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

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

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

Gut microbiome: a surprise in the stomach The stomach’s microbiota, and its effect on immune development, may be key factors in fending off infection with Helicobacter pylori, a bacterium found in the stomach that can lead to gastric upset and, if left untreated, ulcers or stomach cancer. Unlike the intestines, the stomach was thought to contain few bacteria owing to its high acidity, but according to new studies, the stomach harbors its own set of microbiota. Hiroshi Ohno and Naoko Satoh-Takayama at the RIKEN Center for Integrative Medical Sciences and Yokohama City University, Japan, review how gastric microbiota affects development of immune cells in the stomach. They report that the stomach’s unique microbiota influences maturation of particular immune cells, which may be crucial in fighting off H. pylori infection. These findings illuminate a new area in microbiome research

A 'natural' way to provide innate mucosal immunity.

International audienceThe 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

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

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

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

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 gamma-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 kappa B (NF-kappa B)-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 cell

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

International audienceGroup 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

Dissecting Human NK Cell Development and Differentiation

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

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

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

International audienceThe 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