Article

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

Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco, CA 94143-0795, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2010; 107(25):11489-94. DOI: 10.1073/pnas.1003988107
Source: PubMed

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.

Download full-text

Full-text

Available from: Hong-Erh Liang, Jun 11, 2014
  • Source
    • "and data not shown). In this regard, the Lin À GFP hi IL-17RB + c-Kitˉ cells detected in our murine model of food allergy appeared identical to the intestinal IL-25-responding ILC2s that have previously been shown to elicit protective immunity against intestinal worm infection (Moro et al., 2010; Neill et al., 2010; Price et al., 2010; Saenz et al., 2010). In contrast, MMC9s did not respond to IL-25 stimulation in vitro and in vivo and are distinct from both ILC2s and the previously reported IL-25-elicited c-Kit int -GFP + multipotent progenitor (MPP type2 ) (Saenz et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Experimental IgE-mediated food allergy depends on intestinal anaphylaxis driven by interleukin-9 (IL-9). However, the primary cellular source of IL-9 and the mechanisms underlying the susceptibility to food-induced intestinal anaphylaxis remain unclear. Herein, we have reported the identification of multifunctional IL-9-producing mucosal mast cells (MMC9s) that can secrete prodigious amounts of IL-9 and IL-13 in response to IL-33, and mast cell protease-1 (MCPt-1) in response to antigen and IgE complex crosslinking, respectively. Repeated intragastric antigen challenge induced MMC9 development that required T cells, IL-4, and STAT6 transcription factor, but not IL-9 signals. Mice ablated of MMC9 induction failed to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that could be restored by adoptively transferred MMC9s. Finally, atopic patients that developed food allergy displayed increased intestinal expression of Il9- and MC-specific transcripts. Thus, the induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy.
    Full-text · Article · Sep 2015 · Immunity
  • Source
    • "These original studies showed that IL-25-and IL-33-responsive ILC2s were critical for the development of type 2 cytokine – associated inflammation and goblet cell hyperplasia that facilitate expulsion of N. brasiliensis in the absence of adaptive immunity (Moro et al. 2010; Neill et al. 2010; Price et al. 2010). A more recent study has shown that IL-33 is critical for the induction of IL-13 production by ILC2s to mediate worm expulsion (Hung et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORα, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell-derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Full-text · Article · Jan 2015 · Cold Spring Harbor perspectives in biology
  • Source
    • "A first group of ILC (ILC1) includes natural killer cells (NK cells) and other interferon-g (IFN-g)-producing ILC that expresses the transcription factor T-bet (Tbx21) and play important roles in protection against viruses and intracellular pathogens (Bernink et al., 2013; Gordon et al., 2012; Klose et al., 2014; Townsend et al., 2004). A second group of ILC (ILC2) includes ''nuocytes'' or natural helper cells that express the transcription factors Gata-3 and RORa and produce interleukin-5 (IL-5) and IL-13 in response to parasitic infections, allergens, and viruses (Moro et al., 2010; Neill et al., 2010; Price et al., 2010; Wong et al., 2012). A third ILC group (ILC3) includes transcription factor RORgt + lymphoid-tissue inducer cells (LTi cells) and natural cytotoxicity receptor (NCR)-expressing cells that have protective roles against extracellular bacteria and fungi and can be associated with organ-specific inflammation (Cella et al., 2009; Cupedo et al., 2009; Luci et al., 2009; Sanos et al., 2009; Satoh-Takayama et al., 2008; Sawa et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-22 (IL-22) plays a critical role in mucosal defense, although the molecular mechanisms that ensure IL-22 tissue distribution remain poorly understood. We show that the CXCL16-CXCR6 chemokine-chemokine receptor axis regulated group 3 innate lymphoid cell (ILC3) diversity and function. CXCL16 was constitutively expressed by CX3CR1(+) intestinal dendritic cells (DCs) and coexpressed with IL-23 after Citrobacter rodentium infection. Intestinal ILC3s expressed CXCR6 and its ablation generated a selective loss of the NKp46(+) ILC3 subset, a depletion of intestinal IL-22, and the inability to control C. rodentium infection. CD4(+) ILC3s were unaffected by CXCR6 deficiency and remained clustered within lymphoid follicles. In contrast, the lamina propria of Cxcr6(-/-) mice was devoid of ILC3s. The loss of ILC3-dependent IL-22 epithelial stimulation reduced antimicrobial peptide expression that explained the sensitivity of Cxcr6(-/-) mice to C. rodentium. Our results delineate a critical CXCL16-CXCR6 crosstalk that coordinates the intestinal topography of IL-22 secretion required for mucosal defense. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Immunity
Show more