Cupedo, T, Crellin, NK, Papazian, N, Rombouts, EJ, Weijer, K, Grogan, JL et al.. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol 10: 66-74

Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Nature Immunology (Impact Factor: 20). 12/2008; 10(1):66-74. DOI: 10.1038/ni.1668
Source: PubMed


The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue-inducer cells (LTi cells) as lineage-negative RORC+ CD127+ cells with the functional ability to interact with mesenchymal cells through lymphotoxin and tumor necrosis factor. Human LTi cells were committed natural killer (NK) cell precursors that produced interleukin 17 (IL-17) and IL-22. In vitro, LTi cells gave rise to RORC+ CD127+ NK cells that retained the ability to produce IL-17 and IL-22. Postnatally, similar populations of LTi cell-like cells and RORC+ CD127+ NK cells were present in tonsils, and both secreted IL-17 and IL-22 but no interferon-gamma. Our data indicate that lymph node organogenesis is controlled by an NK cell precursor population with adaptive immune features and demonstrate a previously unappreciated link between the innate and adaptive immune systems.

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    • "IFN-γ is the signature Th1 cell associated cytokine, which plays a critical role in inflammation and autoimmune disease, with both proinflammatory and protective functions [5]. IL-17A is the hallmark cytokine of T helper 17 (Th17) cell subset, produced by γδT cells [6], CD8+ T cells [7], [8], natural killer (NK) cells [9], [10] and NKT cells [11], [12]. A pathogenetic role for the Th17 pathway has been established in models of colitis [13]. "
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    ABSTRACT: IFN-γ is a signature Th1 cell associated cytokine critical for the inflammatory response in autoimmunity with both pro-inflammatory and potentially protective functions. IL-17A is the hallmark of T helper 17 (Th17) cell subsets, produced by γδT, CD8+ T, NK and NKT cells. We have taken advantage of our colony of IL-2Rα-/- mice that spontaneously develop both autoimmune cholangitis and inflammatory bowel disease. In this model CD8+ T cells mediate biliary ductular damage, whereas CD4+ T cells mediate induction of colon-specific autoimmunity. Importantly, IL-2Rα-/- mice have high levels of interferon γ (IFN-γ), and interleukin-17A (IL-17A). We produced unique double deletions of mice that were either IL-17A-/-IL-2Rα-/- or IFN-γ-/-IL-2Rα-/- to specifically address the precise role of these two cytokines in the natural history of autoimmune cholangitis and colitis. Of note, deletion of IL-17A in IL-2Rα-/- mice led to more severe liver inflammation, but ameliorated colitis. In contrast, there were no significant changes in the immunopathology of double knock-out IFN-γ-/- IL-2Rα-/- mice, compared to single knock-out IL-2Rα-/- mice with respect to cholangitis or colitis. Furthermore, there was a significant increase in pathogenetic CD8+ T cells in the liver of IL-17A-/-IL-2Rα-/- mice. Our data suggest that while IL-17A plays a protective role in autoimmune cholangitis, it has a pro-inflammatory role in inflammatory bowel disease. These data take on particular significance in the potential use of anti-IL-17A therapy in humans with primary biliary cirrhosis.
    PLoS ONE 08/2014; 9(8):e105351. DOI:10.1371/journal.pone.0105351 · 3.23 Impact Factor
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    • "They play a key role in tissue remodeling, combating microbes, lymphoid tissue development, and tissue homeostasis, including intestine (53,54). Similar to their lymphoid progenitors, ILCs are divided into subtypes based on the pattern of cytokines synthesized and on the expression of specific transcription factors (53-55). It is known that these cells play an important role in gut homeostasis as well as in the pathogenesis of IBD (Figure 1). "
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    ABSTRACT: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 07/2014; DOI:10.1590/1414-431X20143932 · 1.01 Impact Factor
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    • "The recent discovery and characterization of an ILC3 population with immunophenotypic features overlapping those of CD34 À CD117 + CD94 À stage 3 human NK cell developmental intermediate (Cupedo et al., 2009; Freud et al., 2006; Hughes et al., 2009, 2010; Spits et al., 2013; Walker et al., 2013) have challenged us to further examine our original four-stage model of human NK cell development (Freud et al., 2006). Indeed, because stage 3 immature NK cells or IL-1R1 hi ILC3s neither produce IFN-g nor display cytolytic activity ex vivo yet in bulk or singlecell culture can give rise to functionally and phenotypically mature NK cells, Freud et al. originally characterized this population as committed immature NK cells (Freud et al., 2006). "
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    ABSTRACT: Accumulating evidence indicates that human natural killer (NK) cells develop in secondary lymphoid tissue (SLT) through a so-called "stage 3" developmental intermediate minimally characterized by a CD34(-)CD117(+)CD94(-) immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC) types that include interleukin-1 receptor (IL-1R1)-positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here, we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes the differentiation of tonsillar IL-22-producing IL-1R1(hi) human ILC3s to CD56(bright)CD94(+) interferon (IFN)-γ-producing cytolytic mature NK cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, we demonstrate the lineage plasticity of human ILCs by identifying AHR as a transcription factor that prevents IL-1R1(hi) ILC3s from differentiating into NK cells.
    Cell Reports 06/2014; 8(1). DOI:10.1016/j.celrep.2014.05.042 · 8.36 Impact Factor
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