Cutting Edge: NKT Cells Constitutively Express IL-23 Receptor and RORγt and Rapidly Produce IL-17 upon Receptor Ligation in an IL-6-Independent Fashion

Rachitskaya, Aleksandra; Hansen, Anna M.; Horai, Reiko; Li, Zhuqing; Villasmil, Rafael; Luger, Dror; Nussenblatt, Robert B.; Caspi, Rachel R

doi:10.4049/jimmunol.180.8.5167

Cited by 369 publications

(324 citation statements)

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“…Since IL-17 protein is not detectable in absence of exogenous activation [19,20], we analyzed IL-17 mRNA and other mRNAs associated with the IL-17 response. Importantly, IL-17 mRNA level was much higher in iNKT cells from the pancreatic islets than from PLNs and ILNs.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of mRNA encoding RORgt, which is required for iNKT17 cell differentiation [21], revealed its high expression in the stage 2 CD4 À iNKT cells and 3-fold increased in NOD mice. IL-23R is constitutively expressed by iNKT17 cells [20], and its expression is high in stage 2 CD4 À iNKT cells, however, there is no significant difference between NOD and C57BL/6 mice. Interestingly, stage 2 CD4 À iNKT cells also expressed IL-22 mRNA and this expression is 4-fold higher in cells from NOD mice.…”

Section: Enhanced Expression Of Il-17-associated Genes By Thymic Inktmentioning

confidence: 91%

“…Since previous studies have shown that iNKT17 cells can secrete IL-17 through TCR engagement [20], we investigated whether CD1d was required for IL-17A mRNA expression by iNKT17 cells in the pancreas (Fig. 3E).…”

Section: Pancreatic Inkt17 Cells Express Il-17a Mrna In the Absence Omentioning

confidence: 99%

“…Recently, a new population of CD4 À NK1.1 À iNKT cells producing high levels of the pro-inflammatory cytokine IL-17 together with low IL-4 and IFN-g levels in response to several iNKT cell ligands, has been identified and named iNKT17 cells [19]. Consistent with their ability to produce IL-17 rapidly and independently of IL-6, iNKT17 cells, unlike naive T cells, were found to express constitutively IL-23R and Retinoic acid receptor -related orphan receptor gt (RORgt) [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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Section: Discussionmentioning

confidence: 99%

Section: Enhanced Expression Of Il-17-associated Genes By Thymic Inktmentioning

confidence: 91%

Section: Pancreatic Inkt17 Cells Express Il-17a Mrna In the Absence Omentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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“…It has recently been demonstrated that NKT cells, which express IL-23R, secrete IL-17 following stimulation with anti-CD3 and IL-23, independently of . Furthermore, NKT cells can secrete IL-17 in response to the synthetic ligand a-galactosylceramide [27,30].gd T cells and other non-CD4 1 CD8 1 T cells are the primary source of IL-17 during Mycobacterium tuberculosis infection [28]. Vd1 1 gd T cells are also a major source of IL-17 in Escherichia coli infection, where they promote neutrophil recruitment [29].…”

mentioning

confidence: 99%

Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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Invariant natural killer T cells are natural regulators of murine spondylarthritis

Jacques¹,

Venken²,

Beneden³

et al. 2010

Arthritis & Rheumatism

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Objective. To investigate the role of invariant natural killer T (iNKT) cells in TNF⌬ARE/؉ mice, an animal model of spondylarthritis (SpA) with both gut and joint inflammation.Methods. The frequency and activation of iNKT cells were analyzed on mononuclear cells from the lymph nodes and livers of mice, using flow cytometry with ␣-galactosylceramide/CD1d tetramers and quantitative polymerase chain reaction for the invariant V ␣ 14-J ␣ 18 rearrangement. Bone marrow-derived dendritic cells (DCs) were obtained by expansion of primary cells with granulocyte-macrophage colony-stimulating factor followed by coculture with iNKT cell hybridomas, and interleukin-2 release into the cocultures was then measured by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were determined by ELISA or cytometric bead array analyses of freshly isolated DCs and iNKT cells in mixed cocultures. TNF ⌬ARE/؉ mice were backcrossed onto J ␣ 18 ؊/؊ and CD1d ؊/؊ mice, and disease onset was evaluated by clinical scoring, positron emission tomography, and histology. CD1d levels were analyzed on mononuclear cells in paired blood and synovial fluid samples from patients with SpA compared with healthy control subjects. Results. In the absence of iNKT cells, symptoms of gut and joint inflammation in TNF⌬ARE/؉ mice were aggravated. Invariant NKT cells were activated during the course of the disease. This was linked to an enrichment of inflammatory DCs, characterized by high levels of CD1d, particularly at draining sites of inflammation. A similar increase in CD1d levels was observed on DCs from patients with SpA. Inflammatory DCs from TNF ⌬ARE/؉ mice stimulated iNKT cells to produce immunomodulatory cytokines, in the absence of exogenous stimulation. Prolonged, continuous exposure, but not short-term exposure, to tumor necrosis factor (TNF) was found to be responsible for the enhanced DC-NKT cell crosstalk.Conclusion. This mode of iNKT cell activation represents a natural counterregulatory mechanism for the dampening of TNF-driven inflammation.The spondylarthritides (SpA) are a group of chronic inflammatory disorders that primarily affect the joints and are accompanied by a variety of extraarticular manifestations, such as intestinal and ocular inflammation. Joint symptoms include peripheral arthritis and enthesitis (1), sacroiliitis and spondylitis, and new bone formation leading to ankylosis. There is major overlap between the different clinical entities of SpA, and familial clustering has been observed. Mechanisms contributing to their pathogenesis include genetic predisposition (linked to various factors, including HLA-B27, interleukin-23 receptor , and aminopeptidase regulator of tumor necrosis factor [TNF] receptor 1 shedding [ARTS1], among others) and certain environ-

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Cutting Edge: NKT Cells Constitutively Express IL-23 Receptor and RORγt and Rapidly Produce IL-17 upon Receptor Ligation in an IL-6-Independent Fashion

Cited by 369 publications

References 13 publications

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

Induction, function and regulation of IL‐17‐producing T cells

Invariant natural killer T cells are natural regulators of murine spondylarthritis

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