Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 1; pp. 161 - 174
• Main Authors: Molofsky, Ari B., Van Gool, Frédéric, Liang, Hong-Erh, Van Dyken, Steven J., Nussbaum, Jesse C., Lee, Jinwoo, Bluestone, Jeffrey A., Locksley, Richard M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-07-2015
• Subjects: Aging - immunology; Animals; Diet, High-Fat; Enzyme Activation - immunology; Inducible T-Cell Co-Stimulator Protein - biosynthesis; Inducible T-Cell Co-Stimulator Protein - immunology; Interferon-gamma - immunology; Interferon-gamma - pharmacology; Interleukin-2 - pharmacology; Interleukin-33; Interleukins - immunology; Intra-Abdominal Fat - cytology; Intra-Abdominal Fat - immunology; Lectins, C-Type; Listeria monocytogenes - immunology; Listeriosis - immunology; Listeriosis - microbiology; Lung - cytology; Lung - immunology; Lung - pathology; Lymphocyte Activation - immunology; Mice; Mice, Transgenic; Nippostrongylus - immunology; Obesity - immunology; Receptors, Immunologic - biosynthesis; Strongylida Infections - immunology; Strongylida Infections - parasitology; T-Lymphocytes, Regulatory - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.05.019

Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.
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•IL-33-activated ILC2s are required for Treg accumulation in type 2 immune responses•IL-33 induction of Tregs depends on interactions between Treg ICOS and ILC2 ICOSL•IFN-γ represses IL-33-mediated ILC2 activation and limits Treg cell accumulation
Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis and contribute to tissue repair. Locksley and colleagues describe how the cytokines IL-33 and IFN-γ counter-regulate ILC2 activation to control Treg cell numbers and type 2 immune responses.