Takatori H, Kanno Y, Watford WT et al.Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206:35-41

Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2009; 206(1):35-41. DOI: 10.1084/jem.20072713
Source: PubMed


The interleukin (IL) 17 family of cytokines has emerged to be critical for host defense as well as the pathogenesis of autoimmune and autoinflammatory disorders, and serves to link adaptive and innate responses. Recent studies have identified a new subset of T cells that selectively produce IL-17 (Th17 cells; Bettelli, E., T. Korn, and V.K. Kuchroo. 2007. Curr. Opin. Immunol. 19:652-657; Kolls, J.K., and A. Linden. 2004. Immunity. 21:467-476), but the regulation of IL-17 production by innate immune cells is less well understood. We report that in vitro stimulation with IL-23 induced IL-17 production by recombination activating gene (Rag) 2(-/-) splenocytes but not Rag2(-/-) common gamma chain(-/-) splenocytes. We found that a major source of IL-17 was CD4(+)CD3(-)NK1.1(-)CD11b(-)Gr1(-)CD11c(-)B220(-) cells, a phenotype that corresponds to lymphoid tissue inducer-like cells (LTi-like cells), which constitutively expressed the IL-23 receptor, aryl hydrocarbon receptor, and CCR6. In vivo challenge with the yeast cell wall product zymosan rapidly induced IL-17 production in these cells. Genetic deletion of signal transducer and activator of transcription 3 reduced but did not abrogate IL-17 production in LTi-like cells. Thus, it appears that splenic LTi-like cells are a rapid source of IL-17 and IL-22, which might contribute to dynamic organization of secondary lymphoid organ structure or host defense.

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    • "A T-box transcription factor, T-bet, also plays a role in the generation of IL-22-producing ILCs as Tbx21 deficiency leads to elimination of these cells in the intestinal lamina propria and impairs IL-22 production [12]. In humans, LTi cells are characterized by their expression of CD117 and CD127 [13] [14] and are critically involved in the development of secondary lymphoid tissues including lymph nodes, Peyer's patches and cryptopatches [15] "
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    ABSTRACT: IL-22 as a cytokine is described with opposing pro-inflammatory and anti-inflammatory functions. Cell regeneration, tissue remodelling and balance between commensal bacteria in the gut and host immune system are considered as anti-inflammatory features of IL-22, whereas production of IL-22 from Th17 cells links this cytokine to pro-inflammatory pathways. Th17 cells and group 3 innate lymphoid cells (ILC3) are two major producers of IL-22 and both cell types express ROR-ct and Aryl hydrocarbon receptor (AhR) transcription factors. Typically, the immune system cells are the main producers of IL-22. However, targets of this cytokine are mostly non-hematopoietic cells such as hepatocytes, keratinocytes, and epithelial cells of lung and intestine. Association of IL-22 with other cytokines or transcription factors in different cell types might explain its contrasting role in health and disease. In this review we discuss the regulation of IL-22 production by AhR- and IL-23-driven pathways. A clear understanding of the biology of IL-22 will provide new opportunities for its application to improve human health involving many debilitating conditions.
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    • "Indeed, specific innate immunity sources readily produce Th17 cytokines in different physiological and disease conditions. It has been recently demonstrated that common characteristics (such as RORg expression) can induce other lymphocytes to produce IL-17, including CD8þ ab T cells, gd T cells [23], LTi-like innate lymphoid cells (ILCs) [24], natural killer cells (NK) [25], and CD3þ invariant natural killer (iNKT) cells in mice and/or humans [26]. In addition, it is increasingly accepted that diverse innate myeloid immune cells are able to produce IL-17 and are strategically positioned in the barrier tissues, such as lungs, intestines, skin and peripheral lymph nodes to rapidly react to pathogens and allow an immediate response but also activate and amplify the adaptive immunity responses, as well illustrated by intestinal monocytes and macrophages in Crohn disease and ulcerative colitis [27] [28], neutrophils in systemic vasculitis [29], mast cells in psoriatic skin lesions [22] [30] [31], and synovium mast cells in rheumatoid arthritis [32] "
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    ABSTRACT: Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Preview · Article · May 2015 · Journal of Autoimmunity
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    • "ILCs have been shown to produce large quantities of IL-17 and IL-22 [69] and have been implicated in the pathogenesis of murine models of innate-driven bacteria-induced colitis. Rag1 À/À mice that lack functional T or B cells develop colitis when infected with H. hepaticus, and this is dependent on RORgt + and IL-23 responsive ILCs. "
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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.
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