I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis

Abstract

Innate type 2 immune cells are activated in response to helminths, allergens, and certain types of proteases and particulates. Recently, innate type 2 immune pathways have also been implicated in protective host responses to homeostatic perturbations, such as metabolic dysfunction, atherosclerosis, and tissue injury. In this context, innate type 2 cytokines stimulate local tissues, recruit eosinophils, and alternatively activate macrophages to restore homeostasis. As the major source of innate interleukin (IL)-5 and IL-13, group 2 innate lymphoid cells are positioned to initiate and maintain homeostatic type 2 responses. The absence of exogenous stimuli in these processes implicates endogenous pathways in the activation of type 2 immunity and suggests an alternative evolutionary trajectory for type 2 immunity, apart from its role in response to helminths and allergens.

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation

“…ILC2s are systemically distributed in tissues, including skin, lung, gastrointestinal tract, uterus and adipose tissue. When activated they comprise the major innate source of type 2 cytokines such as IL-5, IL-13, IL-9 and GM-CSF, in addition to epithelial growth factors such as amphiregulin (Cheng and Locksley, 2015; von Moltke and Locksley, 2014; Moro et al, 2010; Neill et al, 2010; Price et al, 2010). Studies comparing responses to IL-33 in ILC2-replete Rag-knockout and ILC2-deficient Rag x γc – knockout mice suggest that ILC2s comprise the major innate target of exogenous IL-33 (Brestoff et al, 2014; Mchedlidze et al, 2013; Moro et al, 2010).…”

“…Together, these findings indicate that IL-33 can promote pathologic type 2 immune responses, particularly at barrier surfaces such as the lung and skin. Similar to helminth infections, IL-33 frequently acts in combination with additional signals such as IL-2, IL-9, TSLP, IL-25, leukotrienes, prostaglandins, or TL1A, to promote ILC2 and/or Th2 functions (von Moltke and Locksley, 2014). Inhibition of the IL-33 pathway may be a promising therapeutic approach for limiting these pathologic responses (Fahy, 2015).…”

New insights into basophil heterogeneity

“…Group 2 ILCs (ILC2s) are a rare population of innate immune cells that produce type 2 cytokines which in turn augment anti-helminth immunity and allergic inflammation in a number of settings [52,152–154]. Recently, the importance of the basophil-ILC2 axis has been demonstrated in various allergic disease states [89,153,155].…”

A worm of one's own: how helminths modulate host adipose tissue function and metabolism

“…Resting WAT supports an intriguing combination of regulatory and type 2 immune cells, including ILC2, Treg, eosinophils, and AAM, which strongly resemble helminth-induced immune responses in the lung and intestine [5,47]. As sterile immunity to helminths is rarely achieved, the ultimate purpose of regulated type 2 immune responses may be to limit tissue damage and promote tissue repair [48,49], functions that are likely conserved in resting WAT (Figure 1). It is fascinating that helminths, most of which reside far from visceral adipose tissue, are able to further amplify this WAT type 2 immune ‘module’, including ILC2, type 2 helper T cells (Th2), AAM, and eosinophils [34,35].…”

“…Whether helminths promote signals in WAT that amplify type 2 immunity, such as IL-33, or instead increase the trafficking or function of type 2 immune cells requires additional studies. Other signals regulate ILC2 and Th2 during helminth infection in the lung or intestine, including thymic stromal lymphopoietin (TSLP), IL-2, IL-9, and IL-25 [49], but their function in WAT of resting animals or after helminth infection is unknown.…”