Induced IL-17–Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β

Monteiro, Marta; Almeida, Catarina; Agua-Doce, Ana; Graça, Luís

doi:10.4049/jimmunol.1201010

Cited by 71 publications

(47 citation statements)

References 45 publications

(54 reference statements)

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“…However, Foxp3 expression and acquisition of B cell helper capacity are not found in naive mice, but arise upon immunization (16)(17)(18)(19). These observations strongly support the view that NKT cells are capable of modulating their function in response to signals received in the periphery, which is corroborated by the fact that iNKT cells escaping retinoic acid-related orphan receptor gt imprinting in the thymus can later adopt an NKT17 phenotype and produce IL-17 when activated under Th17 proinflammatory conditions (28,29).…”

Section: Discussionsupporting

confidence: 70%

“…However, it is clear that, in addition to thymic generation of NKT1, NKT2, and NKT17 subsets, some iNKT cells can leave the thymus uncommitted to a particular functional phenotype, namely NKT17, and adopt that phenotype when exposed to adequate inflammatory mediators (14,28,29). We now establish that IL-9-producing NKT cells (NKT9) do not acquire this function in the thymus, but are readily generated in mice and humans upon activation in presence of TGF-b and IL-4.…”

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confidence: 99%

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IL-9 Expression by Invariant NKT Cells Is Not Imprinted during Thymic Development

Monteiro

Agua-Doce

Almeida

et al. 2015

The Journal of Immunology

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Invariant NKT (iNKT) cell thymic development can lead to distinct committed effector lineages, namely NKT1, NKT2, and NKT17. However, following identification of IL-9–producing iNKT cells involved in mucosal inflammation, their development remains unaddressed. In this study, we report that although thymic iNKT cells from naive mice do not express IL-9, iNKT cell activation in the presence of TGF-β and IL-4 induces IL-9 secretion in murine and human iNKT cells. Acquisition of IL-9 production was observed in different iNKT subsets defined by CD4, NK1.1, and neuropilin-1, indicating that distinct functional subpopulations are receptive to IL-9 polarization. Transcription factor expression kinetics suggest that regulatory mechanisms of IL-9 expression are shared by iNKT and CD4 T cells, with Irf4 and Batf deficiency deeply affecting IL-9 production. Importantly, adoptive transfer of an enriched IL-9+ iNKT cell population leads to exacerbated allergic inflammation in the airways upon intranasal immunization with house dust mite, confirming the ability of IL-9–producing iNKT cells to mediate proinflammatory effects in vivo, as previously reported. Taken together, our data show that peripheral iNKT cells retain the capacity of shaping their function in response to environmental cues, namely TGF-β and IL-4, adopting an IL-9–producing NKT cell phenotype able to mediate proinflammatory effects in vivo, namely granulocyte and mast cell recruitment to the lungs.

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Section: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

IL-9 Expression by Invariant NKT Cells Is Not Imprinted during Thymic Development

Monteiro

Agua-Doce

Almeida

et al. 2015

The Journal of Immunology

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“…γ δ T cells are prominent sources of IL-17 when stimulated with IL-23, as shown in a number of models, and iNKT cells also produce IL-17 and IL-22 in response to heat-killed bacteria [66][67][68].…”

Section: Other Sources Of Th17 Cytokinesmentioning

confidence: 98%

Functional Plasticity of Th17 Cells: Implications in Gastrointestinal Tract Function

Garrido-Mesa

Algieri

Nogales

et al. 2013

International Reviews of Immunology

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The gastrointestinal tract is an active player of the human immune system, participating in the innate and adaptive immune responses, keeping the homeostasis of the human being in a healthy status. However, most intestinal conditions are associated with an altered immune response, which implies the activation of CD4(+) T helper (Th) cells. Based on their cytokine secretion, transcription factor expression and immunological functions, the differentiated Th cells were initially subdivided into different lineages: Th1 (that express the transcription factor T-box (T-bet), secrete interferon (IFN)-γ and protect the host against intracellular infections) and Th2 (that express GATA binding protein 3 (GATA-3), secrete interleukin (IL)-4, IL-5 and IL-13, and mediate host defense against helminths). Later, a new subset was identified, the Th17, which selectively produces IL-17A and is crucial for host defense against extracellular pathogens. More recently, a functional plasticity between the Th1 and Th17 lineages has been described, a process sometimes controversial that seems to play a key role in different inflammatory conditions, including those affecting the gastrointestinal system. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut, focusing on these newly identified features of this T cell subset, including plasticity, their relationship with regulatory T cells and their heterogeneity in the inflammatory microenvironment. A better understanding of these issues is critical to elucidate the role of Th17 cells in intestine immunity, and so for the design of novel therapeutic approaches for intestinal diseases specifically targeting Th17 cells.

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“…17 IL-1b, which in the intestine is expressed in lamina propria mononuclear cells but not epithelial cells, 18 is known to promote intestinal TH17 differentiation [19][20][21][22] and increases production of proinflammatory IL-17 by natural killer T cells. 23 , which in the intestine can be expressed in both epithelial cells and lamina propria mononuclear cells, is a potent inducer of proliferation on lymphocytes from patients with CD 24 and is a potent inducer of interferon-g in TH1 and natural killer cells when IL-12 is present. 25 In addition, IL-18 promotes intestinal epithelial cell division and supports regeneration of gut epithelium as part of the recovery from inflammatory damage.…”

Section: Inflammasome Composition and General Functionmentioning

confidence: 99%

Role of Inflammasomes in Intestinal Inflammation and Crohnʼs Disease

Opipari

Franchi

2015

Inflammatory Bowel Diseases

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: Inflammasomes are multiprotein complexes that process procytokines into mature forms of interleukin 1β and interleukin 18 and induce pyroptotic cell death. Evidence linking NLRP3, NLRC4, and NLRP6 inflammasomes to intestinal inflammation is reviewed to provide a basis to understand how the innate immune system discriminates pathogenic bacteria from commensal bacteria and shapes microbial ecology. Inflammasomes have a direct and important role limiting colitis by directing effective immune responses against pathogenic bacterial infections in the intestine. Chronic granulomatous disease is presented to reveal a contrasting proinflammatory effect of inflammasomes. This pathogenic effect is unmasked in a state of immunodeficiency where bacterial growth is poorly controlled increasing inflammasome activity. The role of inflammasomes in inflammation associated with Crohn's disease and ulcerative colitis is discussed. Finally, mechanistic studies linking genetic polymorphisms in ATG16L and NOD2 to inflammasome activation provide a basis for new hypotheses to explain how genetic polymorphism associated with Crohn's disease modulate intestinal inflammation. A deeper understanding of the role of inflammasomes in intestinal inflammation is expected to identify new ways of treating inflammatory bowel disease.

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Induced IL-17–Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β

Cited by 71 publications

References 45 publications

IL-9 Expression by Invariant NKT Cells Is Not Imprinted during Thymic Development

IL-9 Expression by Invariant NKT Cells Is Not Imprinted during Thymic Development

Functional Plasticity of Th17 Cells: Implications in Gastrointestinal Tract Function

Role of Inflammasomes in Intestinal Inflammation and Crohnʼs Disease

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