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Organoids in immunological research

Abstract

Much of our knowledge regarding the interactions between epithelial tissues and the immune system has been gathered from animal models and co-cultures with cell lines. However, unique features of human cells cannot be modelled in mice, and cell lines are often transformed or genetically immortalized. Organoid technology has emerged as a powerful tool to maintain epithelial cells in a near-native state. In this Review, we discuss how organoids are being used in immunological research to understand the role of epithelial cell–immune cell interactions in tissue development and homeostasis, as well as in diseases such as cancer.

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Fig. 1: Immune cells at the intestinal epithelial border.
Fig. 2: Organoid–immune cell co-culture systems in basic research for the study of interactions between immune cells and the epithelium.
Fig. 3: Organoid–immune cell co-culture systems in immuno-oncology research.

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Acknowledgements

The authors thank J. Bernink, R. Millen and T. Mizutani for comments and advice on the manuscript. This work was supported by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO) and the European Research Council (Advanced Grant ERC-AdG 67013-Organoid, to H.C.), and by a VENI grant from the Netherlands Organisation for Scientific Research (Grant NWO-ZonMW, 016.166.140, to K.K.). This work is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society. K.K. is a long-term fellow of the Human Frontier Science Program Organization (HFSPO, LT771/2015).

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Y.E.B.-E. and K.K. researched data for the article and wrote the manuscript. All authors contributed equally to discussion of the content and to reviewing and editing the manuscript before submission.

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Correspondence to Hans Clevers.

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The authors are inventors on patent applications and/or patents for organoid culture and organoid–immune cell co-cultures.

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Nature Reviews Immunology thanks N. C. Zachos and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Feeder cell

A cell line generated from isolated neonatal murine fibroblasts that have been selected for supporting optimal growth of epidermal keratinocytes in 2D culture.

Pluripotent stem cells

(PSCs). Cells with the potential to generate all embryonic tissues, such as embryonic stem cells.

Induced pluripotent stem cells

(iPSCs). Pluripotent cells generated in culture by the (over)expression of defined genetic factors in non-pluripotent cells such as somatic cells.

Intestinal stem cells

(ISCs). Rapidly dividing, LGR5+ columnar crypt bottom cells from which all cells in the intestinal epithelium arise.

Necrotizing enterocolitis

A condition that typically occurs in newborns, in which a part of the intestine dies.

Positive selection

The process leading to the proliferation and survival of thymocytes that have successfully recombined the T cell receptor locus to express a functional T cell receptor on their cell surface.

Negative selection

The process leading to clonal deletion of thymocytes that express a T cell receptor that binds to self-peptide–MHC complexes presented in the thymic medulla.

Nude mice

Mice that are athymic (lacking a thymus) and therefore lack mature, functional T cells and are severely immune deficient.

Tuft cells

A subset of chemosensory cells in the intestinal and airway epithelium.

Enteroendocrine cells

A group of specialized hormone-producing intestinal epithelial cells.

Goblet cells

A subset of mucus-producing cells found in the intestinal and airway epithelium.

Group 2 innate lymphoid cells

(ILC2s). A subset of innate lymphocytes (that is, lymphocytes that do not express an antigen receptor) that produce type 2 cytokines (such as IL-5 and IL-13) upon stimulation.

Peripherally induced regulatory T cells

Regulatory T cells that differentiate from naive T cells in the periphery, as opposed to naturally occurring regulatory T cells that develop in the thymus.

Group 3 innate lymphoid cells

(ILC3s). A subset of innate lymphocytes (that is, lymphocytes that do not express an antigen receptor) that produce TH17 cell-associated cytokines (such as IL-17A and IL-22) upon stimulation.

Air–liquid interphase

A culture method in which cells are grown in a monolayer on a transwell, allowing for contact both with air and with a culture medium in the bottom well.

Graft-versus-host disease

A condition occurring upon allogeneic bone marrow transplantation in which graft-derived immune cells mount an immune response against the host tissues.

Patient-derived xenograft

A system in which pieces of patient-derived tumour material (including the entire tumour microenvironment — in other words, immune cells, endothelial cells and fibroblasts, as well as the tumour epithelium) are transplanted into immunocompromised mice, which allows for the study of tumour behaviour in an in vivo system.

Organotypic tumour spheroids

A culture system in which pieces of tumour (including the entire tumour microenvironment — in other words, immune cells, endothelial cells and fibroblasts, as well as the tumour epithelium) are brought into culture, which allows for the study of tumour characteristics in vitro.

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Bar-Ephraim, Y.E., Kretzschmar, K. & Clevers, H. Organoids in immunological research. Nat Rev Immunol 20, 279–293 (2020). https://doi.org/10.1038/s41577-019-0248-y

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