Type 2 immune responses operate under varying conditions in distinct tissue environments and are crucial for protection against helminth infections and for the maintenance of tissue homeostasis. Here we explore how different layers of heterogeneity influence type 2 immunity. Distinct insults, such as allergens or infections, can induce type 2 immune responses through diverse mechanisms, and this can have heterogeneous consequences, ranging from acute or chronic inflammation to deficits in immune regulation and tissue repair. Technological advances have provided new insights into the molecular heterogeneity of different developmental lineages of type 2 immune cells. Genetic and environmental heterogeneity also contributes to the varying magnitude and quality of the type 2 immune response during infection, which is an important determinant of the balance between pathology and disease resolution. Hence, understanding the mechanisms underlying the heterogeneity of type 2 immune responses between individuals and between different tissues will be crucial for treating diseases in which type 2 immunity is an important component.
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This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, and NIH grants AI131634-01A1, DK113790 and AI131634 to W.C.G.; NIH grants DK103788, HL084312, AI133977 and AI130945 and DOD grant W81XWH-16-1-0256 to P.L.; and NIH grants AI089824 and CA212376 to C.R., who is a Howard Hughes Medical Institute Faculty Scholar. The authors apologize to those authors whose exemplary work they were unable to cite owing to space limitations.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Alternative activation
Historically, macrophages activated in vitro have been described as ‘M1 or classically activated’ or ‘M2 or alternatively activated’, depending on whether they have been activated with IFNγ and lipopolysaccharide or with IL-4 or IL-10, respectively. However, in vivo macrophages are highly specialized, dynamic and heterogeneous with regard to their lineages, phenotypes and functions, and their activation is continuously shaped by multiple matrix and cellular signals in the tissue microenvironment. Therefore, the classical (M1) versus alternatively activated (M2) classification and terminology is useful but overly simplistic, with each broadly different phenotype actually showing considerable heterogeneity.
- Charcot–Leyden crystals
Slender birefringent crystals composed of self-aggregating galectin-10 that is produced by human eosinophils and found in tissues associated with eosinophilic inflammation.
- Frustrated phagocytosis
Situation in which a myeloid cell attempts to phagocytose something, most often opsonized, that it cannot internalize, often resulting in the release of lysosomal contents, and in some cases cell death.
- Tuft cells
Chemosensory epithelial cells lining the intestinal wall that have tufts or brush-like microvilli on their surface. They can increase greatly following parasitic infections and are the major producer of IL-25 in the intestine, playing an essential role in driving group 2 innate lymphoid cell (ILC2) activation. They are also present in the respiratory epithelium, where they are called brush cells.
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Gause, W.C., Rothlin, C. & Loke, P. Heterogeneity in the initiation, development and function of type 2 immunity. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0301-x