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Plasticity of innate lymphoid cell subsets

Nature Reviews Immunology volume 20, pages 552–565 (2020)Cite this article

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Abstract

Innate lymphoid cells (ILCs) are important for tissue homeostasis and for the initiation of immune responses. Based on their transcriptional regulation and cytokine profiles, ILCs can be categorized into five subsets with defined phenotypes and functional profiles, but they also have the ability to adapt to local environmental cues by changing these profiles. This plasticity raises the question of the extent to which the cytokine production profiles of ILCs are pre-programmed or are a reflection of the tissue microenvironment. Here, we review recent advances in research on ILCs, with a focus on the plasticity of these cells. We highlight the ability of ILCs to communicate with the surrounding microenvironment and discuss the possible consequences of ILC plasticity for our understanding of the biological roles of these cells. Finally, we discuss how we might use this knowledge of ILC plasticity to develop or improve options for the treatment of inflammatory diseases.

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Fig. 1: Development of human ILC subsets from naive precursors.
Fig. 2: Plasticity of innate lymphoid cells.
Fig. 3: Innate lymphoid cell plasticity in disease.

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Acknowledgements

The authors thank I. Martinez-Gonzalez, J. Bernink, B. Heesters, L. Krabbendam and B. Blom for critically reading the manuscript. This work is supported by an advanced grant from the European Research Council to H.S. (No. 341038). S.M.B. is supported by a Lung Foundation Fellowship (No. 6.2.17.196JO).

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Authors and Affiliations

  1. Department of Experimental Immunology, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, Netherlands

    Suzanne M. Bal, Korneliusz Golebski & Hergen Spits

  2. Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands

    Suzanne M. Bal, Korneliusz Golebski & Hergen Spits

  3. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands

    Suzanne M. Bal

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  1. Suzanne M. Bal
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  2. Korneliusz Golebski
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  3. Hergen Spits
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The authors contributed equally to all aspects of the article.

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Correspondence to Hergen Spits.

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H.S. consults for GSK and AIMM Therapeutics and owns stock in AIMM Therapeutics. S.M.B. and K.G. declare no competing interests.

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Glossary

Group 1 ILCs

(ILC1s). Group 1 innate lymphoid cells (ILCs) are non-cytotoxic or weakly cytotoxic tissue-resident cells that function as the first line of defence against infections with viruses and certain bacteria. ILC1s produce interferon-γ (IFNγ) and require T-bet for their function. They express CD127 in humans and CD200R in mice, and express NKp46 in both humans and mice.

Group 2 ILCs

(ILC2s). Group 2 innate lymphoid cells (ILCs) mediate parasite expulsion and produce the type 2 cytokines IL-4, IL-5 and IL-13 in response to IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). The transcription factor GATA-binding protein 3 (GATA3) is necessary for ILC2 development and function. Human ILC2s express CRTH2 and high levels of CD161, whereas most mouse ILC2s express ST2.

Group 3 ILCs

(ILC3s). Group 3 innate lymphoid cells (ILCs) are abundant at mucosal sites and are involved in immune responses to extracellular bacteria and the containment of intestinal commensals. ILC3s produce IL-22, by which they promote intestinal homeostasis. Both human and mouse ILC3s can also produce granulocyte–macrophage colony-stimulating factor (GM-CSF). Their development and function depend on retinoic acid receptor-related orphan receptor-γt (RORγt). Two subsets of ILC3s can be distinguished on the basis of cell surface expression of NKp44 in humans and NKp46 in mice.

Plasticity

Plasticity or transdifferentiation is the process by which a cell adapts phenotypically and functionally to a changing local tissue environment.

RNA velocity analysis

Whereas RNA abundance is an indicator of the state of individual cells, RNA velocity is the time derivative of the gene expression state in time. This can be directly estimated by distinguishing between unspliced and spliced mRNAs in common single-cell RNA sequencing protocols. It predicts the future state of individual cells on a timescale of hours.

Rag2 –/– Il2rg –/– mice

A lymphopenic mouse model that lacks T cells, B cells, innate lymphoid cells and natural killer cells.

Inflammatory ILC2s

(iILC2s). These group 2 innate lymphoid cells (ILC2s), which are found predominantly in the circulation, can produce both IL-17 and IL-13, express GATA-binding protein 3 (GATA3) and retinoic acid receptor-related orphan receptor-γt (RORγt), and respond to IL-25. In mice, iILC2s can be identified by the expression of killer cell lectin-like receptor G1 (KLRG1), CC-chemokine receptor 9 (CCR9) and the IL-25 receptor (IL-25R), whereas in humans they lack expression of KLRG1 and CCR9. It should be noted that there is no consensus regarding this terminology in the field and that IL-25-responsive ILC2s can also be found under non-inflammatory conditions.

Tuft cells

Also known as brush cells. ‘Tuft’ refers to the microvilli that project from the surface of these cells. They are secretory epithelial cells found in the intestines and airways that can produce IL-25. They express DCLK1 and TRPM5, and ATOH1 expression is required for their specification.

Polychromic reporter mice

A mouse model consisting of two or more combinatorial reporter genes that enables visualization of more than one protein in the same mouse. Using such mice, researchers have been able to readily identify precursor cells on the basis of expression of one or more transcription factors.

Common cytokine receptor γ-chain

(IL-2Rγ). The common cytokine receptor γ-chain (CD132; encoded by IL2RG) is a component of the receptors for a family of cytokines consisting of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

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Bal, S.M., Golebski, K. & Spits, H. Plasticity of innate lymphoid cell subsets. Nat Rev Immunol 20, 552–565 (2020). https://doi.org/10.1038/s41577-020-0282-9

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