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.
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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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.
The author declares no competing financial interests.
- Crohn disease
A type of chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract from the mouth to the anus. Crohn disease is caused by a combination of environmental, nutritional, immunological and bacterial factors in genetically susceptible individuals.
- Adaptive thermogenesis
The thermic effect of factors such as cold, fear, stress and several drugs that can increase the rate of energy expenditure above normal levels. In individuals with obesity, adaptive thermogenesis impedes weight loss, compromises the maintenance of weight loss and creates the ideal metabolic response to support rapid weight regain.
- Eosinophilic oesophagitis
An allergic inflammatory condition of the oesophagus that involves eosinophils and that can lead to oesophageal narrowing, impaired swallowing, food impaction, dysphagia, vomiting and weight loss.
- Chronic schistosomiasis
A chronic disease caused by parasitic worms of the genus Schistosoma that in some infected individuals leads to the development of severe interleukin-13-driven eosinophilic inflammation and hepatic fibrosis.
- Immunostimulatory CpG sequences
Short single-stranded synthetic DNA molecules that contain a cytosine triphosphate deoxynucleotide (C) followed by a guanine triphosphate deoxynucleotide (G); they have potent immunostimulatory activity when recognized by the pattern recognition receptor Toll-like receptor 9.
- Clodronate liposomes
Liposome-encapsulated clodronate is a commonly used tool that is used to deplete phagocytic cells such as macrophages in vivo. At a certain intracellular concentration, clodronate induces macrophage apoptosis.
- Cd11b–DTR mice
Cd11b-transgenic mice that have a diphtheria toxin-inducible system that transiently depletes macrophages in various tissues. Intraperitoneal injection of diphtheria toxin ablates CD11b+ monocytes and/or macrophages.
- Polarized type 2 immune responses
Immune responses that are dominated by the production of interleukin-4 (IL-4), IL-5, IL-9 and/or IL-13.
- Cre recombinase
An enzyme that facilitates site-specific recombination events and is commonly used in genome modification strategies.
- Arg1lox/deltaLysM–Cre mice
Mice that lack expression of arginase 1 (Arg1) specifically in monocytes and macrophages (which express lysozyme M (LysM)).
- Arg1lox/deltaTie2–Cre mice
Mice that lack expression of arginase 1 (Arg1) specifically in endothelial cells and most haematopoietic cells, which express the receptor tyrosine kinase promoter/enhancer (which is encoded by Tie2; also known as Tek).
- Portal hypertension
An increase in the pressure within the portal vein (the vein that carries blood from the digestive organs to the liver). The increase in pressure is caused by a blockage in the blood flow through the liver, which is commonly associated with cirrhosis or scarring of the liver.
Abdominal fluid that accumulates as a result of high pressure in the blood vessels of the liver, often a result of chronic liver injury.
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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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