Systemically dispersed innate IL-13–expressing cells in type 2 immunity

Abstract

Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13-expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.T ype 2 immune responses are important for the control of infections at mucosal barriers and the development of allergic inflammation. These responses are characterized by eosinophilia, elevated IgE, goblet cell metaplasia with enhanced mucus production, and smooth muscle hyperreactivity, all of which rely critically on production of the canonical type 2-associated cytokines IL-4, IL-5, and IL-13 (1, 2). Although adaptive Th2 cells and follicular T cells are important sources of these cytokines (3), various innate cells, including eosinophils, basophils, and mast cells, have also been implicated as producers of these cytokines in various model systems (1, 2, 4, 5). More recently, the cytokines IL-25 and IL-33, members of the IL-17 and IL-1 cytokine families, respectively, were found to induce type 2 cytokine production when administered to mice, implicating these cytokines in the initiation of type 2 immune responses (6, 7). IL-25 and IL-33 are expressed by epithelial cells, macrophages, and possibly other cell types (8), and they are expressed at elevated levels during infection with parasitic helminths (9, 10) or after challenge with allergens (9, 11). Administration of exogenous IL-25 or IL-33 to mice leads to markedly enhanced levels of IL-4, IL-5, and IL-13 and many of the tissue features of a type 2 immune response (6, 7). Conversely, deficiency in IL-25 leads to diminished IL-4, IL-5, and IL-13 production and variable delays in worm clearance in different helminth models (12, 13). Similarly, mice unable to respond to IL-33 because of deficiency in the T1-ST2 subunit of the IL-33 receptor display diminished Th2-associated cytokines and decreased granuloma formation after injection of Schistosoma mansoni eggs (14).Some of the original descriptions of these cytokines as well as more recent reports have noted the capacity of exogenous ...

Immunity to gastrointestinal nematode infections

“…Whereas neurons relay their signals via the neurotransmitter neuromedin U, 23 14,32,33 that strongly synergize and prompt the release of IL-4, IL-5, IL-9, and IL-13 from various sources, notably type 2 innate lymphoid cells (ILC2). [15][16][17]25,[34][35][36][37][38] Epithelium-derived IL-25 and IL-33, in particular, are important for driving IL-5 and IL-13 production from ILC2, the latter of which induces a number of responses, including goblet and tuft cell expansion, resulting in a strong positive feedback loop with increased production of IL-25 by epithelial cells. [15][16][17]31,[34][35][36][37] As a consequence, mice lacking IL-25 have less efficient expulsion of T. muris, 26 T. spiralis, 39 N. brasiliensis, 25,27,40 and H. polygyrus 28 worms.…”

Innate Lymphoid Cells in Graft-Versus-Host Disease

“…ILC2 secrete type 2 cytokines; IL‐4, IL‐5, IL‐9, and IL‐13 in response to IL‐33, IL‐25, and thymic stromal lymphopoietin (TSLP) 14, 15, 16. Additionally, ILC2 produce amphiregulin, which is crucial in tissue regeneration 2.…”

Innate Lymphoid Cells in Type 2 Immune Responses

“…These cells expanded in response to IL-33 and were found to enhance gut helminth expulsion. Similarly, Price et al (2010) and Neill et al (2010) identified Lin -ILC populations that expressed IL-33 and IL-25 receptors in gut and lung tissues, using IL-4 and IL-13 reporter mice, respectively. These cells were also shown to be important in mediating gut parasite expulsion and were named innate helper cells (Price et al 2010) and nuocytes (Neill et al 2010) by these respective groups.…”

“…Perhaps the bestdescribed functions for ILC2 are in gut immunity and as a key effector population in anti-helminth immunity (Moro et al 2010;Neill et al 2010;Price et al 2010). Moro et al (2010) demonstrated that alymphoid gc -/-Rag2 -/-mice had profoundly reduced goblet cell hyperplasia, mucus deposition and diminished levels of IL-13 in the peritoneal cavity in response to N. brasiliensis infection.…”