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Group 3 innate lymphoid cells in intestinal health and disease

Nature Reviews Gastroenterology & Hepatology (2024)Cite this article

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Abstract

The gastrointestinal tract is an immunologically rich organ, containing complex cell networks and dense lymphoid structures that safeguard this large absorptive barrier from pathogens, contribute to tissue physiology and support mucosal healing. Simultaneously, the immune system must remain tolerant to innocuous dietary antigens and trillions of normally beneficial microorganisms colonizing the intestine. Indeed, a dysfunctional immune response in the intestine underlies the pathogenesis of numerous local and systemic diseases, including inflammatory bowel disease, food allergy, chronic enteric infections or cancers. Here, we discuss group 3 innate lymphoid cells (ILC3s), which have emerged as orchestrators of tissue physiology, immunity, inflammation, tolerance and malignancy in the gastrointestinal tract. ILC3s are abundant in the developing and healthy intestine but their numbers or function are altered during chronic disease and cancer. The latest studies provide new insights into the mechanisms by which ILC3s fundamentally shape intestinal homeostasis or disease pathophysiology, and often this functional dichotomy depends on context and complex interactions with other cell types or microorganisms. Finally, we consider how this knowledge could be harnessed to improve current treatments or provoke new opportunities for therapeutic intervention to promote gut health.

Key points

  • Group 3 innate lymphoid cells (ILC3s) have emerged as critical orchestrators of intestinal health and disease.

  • At homeostasis, ILC3s instruct lymphoid tissue organogenesis and persist throughout life to protect from enteric pathogens whilst supporting barrier integrity and tolerance towards microbiota and dietary antigens.

  • A balance between ILC3s and adaptive immune responses is essential to protect from enteric pathogens and promote immune regulation, whereas disruption of ILC3s unleashes chronic gut inflammation.

  • Dysregulation of ILC3s also contributes to experimental intestinal inflammation and cancer but critically depends on contextual factors such as the presence of adaptive immunity and disease timepoint.

  • Gut-protective ILC3s are dramatically reduced in both inflammatory bowel disease and colorectal cancer, whereas the remaining cells show increased plasticity towards inflammatory phenotypes.

  • Modulating ILC3 numbers or function could considerably improve gastrointestinal health by limiting inflammation, promoting mucosal healing or supporting antitumour responses.

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Fig. 1: Phenotype and spatiotemporal properties of ILC3 subsets in the human and mouse intestine.
Fig. 2: ILC3s orchestrate tissue physiology and immune tolerance in the gut.
Fig. 3: ILC3s in human IBD and CRC.
Fig. 4: Harnessing ILC3s as a novel therapy to promote gut health.

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Acknowledgements

We thank members of the Sonnenberg Laboratory for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R37AI174468, R01AI162936 and R01CA274534), the NIAID Mucosal Immunology Studies Team (MIST), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, the Cancer Research Institute, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. V.H. is supported by a DFG Walter Benjamin Fellowship (HO 7399/1-1). G.F.S. is a CRI Lloyd J. Old STAR.

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  1. Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Veronika Horn & Gregory F. Sonnenberg

  2. Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Veronika Horn & Gregory F. Sonnenberg

  3. Department of Microbiology & Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Veronika Horn & Gregory F. Sonnenberg

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Horn, V., Sonnenberg, G.F. Group 3 innate lymphoid cells in intestinal health and disease. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00906-3

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