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
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.
Figures in this publication
Available from: Jean-Christophe Renauld
- "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). These different ILC groups have been identified in multiple tissues and in the circulation (Spits and Di Santo, 2011). "
[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.
Available from: Zhe-Xiong Lian
- "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 . IL-17A is the hallmark cytokine of T helper 17 (Th17) cell subset, produced by γδT cells , CD8+ T cells , , natural killer (NK) cells ,  and NKT cells , . A pathogenetic role for the Th17 pathway has been established in models of colitis . "
[Show abstract] [Hide abstract]
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.
Available from: Helioswilton Sales-Campos
- "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). "
[Show abstract] [Hide abstract]
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.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.