Publications by authors named "Naoko Satoh-Takayama"

25 Publications

  • Page 1 of 1

Dietary Derived Micronutrients Modulate Immune Responses Through Innate Lymphoid Cells.

Front Immunol 2021 29;12:670632. Epub 2021 Apr 29.

Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Innate lymphoid cells (ILCs) are a group of innate immune cells that possess overlapping features with T cells, although they lack antigen-specific receptors. ILCs consist of five subsets-ILC1, ILC2, ILC3, lymphoid tissue inducer (LTi-like) cells, and natural killer (NK) cells. They have significant functions in mediating various immune responses, protecting mucosal barrier integrity and maintaining tissue homeostasis in the lung, skin, intestines, and liver. ILCs react immediately to signals from internal and external sources. Emerging evidence has revealed that dietary micronutrients, such as various vitamins and minerals can significantly modulate immune responses through ILCs and subsequently affect human health. It has been demonstrated that micronutrients control the development and proliferation of different types of ILCs. They are also potent immunoregulators in several autoimmune diseases and play vital roles in resolving local inflammation. Here, we summarize the interplay between several essential micronutrients and ILCs to maintain epithelial barrier functions in various mucosal tissues and discuss their limitations and potentials for promoting human health.
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http://dx.doi.org/10.3389/fimmu.2021.670632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116705PMC
April 2021

The Role of Innate Lymphoid Cells in the Regulation of Immune Homeostasis in Sepsis-Mediated Lung Inflammation.

Diagnostics (Basel) 2020 Oct 12;10(10). Epub 2020 Oct 12.

Department of Molecular Pathobiology and Cell Adhesion Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu City, Mie 514-8507, Japan.

Septic shock/severe sepsis is a deregulated host immune system response to infection that leads to life-threatening organ dysfunction. Lung inflammation as a form of acute lung injury (ALI) is often induced in septic shock. Whereas macrophages and neutrophils have been implicated as the principal immune cells regulating lung inflammation, group two innate lymphoid cells (ILC2s) have recently been identified as a new player regulating immune homeostasis. ILC2 is one of the three major ILC subsets (ILC1s, ILC2s, and ILC3s) comprised of newly identified innate immune cells. These cells are characterized by their ability to rapidly produce type 2 cytokines. ILC2s are predominant resident ILCs and, thereby, have the ability to respond to signals from damaged tissues. ILC2s regulate the immune response, and ILC2-derived type 2 cytokines may exert protective roles against sepsis-induced lung injury. This focused review not only provides readers with new insights into the signaling mechanisms by which ILC2s modulate sepsis-induced lung inflammation, but also proposes ILC2 as a novel therapeutic target for sepsis-induced ALI.
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http://dx.doi.org/10.3390/diagnostics10100808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600279PMC
October 2020

Unraveling the Heterogeneity and Specialization of ILCs.

Immunity 2020 10;53(4):699-701

Laboratory for Intestinal Ecosystem, Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Immunobiology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Laboratory for Immune Regulation, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba 260-8670, Japan; Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan.

In this issue of Immunity, Zeis et al. report the generation of a single-cell atlas of lung innate lymphoid cells (ILCs). Their findings provide insight into the how ILCs are locally maintained, revealing in situ differentiation and diversification as mechanisms of ILC renewal and function.
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http://dx.doi.org/10.1016/j.immuni.2020.09.017DOI Listing
October 2020

Stomach microbiota, Helicobacter pylori, and group 2 innate lymphoid cells.

Exp Mol Med 2020 09 10;52(9):1377-1382. Epub 2020 Sep 10.

Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.

The stomach has been thought to host few commensal bacteria because of the existence of barriers, such as gastric acid. However, recent culture-independent, sequencing-based microbial analysis has shown that the stomach also harbors a wide diversity of microbiota. Although the stomach immune system, especially innate lymphoid cells (ILCs), has not been well elucidated, recent studies have shown that group 2 ILCs (ILC2s) are the dominant subtype in the stomach of both humans and mice. Stomach ILC2s are unique in that their existence is dependent on stomach microbiota, in sharp contrast to the lack of an impact of commensal microbiota on ILC2s in other tissues. The microbiota dependency of stomach ILC2s is partly explained by their responsiveness to interleukin (IL)-7. Stomach ILC2s express significantly higher IL-7 receptor protein levels on their surface and proliferate more in response to IL-7 stimulation in vitro than small intestinal ILC2s. Consistently, the stomach expresses much higher IL-7 protein levels than the small intestine. IL-5 secreted from stomach ILC2s promotes immunoglobulin (Ig) A production by plasma B cells. In a murine model, stomach ILC2s are important in containing Helicobacter pylori infection, especially in the early phase of infection, by promoting IgA production.
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http://dx.doi.org/10.1038/s12276-020-00485-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080604PMC
September 2020

Innate Lymphoid Cells: Important Regulators of Host-Bacteria Interaction for Border Defense.

Microorganisms 2020 Sep 2;8(9). Epub 2020 Sep 2.

Laboratory for Intestinal Ecosystem, Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.

Innate lymphoid cells (ILCs) are a recently discovered type of innate immune lymphocyte. They include three different groups classified by the nature of the transcription factors required for their development and by the cytokines they produce. ILCs mainly reside in tissues close to the mucosal barrier such as the respiratory and gastrointestinal tracts. Due to their close proximity to the mucosal surface, ILCs are exposed to a variety of both commensal and pathogenic bacteria. Under non-pathological conditions, ILCs have been shown to be important regulators for the maintenance of tissue homeostasis by mutual interactions with the microbiome. Besides these important functions at homeostasis, several studies have also provided emerging evidence that ILCs contribute to defense against pathogenic bacterial infection by responding rapidly to the pathogens as well as orchestrating other immune cells. In this review, we summarize recent advances in our understanding of the interactions of ILCs and bacteria, with special focus on the function of the different ILC subsets in bacterial infections.
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http://dx.doi.org/10.3390/microorganisms8091342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563982PMC
September 2020

Sepsis Induces Deregulation of IL-13 Production and PD-1 Expression in Lung Group 2 Innate Lymphoid Cells.

Shock 2021 Mar;55(3):357-370

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu City, Mie, Japan.

Abstract: Deregulation of the immune system in sepsis plays the central role in the pathogenesis of multiple organ failure including septic lung injury. Group 2 innate lymphoid cells (ILC2s) have emerged as a new player in regulating immune homeostasis in the lung; however, the role of ILC2s in lung injury in sepsis remains poorly understood. Here, we investigated temporal changes in stimulatory and inhibitory receptor expression and intracellular type 2 cytokine expression of ILC2s in the lung using a cecal ligation and puncture mouse sepsis model. We found that IL-13 production by ILC2s, which were predominately composed of the resident natural ILC2 subset rather than the migratory inflammatory ILC2 subset, was reduced in the lungs of sepsis mice on day 1 and gradually restored through day 7. Although the expression levels of ST2 and inducible T-cell costimulator (stimulatory receptors) were high, IL-13 production by ILC2s was reduced while showing high programmed cell death 1 (PD-1) (inhibitory receptor) expression. Furthermore, using IL-33 knockout mice, we have shown that IL-33 regulates the capacity of ILC2s to produce IL-13, possibly through the modulation of ST2 and PD-1 expression and signaling in the septic lung. To the best of our knowledge, this is the first report showing differential costimulatory/inhibitory receptor expression on ILC2s in a septic lung in the context of an IL-33/IL-13 pathway-mediated type 2 immune response in the progression and resolution of inflammation. Our present findings contribute to a better understanding of the underlying immunological mechanism of ILC2s and may fill the critical knowledge gap regarding immune homeostasis in the lung that hampers the development of new therapeutic strategies for sepsis-induced acute lung injury.
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http://dx.doi.org/10.1097/SHK.0000000000001647DOI Listing
March 2021

Bacteria-Induced Group 2 Innate Lymphoid Cells in the Stomach Provide Immune Protection through Induction of IgA.

Immunity 2020 04 1;52(4):635-649.e4. Epub 2020 Apr 1.

Laboratory for Intestinal Ecosystem, Center for Integrative Medical Sciences, RIKEN Yokohama, Kanagawa 230-0045, Japan; Immunobiology Laboratory, Graduate School of Medical Life Science, Yokohama City University Yokohama, Kanagawa 230-0045, Japan; Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology Ebina, Kanagawa 243-0435, Japan. Electronic address:

The intestinal microbiota shapes and directs immune development locally and systemically, but little is known about whether commensal microbes in the stomach can impact their immunological microenvironment. Here, we report that group 2 innate lymphoid cells (ILC2s) were the predominant ILC subset in the stomach and show that their homeostasis and effector functions were regulated by local commensal communities. Microbes elicited interleukin-7 (IL-7) and IL-33 production in the stomach, which in turn triggered the propagation and activation of ILC2. Stomach ILC2s were also rapidly induced following infection with Helicobacter pylori. ILC2-derived IL-5 resulted in the production of IgA, which coated stomach bacteria in both specific pathogen-free (SPF) and H. pylori-infected mice. Our study thus identifies ILC2-dependent IgA response that is regulated by the commensal microbiota, which is implicated in stomach protection by eliminating IgA-coated bacteria including pathogenic H. pylori.
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http://dx.doi.org/10.1016/j.immuni.2020.03.002DOI Listing
April 2020

Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice.

Int Immunol 2020 04;32(4):259-272

Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.

Gain-of-function (GOF) mutations in the gene for signal transducer and activator of transcription 1 (STAT1) account for approximately one-half of patients with chronic mucocutaneous candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice [GOF-Stat1 knock-in (GOF-Stat1R274Q)]. To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4+ T cells, those with 'normal' or 'high' level of basal STAT1 protein in Stat1R274Q/R274Q mice. Upon IFN-γ stimulation, the 'normal' level CD4+ T cells were more efficiently phosphorylated than those from WT mice, whereas the 'high' level CD4+ T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the SI. Inoculation of Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγt+ cells. Stat1R274Q/R274Q mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was up-regulation of T-bet in CD4+ T cells. GOF-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder.
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http://dx.doi.org/10.1093/intimm/dxz079DOI Listing
April 2020

Dietary Antigens Induce Germinal Center Responses in Peyer's Patches and Antigen-Specific IgA Production.

Front Immunol 2019 15;10:2432. Epub 2019 Oct 15.

Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

The primary induction sites for intestinal IgA are the gut-associated lymphoid tissues (GALT), such as Peyer's patches (PPs) and isolated lymphoid follicles (ILFs). The commensal microbiota is known to contribute to IgA production in the gut; however, the role of dietary antigens in IgA production is poorly understood. To understand the effect of dietary antigens on IgA production, post-weaning mice were maintained on an elemental diet without any large immunogenic molecules. We found that dietary antigens contribute to IgA production in PPs through induction of follicular helper T cells and germinal center B cells. The role of dietary antigens in the PP responses was further confirmed by adding bovine serum albumin (BSA) into the elemental diet. Although dietary antigens are important for PP responses, they have fewer effects than the microbiota on the development and maturation of ILFs. Furthermore, we demonstrated that dietary antigens are essential for a normal antigen-specific IgA response to serovar Typhimurium infection. These results provide new insights into the role of dietary antigens in the regulation of mucosal immune responses.
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http://dx.doi.org/10.3389/fimmu.2019.02432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803481PMC
November 2020

Understanding the immune signature fingerprint of peritoneal dialysis-related peritonitis.

Kidney Int 2017 07;92(1):16-18

Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address:

Although acute peritonitis is a common and severe complication associated with peritoneal dialysis, the culture-based test used as the diagnostic criterion for this disease is often too slow to allow appropriate point-of-care diagnosis of specific bacterial infection. To address this problem, Zhang et al. report the efficacy of a novel set of immune biomarkers derived from a machine-learning algorithm applied to patient data. This fingerprint could predict major pathogenic causes of peritonitis.
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http://dx.doi.org/10.1016/j.kint.2017.02.027DOI Listing
July 2017

Phenotypic and Functional Plasticity of Murine Intestinal NKp46+ Group 3 Innate Lymphoid Cells.

J Immunol 2016 06 22;196(11):4731-8. Epub 2016 Apr 22.

Unité d'Immunité Innée, Institut Pasteur, 75724 Paris, France; INSERM U1223, 75724 Paris, France;

Group 3 innate lymphoid cells (ILC3) actively participate in mucosal defense and homeostasis through prompt secretion of IL-17A, IL-22, and IFN-γ. Reports identify two ILC3 lineages: a CCR6(+)T-bet(-) subset that appears early in embryonic development and promotes lymphoid organogenesis and a CCR6(-)T-bet(+) subset that emerges after microbial colonization and harbors NKp46(+) ILC3. We demonstrate that NKp46 expression in the ILC3 subset is highly unstable. Cell fate mapping using Ncr1(CreGFP) × Rosa26(RFP) mice revealed the existence of an intestinal RFP(+) ILC3 subset (Ncr1(FM)) lacking NKp46 expression at the transcript and protein levels. Ncr1(FM) ILC3 produced more IL-22 and were distinguishable from NKp46(+) ILC3 by differential CD117, CD49a, DNAX accessory molecule-1, and, surprisingly, CCR6 expression. Ncr1(FM) ILC3 emerged after birth and persisted in adult mice following broad-spectrum antibiotic treatment. These results identify an unexpected phenotypic instability within NKp46(+) ILC3 that suggests a major role for environmental signals in tuning ILC3 functional plasticity.
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http://dx.doi.org/10.4049/jimmunol.1502673DOI Listing
June 2016

Heterogeneity and diversity of group 3 innate lymphoid cells: new cells on the block.

Int Immunol 2016 Jan 13;28(1):29-34. Epub 2015 Oct 13.

Laboratory for Intestinal Ecosystem, Center for Integrative Medical Science, RIKEN, 1-7-22 Suehiro-cho, Tsurumi, Yokohama city, Kanagawa 230-0045, Japan

Innate lymphoid cells (ILCs) are a newly identified subset of innate cells that play fundamentally crucial roles for early immune defense at mucosal and non-mucosal sites. ILCs consist of ILC1s, ILC2s and ILC3s, which each have distinct transcription factors controlling their development and function. Interestingly, each of the ILC subsets represents the innate counterparts of CD4(+) helper T-cell subsets T(h1), T(h2) and T(h17) on the basis of transcriptional regulation. ILC1s that produce IFN-γ or TNF-α, ILC2s that produce T(h2)-type cytokines mainly such as IL-5 or IL-13 and ILC3s have been recently reported and reviewed in terms of IL-22- or IL-17-producing function and cell development. However, in this relatively new field, it remains likely that additional functional and regulatory mechanisms remain to be explored. More recent findings show that ILC3s are regulated by RORγt, which plays an important role for the mucosal barrier and surface protection against pathogenic bacterial infection. ILC3s might cooperate with other cells (e.g. T cells or dendritic cells) directly or indirectly, and subsequently ILC3s have impact on tissues with prompt regulation. Especially, ILC3s in mucosal site are well known to protect the intestinal surface barrier through inducible anti-microbial peptides via IL-22. Here, I will summarize and discuss the roles, function and heterogeneity of ILC3s in mucosal tissues.
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http://dx.doi.org/10.1093/intimm/dxv054DOI Listing
January 2016

The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells.

Immunity 2014 Nov 6;41(5):776-88. Epub 2014 Nov 6.

Innate Immunity Unit, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France; Inserm U668, 75724 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.immuni.2014.10.007DOI Listing
November 2014

Conditional ablation of NKp46+ cells using a novel Ncr1(greenCre) mouse strain: NK cells are essential for protection against pulmonary B16 metastases.

Eur J Immunol 2014 Nov 19;44(11):3380-91. Epub 2014 Sep 19.

Département d'Immunologie, Unité d'Immunité Innée, Institut Pasteur, Paris, France; Institut Pasteur, INSERM U668, Paris, France; Cellule Pasteur, Sorbonne Paris Cité, Univ. Paris Diderot, Paris, France.

To study gene functions specifically in NKp46+ cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1(greenCre) mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46+ cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46+ cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46+ cell-specific expression of RFP in Ncr1(greenCre) Rosa-dtRFP reporter mice. We generated Ncr1(greenCre) Il2rg(fl/fl) mice that lack NKp46+ cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γc ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, -9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1(greenCre) Il2rg(fl/fl) mice, NK cells are severely reduced and the few remaining NKp46+ cells escaping γc deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46+ cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Finally, Ncr1(greenCre) Il2rg(fl/fl) mice are unable to reject B16 lung metastases demonstrating the essential role of NKp46+ cells in antimelanoma immune responses.
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http://dx.doi.org/10.1002/eji.201444643DOI Listing
November 2014

Gata3 drives development of RORγt+ group 3 innate lymphoid cells.

J Exp Med 2014 Feb 13;211(2):199-208. Epub 2014 Jan 13.

Innate Immunity Unit, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.

Group 3 innate lymphoid cells (ILC3) include IL-22-producing NKp46(+) cells and IL-17A/IL-22-producing CD4(+) lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt(+) ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt(+) ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.
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http://dx.doi.org/10.1084/jem.20131038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920560PMC
February 2014

IL-22 is produced by γC-independent CD25+ CCR6+ innate murine spleen cells upon inflammatory stimuli and contributes to LPS-induced lethality.

Eur J Immunol 2011 Apr 14;41(4):1075-85. Epub 2011 Mar 14.

Ludwig Institute for Cancer Research, Brussels Branch, Belgium.

IL-22 is a Th17 cytokine that plays a key role in immune responses against extracellular bacteria. In mucosal lymphoid tissues, IL-22 production is mainly due to an IL-23-responsive NK-like cell subset that shares some markers with lymphoid tissue inducer (LTi) cells. Here, we identified a new spleen cell population responsible for IL-22 production upon either in vitro stimulation by anti-CD3 antibodies or in vivo stimulation by lipopolysaccharide (LPS) via IL-2- and an IL-23-dependent mechanisms, respectively. These cells represent 1% of spleen cells from recombination activating gene (Rag2)-deficient mice, and correspond to a discrete innate lymphoid cell population expressing CD25, CCR6 and IL-7R. This population comprises 60-70% CD4(+) cells, which produce IL-22, and are still present in common γ chain-deficient mice; the CD4(-) subset coexpresses IL-22 and IL-17, and is common γ chain-dependent. The importance of IL-22 production for the LPS-triggered response is highlighted by the fact that IL-22-deficient mice are more resistant to LPS-induced mortality.
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http://dx.doi.org/10.1002/eji.201040878DOI Listing
April 2011

Lymphotoxin-β receptor-independent development of intestinal IL-22-producing NKp46+ innate lymphoid cells.

Eur J Immunol 2011 Mar 1;41(3):780-6. Epub 2011 Feb 1.

Innate Immunity Unit, Institut Pasteur, Paris, France.

The natural cytotoxicity receptor NKp46 is an activating receptor expressed by several distinct innate lymphoid cell (ILC) subsets, including NK cells, some γδ T cells and intestinal RORγt(+) IL-22(+) cells (NCR22 cells, IL-22-producing NKp46(+) cell). NCR22 cells may play a role in mucosal barrier function through IL-22-mediated production of anti-bacterial peptides from intestinal epithelial cells. Previous studies identified a predominant proportion of NCR22 cells in gut cryptopatches (CP), lymphoid structures that are strategically positioned to collect and integrate signals from luminal microbes; however, whether CP or other lymphoid structures condition NCR22 cell differentiation is not known. Programmed and inducible lymphoid tissue development requires cell-surface-expressed lymphotoxin (LT)α(1) β(2) heterotrimers (provided by lymphoid tissue inducer (LTi) cells) to signal lymphotoxin-β receptor (LTR)(+) stromal cells. Here, we analyzed NCR22 cells in LTβR-deficient Ncr1(GFP/+) mice that lack organized secondary lymphoid tissues. We found that NCR22 cells develop in the absence of LTβR, become functionally competent and localize to the lamina propria under steady-state conditions. Following infection of LTβR(-/-) mice with the Gram-negative pathogen Citrobacter rodentium, IL-22 production from NCR22 cells was not affected. These results indicate that organized lymphoid tissue structures are not critical for the generation of an intact and fully functional intestinal NCR22 cell compartment.
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http://dx.doi.org/10.1002/eji.201040851DOI Listing
March 2011

RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota.

Nat Immunol 2011 Apr 20;12(4):320-6. Epub 2011 Feb 20.

Institut Pasteur, Lymphoid Tissue Development Unit, Paris, France.

Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T(H)17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue-inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to T(H)17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.
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http://dx.doi.org/10.1038/ni.2002DOI Listing
April 2011

Regulation of cytokine secretion in human CD127(+) LTi-like innate lymphoid cells by Toll-like receptor 2.

Immunity 2010 Nov 4;33(5):752-64. Epub 2010 Nov 4.

Department of Immunology, Genentech, South San Francisco, CA 94080, USA.

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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http://dx.doi.org/10.1016/j.immuni.2010.10.012DOI Listing
November 2010

Lineage relationship analysis of RORgammat+ innate lymphoid cells.

Science 2010 Oct 23;330(6004):665-9. Epub 2010 Sep 23.

Lymphoid Tissue Development Unit, Institut Pasteur, 75724 Paris, France.

Lymphoid tissue-inducer (LTi) cells initiate the development of lymphoid tissues through the activation of local stromal cells in a process similar to inflammation. LTi cells express the nuclear hormone receptor RORγt, which also directs the expression of the proinflammatory cytokine interleukin-17 in T cells. We show here that LTi cells are part of a larger family of proinflammatory RORγt(+) innate lymphoid cells (ILCs) that differentiate from distinct fetal liver RORγt(+) precursors. The fate of RORγt(+) ILCs is determined by mouse age, and after birth, favors the generation of cells involved in intestinal homeostasis and defense. Contrary to RORγt(+) T cells, however, RORγt(+) ILCs develop in the absence of microbiota. Our study indicates that RORγt(+) ILCs evolve to preempt intestinal colonization by microbial symbionts.
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http://dx.doi.org/10.1126/science.1194597DOI Listing
October 2010

Cutting edge: Thymic NK cells develop independently from T cell precursors.

J Immunol 2010 Nov 1;185(9):4993-7. Epub 2010 Oct 1.

Unité d'Immunité Innée, Institut Pasteur, INSERM U668, Paris, France.

Although NK cells in the mouse are thought to develop in the bone marrow, a small population of NK cells in the thymus has been shown to derive from a GATA3-dependent pathway. Characteristically, thymic NK cells express CD127 and few Ly49 molecules and lack CD11b. Because these NK cells develop in the thymus, the question of their relationship to the T cell lineage has been raised. Using several different mouse models, we find that unlike T cells, thymic NK cells are not the progeny of Rorc-expressing progenitors and do not express Rag2 or rearrange the TCRγ locus. We further demonstrate that thymic NK cells develop independently of the Notch signaling pathway, supporting the idea that thymic NK cells represent bona fide NK cells that can develop independently of all T cell precursors.
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http://dx.doi.org/10.4049/jimmunol.1002273DOI Listing
November 2010

A 'natural' way to provide innate mucosal immunity.

Curr Opin Immunol 2010 Aug 21;22(4):435-41. Epub 2010 Jun 21.

Innate Immunity Unit, Institut Pasteur, Paris, France.

The mucosal barrier comprises a layered defense system including physio-chemical and immunological strategies to contain commensal microflora while protecting the host against potential pathogens. In contrast to the clearly established and well-characterized role for the adaptive immune system in intestinal defense, our knowledge on innate immune mechanisms that operate in the gut is much less defined. The recent identification of novel innate lymphoid cells (ILC), including 'NK-like' cells that naturally produce IL-22 and appear to play a role in intestinal defense, demonstrates an unexpected and increasing complexity in mucosal innate immunity.
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http://dx.doi.org/10.1016/j.coi.2010.05.004DOI Listing
August 2010

IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors.

J Exp Med 2010 Feb 8;207(2):273-80. Epub 2010 Feb 8.

Cytokines and Lymphoid Development Unit, Institut Pasteur, 75724 Paris, France.

The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3(-)NKp46(+) cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1(+), Ly49(+)) but also a large CD127(+)NK1.1(-) subset of lymphoid tissue inducer (LTi)-like Rorc(+) cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3(-)NKp46(+) subsets. Gut CD3(-)NKp46(+) cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1(+) cells within the gut but had no effect on absolute numbers of the CD127(+)NK1.1(-)Rorc(+) subset of CD3(-)NKp46(+) cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3(-)NKp46(+)NK1.1(-) cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1(+) cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1(+)CD127(-) cells are not the progeny of Rorc-expressing progenitors, indicating that CD127(+)NK1.1(-)Rorc(+) cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46(+) cell subsets.
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http://dx.doi.org/10.1084/jem.20092029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822619PMC
February 2010

The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium.

J Immunol 2009 Nov 21;183(10):6579-87. Epub 2009 Oct 21.

Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France.

Natural cytotoxicity receptors (including NKp30, NKp44, and NKp46 in humans and NKp46 in mice) are type I transmembrane proteins that signal NK cell activation via ITAM-containing adapter proteins in response to stress- and pathogen-induced ligands. Although murine NKp46 expression (encoded by Ncr1) was thought to be predominantly restricted to NK cells, the identification of distinct intestinal NKp46(+) cell subsets that express the transcription factor Rorc and produce IL-22 suggests a broader function for NKp46 that could involve intestinal homeostasis and immune defense. Using mice carrying a GFP-modified Ncr1 allele, we found normal numbers of gut CD3(-)GFP(+) cells with a similar cell surface phenotype and subset distribution in the absence of Ncr1. Splenic and intestinal CD3(-)NKp46(+) cell subsets showed distinct patterns of cytokine secretion (IFN-gamma, IL-22) following activation via NK1.1, NKp46, IL-12 plus IL-18, or IL-23. However, IL-22 production was sharply restricted to intestinal CD3(-)GFP(+) cells with the CD127(+)NK1.1(-) phenotype and could be induced in an Ncr1-independent fashion. Because NKp46 ligands can trigger immune activation in the context of infectious pathogens, we assessed the response of wild-type and Ncr-1-deficient Rag2(-/-) mice to the enteric pathogen Citrobacter rodentium. No differences in the survival or clinical score were observed in C. rodentium-infected Rag2(-/-) mice lacking Ncr1, indicating that NKp46 plays a redundant role in the differentiation of intestinal IL-22(+) cells that mediate innate defense against this pathogen. Our results provide further evidence for functional heterogeneity in intestinal NKp46(+) cells that contrast with splenic NK cells.
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http://dx.doi.org/10.4049/jimmunol.0901935DOI Listing
November 2009

Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense.

Immunity 2008 Dec 11;29(6):958-70. Epub 2008 Dec 11.

Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris F-75724, France.

Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-gamma (IFN-gamma) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46+ cells were distinguished from classical NK cells by limited IFN-gamma production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORgammat) and interleukin-22 (IL-22). Intestinal NKp46+IL-22+ cells were generated via a local process that was conditioned by commensal bacteria and required RORgammat. Mice lacking IL-22-producing NKp46+ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46+ cells in immune protection. RORgammat-driven diversification of intestinal NKp46+ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces.
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http://dx.doi.org/10.1016/j.immuni.2008.11.001DOI Listing
December 2008
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