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Functional interactions between innate lymphoid cells and adaptive immunity

Abstract

Innate lymphoid cells (ILCs) are enriched at barrier surfaces of the mammalian body where they rapidly respond to host, microbial or environmental stimuli to promote immunity or tissue homeostasis. Furthermore, ILCs are dysregulated in multiple human diseases. Over the past decade, substantial advances have been made in identifying the heterogeneity and functional diversity of ILCs, which have revealed striking similarities to T cell subsets. However, emerging evidence indicates that ILCs also have a complex role in directly influencing the adaptive immune response in the context of development, homeostasis, infection or inflammation. In turn, adaptive immunity reciprocally regulates ILCs, which indicates that these interactions are a crucial determinant of immune responses within tissues. Here, we summarize our current understanding of functional interactions between ILCs and the adaptive immune system, discuss limitations and future areas of investigation, and consider the potential for these interactions to be therapeutically harnessed to benefit human health.

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Fig. 1: A dialogue between innate and adaptive lymphocytes throughout the lifetime of a human.
Fig. 2: Anatomical distribution of ILCs and their interface with adaptive immunity.
Fig. 3: ILCs modulate adaptive immunity by producing soluble mediators with direct or indirect effects.
Fig. 4: ILCs control adaptive immunity through direct cellular interactions.
Fig. 5: Counter-regulation of ILCs by adaptive immunity.

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Acknowledgements

The authors thank members of the Hepworth and Sonnenberg Laboratories for discussions and critical reading of the manuscript. The Hepworth Laboratory is supported by a Royal Society and Wellcome Trust Sir Henry Dale Fellowship (Grant Number 105644/Z/14/Z) and a Lister Institute of Preventative Medicine Prize. The Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989 and U01AI095608), the NIAID Mucosal Immunology Studies Team (MIST), the Crohn’s and Colitis Foundation, the Searle Scholars Program, the American Asthma Foundation Scholar Award, Pilot Project Funding from the Center for Advanced Digestive Care (CADC), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative and the Roberts Institute for Research in IBD. G.F.S. is a CRI Lloyd J. Old STAR.

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Glossary

Alarmins

Immune-activating molecules that are released in response to tissue damage, infection or immune activation, such as IL-33, DNA or uric acid.

Lymphoid tissue-inducer cells

(LTi cells). Members of the group 3 innate lymphoid cell family that are present during fetal development and initiate the generation of secondary lymphoid structures.

Tertiary lymphoid structures

Organized lymphoid aggregates that develop after birth in response to microbiota colonization or chronic inflammation.

Trogocytosis

A process whereby cellular interaction results in the transfer of a surface protein from a donor cell to a recipient cell and continued expression of that protein on the surface of the recipient cell.

Invariant natural killer T cells

(Invariant NKT cells). A population of T cells that express surface molecules shared with natural killer cells and a restricted αβ T cell-receptor repertoire.

Type 2 immune responses

Immune responses that develop in response to parasitic helminth or allergen exposure and are characterized by cells expressing the transcription factor GATA-binding factor 3 (GATA3), the cytokines IL-4, IL-5 and IL-13 (such as T helper 2 cells and group 2 innate lymphoid cells) and infiltration of eosinophils, mast cells and/or basophils.

Type 3 immune responses

Immune responses that develop in response to microbial exposure or chronic inflammation and are characterized by cells expressing the transcription factor retinoic acid receptor-related orphan receptor-γt and the cytokines IL-17A, IL-17F or IL-22 (such as T helper 17 cells and group 3 innate lymphoid cells).

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Sonnenberg, G.F., Hepworth, M.R. Functional interactions between innate lymphoid cells and adaptive immunity. Nat Rev Immunol 19, 599–613 (2019). https://doi.org/10.1038/s41577-019-0194-8

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