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.

Figure 1. Generic model of type 2 signaling in homeostasis

(1) At rest, tonic activation of group 2 innate lymphoid cells (ILC2s) by as yet undefined signals drives expression of IL-5, which is required for systemic maintenance of eosinophils. (2) Disrupted homeostasis further activates ILC2s to increase IL-5 and IL-13 production, leading to eosinophil recruitment and alternatively activated macrophages (AAMs). Eosinophils, AAMs, and type 2 cytokines cooperate to restore tissue homeostasis. (3) If homeostatic disruptions are severe or prolonged, dendritic cells recirculate to lymph nodes and prime an adaptive type 2 response. Recruited helper type 2 (Th2) and type 2 invariant natural killer T (iNKT) cells provide IL-4, -5, and -13 to amplify the type 2 response. (4) Failure to resolve the type 2 response can lead to pathology, such as fibrosis or allergy.

Figure 2. Integrating endogenous signals

Group 2 innate lymphoid cells (ILC2s) are activated by diverse endogenous signals. One such signal, IL-33, is released by necrotic cell death and therefore signals tissue damage. The mechanisms that induce the other signals remain poorly understood, but we propose that they provide ILC2s with information about disrupted tissue homeostasis. When activated, ILC2s secrete IL-5, IL-13, IL-9, and perhaps IL-4. IL-9 enhances activation via an autocrine loop. Abbreviations: thymic stromal lymphopoietin (TSLP); vasoactive intestinal peptide (VIP); prostaglandin D2 (PGD2); cysteinyl leukotriene C4/D4 (LTC4/LTD4); death receptor 3 (DR3); chemoattractant receptor-homologous expressed on Th2 cells (CRTH2); cysteinyl leukotriene receptor 1 (CYSLTR1); vasoactive intestinal peptide receptor 2 (VPAC2).