Notch signaling is necessary for adult, but not fetal, development of RORγt(+) innate lymphoid cells.
TL;DR: It is shown that common lymphoid progenitors lost B cell and T cell potential as they successively acquired expression of the integrin α4β7 and CXCR6 and that adult bone marrow–derived RORγt+ ILCs matured outside the bone marrow, in a Notch2-dependent manner.
Abstract: The transcription factor RORγt is required for the development of several innate lymphoid populations, such as lymphoid tissue-inducer cells (LTi cells) and cells that secrete interleukin 17 (IL-17) or IL-22. The progenitor cells as well as the developmental stages that lead to the emergence of RORγt(+) innate lymphoid cells (ILCs) remain undefined. Here we identify the chemokine receptor CXCR6 as an additional marker of the development of ILCs and show that common lymphoid progenitors lost B cell and T cell potential as they successively acquired expression of the integrin α(4)β(7) and CXCR6. Whereas fetal RORγt(+) cells matured in the fetal liver environment, adult bone marrow-derived RORγt(+) ILCs matured outside the bone marrow, in a Notch2-dependent manner. Therefore, fetal and adult environments influence the differentiation of RORγt(+) cells differently.
Citations
More filters
TL;DR: This work summarizes the studies that formally identified innate lymphoid cells and highlights their emerging roles in controlling tissue homeostasis in the context of infection, chronic inflammation, metabolic disease and cancer.
Abstract: The innate immune system is composed of a diverse array of evolutionarily ancient haematopoietic cell types, including dendritic cells, monocytes, macrophages and granulocytes. These cell populations collaborate with each other, with the adaptive immune system and with non-haematopoietic cells to promote immunity, inflammation and tissue repair. Innate lymphoid cells are the most recently identified constituents of the innate immune system and have been the focus of intense investigation over the past five years. We summarize the studies that formally identified innate lymphoid cells and highlight their emerging roles in controlling tissue homeostasis in the context of infection, chronic inflammation, metabolic disease and cancer.
1,281 citations
TL;DR: Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages, but not into conventional natural killer cells that have been considered an ILC1 subset, presenting evidence for a new ILC lineage that protects barrier surfaces against intracellular infections.
909 citations
Cites background from "Notch signaling is necessary for ad..."
...While Lin a4b7 + Flt3 RORgt fetal liver cells are progenitors to ILC3s that sequentially initiate expression of Id2 and RORgt (Cherrier et al., 2012; Possot et al., 2011), we now show that Id2+ a4b7 + Flt3 RORgt fetal liver cells have the potential to differentiate into all three helper-like ILC…...
[...]
...OP9-DL1 cells were chosen because it was previously shown that the development of adult RORgt cells and of ILCs from bone marrow progenitors requires Notch ligands (Possot et al., 2011)....
[...]
...While Lin a4b7 + Flt3 RORgt fetal liver cells are progenitors to ILC3s that sequentially initiate expression of Id2 and RORgt (Cherrier et al., 2012; Possot et al., 2011), we now show that Id2 a4b7 + Flt3 RORgt fetal liver cells have the potential to differentiate into all three helper-like ILC subsets....
[...]
...OP9-DL1 cells were chosen because it was previously shown that the development of adult RORgt+ cells and of ILCs from bone marrow progenitors requires Notch ligands (Possot et al., 2011)....
[...]
...An Id2-Expressing Progenitor to All IL-7Ra Helper-like ILC Lineages ILCs are of the lymphoid lineage as they can be generated from the CLP (Possot et al., 2011)....
[...]
01 Jan 2010
816 citations
TL;DR: A human ILC1 subset that produced interferon-γ (IFN-γ) in response to IL-12 and IL-15 and had a unique integrin profile, intraepithelial location, hallmarks of TGF-β imprinting, and a memory-activated phenotype is characterized.
791 citations
Cites background from "Notch signaling is necessary for ad..."
...ILC3 development requires IL-7 signaling and the transcription factors Id2, RORgt (Cherrier et al., 2012; Spits et al., 2013), AHR (Kiss et al., 2011; Lee et al., 2012; Qiu et al., 2012), and Notch (Lee et al., 2012; Possot et al., 2011)....
[...]
TL;DR: It is demonstrated that GATA-3 is essential for ILC2 fate decisions and similarities between the transcriptional programs controlling ILC and T helper cell fates are revealed.
750 citations
Cites background from "Notch signaling is necessary for ad..."
...Both ILC subsets develop from the common lymphoid progenitor (CLP) in a process that requires Notch signaling (Possot et al., 2011; Wong et al., 2012)....
[...]
References
More filters
TL;DR: The Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) population from adult mouse bone marrow possessed a rapid lymphoid-restricted (T, B, and NK) reconstitution capacity in vivo but completely lacked myeloid differentiation potential either in vivo or in vitro.
2,296 citations
TL;DR: The identification and functional characterization of a new innate type-2 immune effector leukocyte that is named the nuocyte is presented, which represents a critically important innate effector cell in type- 2 immunity.
Abstract: Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity-responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma-consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity.
1,896 citations
TL;DR: In this article, a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity was reported. But these cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R.
Abstract: Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines. Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue 'FALC' (fat-associated lymphoid cluster). FALC Lin(-)c-Kit(+)Sca-1(+) cells are distinct from lymphoid progenitors and lymphoid tissue inducer cells. These cells proliferate in response to IL2 and produce large amounts of T(H)2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody production and self-renewal of B1 cells. Indeed, FALC Lin(-)c-Kit(+)Sca-1(+) cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection. After helminth infection and in response to IL33, FALC Lin(-)c-Kit(+)Sca-1(+) cells produce large amounts of IL13, which leads to goblet cell hyperplasia-a critical step for helminth expulsion. In mice devoid of FALC Lin(-)c-Kit(+)Sca-1(+) cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin(-)c-Kit(+)Sca-1(+) cells are T(H)2-type innate lymphocytes, and we propose that these cells be called 'natural helper cells'.
1,649 citations
TL;DR: RORgammat-driven diversification of intestinal NKp46+ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces.
1,001 citations
TL;DR: It is shown that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-γ in the colon, and IL-23-responsive innate intestinal cells are identified, which may represent a target in inflammatory bowel disease.
Abstract: The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-gamma in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-gammat and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-gammat, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.
976 citations