basel），瑞士吉塔（SwitzerlandBruno Gjeta＆Umut KilikGustave Roussy Cancer Campus），巴黎萨克雷大学（University Paris Saclay），巴黎（FranceMarius F.）。

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PubMed Google ScholarContributionsT.R., N.G., J.G.C., L.C. and M. Bscheider conceived the study. T.R., N.G. and J.G.C. wrote the manuscript. T.R., L.S. and M.F.H. were involved in designing and performing most experiments in the manuscript. B.G. and L.A. led the bioinformatics efforts and analysed all scRNA-seq data.

PubMed谷歌学术贡献者。R、 ，N.G.，J.G.C.，L.C.和M.Bscheider构思了这项研究。T、 。T、 R.，L.S.和M.F.H.参与了手稿中大多数实验的设计和执行。B、 G.和L.A.领导了生物信息学的工作，并分析了所有scRNA-seq数据。

T.R., L.S., M. Bellavista, U.K. and D.P. performed scRNA-seq experiments. L.S., M.F.H., K.K., M.P.M. and G.L. performed revision experiments. M.N., R.K. and M. Bickle performed or analysed live-imaging experiments. T.R., L.S., R.G., M.P.M. and B.S. isolated and banked organoids and TRM cells from primary intestinal samples.Corresponding authorsCorrespondence to.

T、 。五十、 S.，M.F.H.，K.K.，M.P.M.和G.L.进行了修订实验。M、 N.，R.K.和M.Bickle进行或分析了实时成像实验。T、 R.，L.S.，R.G.，M.P.M.和B.S.从原代肠道样品中分离并储存了类器官和TRM细胞。通讯作者通讯。

Lauriane Cabon, J. Gray Camp or Nikolche Gjorevski.Ethics declarations

Lauriane Cabon，J.Gray Camp或Nikolche Gjorevski。道德宣言

Competing interests

相互竞争的利益

All authors are employees of Hoffmann-LaRoche. The company provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

所有作者都是霍夫曼·拉罗什的员工。该公司以作者工资的形式提供支持，但在研究设计，数据收集和分析，决定出版或准备手稿方面没有任何额外的作用。

Peer review

同行评审

Peer review information

同行评审信息

Nature thanks Linheng Li, Toshiro Sato and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

《自然》杂志感谢李林恒、佐藤俊弘和其他匿名审稿人对这项工作的同行评审所做的贡献。同行评审报告可供查阅。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Intestinal TRM isolation and comparison to circulating T cells.a, Comparison of viable CD45+ count in matched donors subjected to either digestion- or crawl out- based isolation.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。。

Two-tailed paired T-test. 7 biological replicates. b, Comparison of immune cell proportions subjected to either digestion- or crawl out- based isolation. Values represent percentages of parent population listed above each bar, as determined via flow cytometry. LPL lamina propria lymphocyte, IEL intraepithelial lymphocyte.

双尾配对T检验。7个生物学重复。b、 比较基于消化或爬行分离的免疫细胞比例。数值表示通过流式细胞术确定的每个条上方列出的亲本群体的百分比。。

Mean ± SD of 5 (Digest CD4 LPL, CD4 IEL, CD8 LPL, CD8 IEL, B cells) or 6 (all other conditions) biological replicates. Different symbol shapes represent individual donors. c, Flow cytometry-generated tSNE analysis of one intestinal lymphocyte isolation incorporating lineage-defining immune cell markers.

平均值±SD为5（消化CD4 LPL，CD4 IEL，CD8 LPL，CD8 IEL，B细胞）或6（所有其他条件）生物学重复。不同的符号形状代表个体捐赠者。c、 。

Leftmost plot represents annotated cell populations with smaller plots displaying heatmaps for each of the 10 key surface markers assessed. DP double positive, DN double negative. Data is representative of six biologically-independent replicates. d, Bar charts comparing expression of key activation markers in gut-derived CD4+ and CD8+ T cells isolated via crawl out in cytokine-free or cytokine-supplemented (10IU/ml IL-2, 2 ng/ml IL-15) media in four biological replicates.

最左边的图表示注释的细胞群，较小的图显示评估的10个关键表面标记中的每一个的热图。DP双正，DN双负。数据代表六个生物学上独立的重复。d、 条形图比较了在四个生物学重复中通过无细胞因子或补充细胞因子（10IU/ml IL-2,2ng/ml IL-15）培养基中爬行分离的肠源性CD4+和CD8+T细胞中关键活化标志物的表达。

Two-tailed paired T-test. e, Flow cytometry assessment of key functionality markers in CD4+ T cells (left graph) and CD8+ T cells (right graph) after crawl out isolation. Violin plots collate data from 10 (8 for CD117) independent intestinal tissue resections, 5 (3 for CD117) of which have matched blood-.

双尾配对T检验。e、 爬行分离后CD4+T细胞（左图）和CD8+T细胞（右图）中关键功能标志物的流式细胞术评估。小提琴图整理了来自10个（CD117为8个）独立肠组织切除的数据，其中5个（CD117为3个）具有匹配的血液。

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Reprints and permissionsAbout this articleCite this articleRecaldin, T., Steinacher, L., Gjeta, B. et al. Human organoids with an autologous tissue-resident immune compartment.

转载和许可本文引用本文Recaldin，T.，Steinacher，L.，Gjeta，B。等人。具有自体组织驻留免疫隔室的人类类器官。

Nature (2024). https://doi.org/10.1038/s41586-024-07791-5Download citationReceived: 31 August 2023Accepted: 05 July 2024Published: 14 August 2024DOI: https://doi.org/10.1038/s41586-024-07791-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《自然》（2024）。https://doi.org/10.1038/s41586-024-07791-5Download引文接收日期：2023年8月31日接收日期：2024年7月5日发布日期：2024年8月14日OI：https://doi.org/10.1038/s41586-024-07791-5Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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