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Type 2 cytokines: mechanisms and therapeutic strategies

Key Points

  • Although the type 2 cytokine response has many important host-protective functions, dysregulated, chronic or hyperreactive type 2 immunity can contribute to the development of disease. Type 2 cytokines are crucial to the pathogenesis of many allergic and fibrotic diseases, they suppress the development of protective type 1 immunity to a wide range of viral, bacterial and protozoan pathogens, and they can promote tumorigenesis and tumour cell growth.

  • As dysregulated type 2 immune responses are major drivers of disease, the mechanisms that control the intensity, maintenance and resolution of type 2 immunity are probably important regulators of disease progression. Several endogenous regulatory mechanisms work collaboratively to prevent or to limit the pathological consequences of sustained type 2 immunity.

  • Inflammatory monocytes and tissues macrophages have emerged as important regulators of established type 2 immune responses. Therapeutic strategies that disrupt the recruitment, the expansion or maintenance of crucial myeloid cell populations could emerge as novel therapeutic approaches for a variety of type 2-driven diseases.

  • Interferon-γ- and interleukin-4 (IL-4)- and/or IL-13-activated macrophages antagonize type 2 inflammation and fibrosis by competing with activated myofibroblasts that require the metabolites l-arginine and l-proline for collagen synthesis. IL-4- and/or IL-13-primed macrophages expressing arginase 1 also inhibit IL-13-driven fibrosis by suppressing the proliferation and the expansion of the CD4+ T helper 2 (TH2) cell population.

  • The IL-13 decoy receptor (IL-13Rα2), the immunosuppressive cytokine IL-10 and type 1 cytokines collaboratively suppress the development of type 2 cytokine-driven disease and immunity.

  • Therapeutic strategies targeting type 2 cytokine signalling pathways, eosinophil development and recruitment, epithelial cell-derived alarmins, prostaglandins and regulatory T (TReg) cell activity are at different stages of development for type 2-driven disease.

Abstract

Type 2 immune responses are defined by the cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13, which can either be host protective or have pathogenic activity. Type 2 immunity promotes antihelminth immunity, suppresses type 1-driven autoimmune disease, neutralizes toxins, maintains metabolic homeostasis, and regulates wound repair and tissue regeneration pathways following infection or injury. Nevertheless, when type 2 responses are dysregulated, they can become important drivers of disease. Type 2 immunity induces a complex inflammatory response characterized by eosinophils, mast cells, basophils, type 2 innate lymphoid cells, IL-4-and/or IL-13-conditioned macrophages and T helper 2 (TH2) cells, which are crucial to the pathogenesis of many allergic and fibrotic disorders. As chronic type 2 immune responses promote disease, the mechanisms that regulate their maintenance are thought to function as crucial disease modifiers. This Review discusses the many endogenous negative regulatory mechanisms that antagonize type 2 immunity and highlights how therapies that target some of these pathways are being developed to treat type 2-mediated disease.

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Figure 1: The yin and yang of type 2 immunity.
Figure 2: Monocytes and macrophages contribute to the regulation of type 2-driven repair and fibrosis.
Figure 3: Collaboration between interleukin-10, the IL-13 decoy receptor and type 1 immunity in the suppression of type 2 immunity.
Figure 4: Novel targeted therapies for type 2-driven disease.

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Acknowledgements

The author is supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.

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Wynn, T. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol 15, 271–282 (2015). https://doi.org/10.1038/nri3831

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