Regulation of Cytokine Secretion in Human CD127(+) LTi-like Innate Lymphoid Cells by Toll-like Receptor 2

Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
Immunity (Impact Factor: 21.56). 11/2010; 33(5):752-64. DOI: 10.1016/j.immuni.2010.10.012
Source: PubMed


Lymphoid tissue inducer cells are members of an emerging family of innate lymphoid cells (ILC). Although these cells were originally reported to produce cytokines such as interleukin-17 (IL-17) and IL-22, we demonstrate here that human CD127(+)RORC(+) and CD56(+)CD127(+) LTi-like ILC also express IL-2, IL-5, and IL-13 after activation with physiologic stimuli such as common γ-chain cytokines, Toll-like receptor (TLR) 2 ligands, or IL-23. Whereas TLR2 signaling induced IL-5, IL-13, and IL-22 expression in a nuclear factor κB (NF-κB)-dependent manner, IL-23 costimulation induced only IL-22 production. CD127(+) LTi-like ILC displayed clonal heterogeneity for IL-13 and IL-5 production, suggesting in vivo polarization. Finally, we identified a role for autocrine IL-2 signaling in mediating the effects of TLR2 stimulation on CD56(+)CD127(+) and CD127(+) LTi-like ILC. These results indicate that human LTi-like ILC can directly sense bacterial components and unravel a previously unrecognized functional heterogeneity among this important population of innate lymphoid cells.

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Available from: James P Di Santo, Sep 23, 2015
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    • "RORgt-expressing CD127 + group 3 ILCs are involved in organizing tertiary lymphoid structures (van de Pavert and Mebius, 2010), are critical in controlling containment of commensals (Sonnenberg et al., 2012), and also promote antimicrobial peptide production and the proliferation of epithelial cells (Cella et al., 2009; Crellin et al., 2010). Furthermore, IL-22 producing group 3 ILCs protect against certain bacterial pathogens such as Citrobacter rodentium, which is used as a model in mice for the attaching and effacing enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) (Satoh-Takayama et al., 2008; Sonnenberg et al., 2011). "
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    ABSTRACT: Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 07/2015; 43(1). DOI:10.1016/j.immuni.2015.06.019 · 21.56 Impact Factor
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    • "Indeed, inhibition of IL-12p40 (ustekinumab), the common receptor subunit of IL-12 and IL-23, is effective in treating CD [72]. ILCs can directly sense bacteria (at least through TLR2 [73]) to induce their effector functions; however , their most potent effector functions are stimulated by sensing the production of IL-23 by macrophages and DCs activated in response to microbial stimulation [57]. An essential function of ILCs is the production of IL-22. "
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    ABSTRACT: Abstract The innate immune system is a key factor in understanding the pathogenesis of inflammatory bowel disease (IBD) and in the hopes of improving its treatment. NOD2, a pattern recognition receptor, was one of the first major susceptibility genes identified in Crohn's disease (CD). This discovery has been followed by genome-wide association studies that have identified other genes involved in innate immune responses. Most notably, polymorphisms in the interleukin (IL)-23 receptor have also been linked to IBD - both CD and ulcerative colitis. At the core of the innate immune defects associated with IBD is a lack of generating a robust response to control invasive commensal or pathogenic bacteria. The defect sometimes lies in a failure of the epithelium to express antimicrobial peptides or in defective control of intracellular bacteria by phagocytic cells such as dendritic cells, macrophages, or neutrophils. The recent identification of innate lymphoid cells that express the IL-23 receptor and generate both proinflammatory and protective or regulatory responses to commensal or pathogenic bacteria provides another layer of complexity to the interplay of host protection and dysregulated inflammation. Although inhibition of tumor necrosis factor has been highly successful as a strategy in treating IBD, we must better understand the nuanced role of other innate cytokines before we may incorporate these in the treatment of IBD.
    Scandinavian Journal of Gastroenterology 01/2015; 50(1):24-33. DOI:10.3109/00365521.2014.966321 · 2.36 Impact Factor
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    • "Another possibility is that AhR-dependent modulation of ILCs3 function is mediated by bacterial metabolites, as, under conditions of unrestricted tryptophan availability, Lactobacilli species produce indole-3-aldehyde, an AhR ligand, which enhances IL-22 expression in ILCs3 [43]. Interestingly, human ILCs3 express also RNA transcripts of Toll-like receptors (TLR) 1, 2, 5, 6, 7, and 9, though it seems that only TLR2 agonists induce cytokine production by human ILC3 in the presence of IL-2, IL-15, and IL-23 [44], supporting the hypothesis that bacteria can directly stimulate ILCs3 to synthesize effector cytokines. "
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    ABSTRACT: Innate lymphoid cells (ILCs) are a group of hematopoietic cells devoid of antigen receptors that have important functions in lymphoid organogenesis, in the defense against extracellular pathogens, and in the maintenance of the epithelial barrier. Three distinct groups of ILCs have been identified on the basis of phenotypic and functional criteria and termed ILCs1, ILCs2, and ILCs3. Specifically, ILCs1 express the transcription factor T-bet and secrete T helper type-1- (Th1-) related cytokines, ILCs2 are dependent on the transcription factor RORα and express Gata-3 and the chemokine receptor homologous molecule (CRTH2) and produce Th2-related cytokines, and ILCs3 express the transcription factor RORγt and synthesize interleukin- (IL-) 17, IL-22, and, under specific stimuli, interferon-γ. ILCs represent a relatively small population in the gut, but accumulating evidence suggests that these cells could play a decisive role in orchestrating both protective and detrimental immune responses. In this review, we will summarize the present knowledge on the distribution of ILCs in the intestinal mucosa, with particular focus on their role in the control of both infections and effector cytokine response in immune-mediated pathologies.
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