Interleukin-23 Restrains Regulatory T Cell Activity to Drive T Cell-Dependent Colitis

Ízcue, Ana; Hüe, Sophie; Buonocore, Sofia; Arancibia‐Cárcamo, Carolina V.; Ahern, Philip P.; Iwakura, Yoichiro; Maloy, Kevin J.; Powrie, Fiona

doi:10.1016/j.immuni.2008.02.019

Cited by 367 publications

(373 citation statements)

References 55 publications

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“…In an infection model, IL-23 was found to be dispensable for the generation of IL-17-producing T cells, but was essential for schistosome egg-induced immunopathology [84]. This is consistent with a recent study on colitis, which demonstrated that IL-17-producing T cells are not required for the development of intestinal inflammation, but that IL-23 does have a pathogenic role by inhibiting Treg cells [85], and thereby enhancing Th1 responses. It has also been demonstrated that IL-23, as well as promoting IL-17 producing T cells, can enhance IFN-g-producing Th1 cells [62].…”

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confidence: 87%

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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confidence: 87%

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

2008

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“…Naïve CD4 1 CD45RB high T cells were isolated from spleens of B6 or BALB/c mice via FACS sorting as previously described [22]. Rag À/À mice were then i.p.…”

Section: Induction Of Colitismentioning

confidence: 99%

“…Analysis of ALDH activity was performed using the ALDEFLUOR staining kit according to manufacturer's instructions (STEMCELLS Technologies). Foxp3 staining as well as the analysis of intracellular cytokines was performed as described elsewhere [22]. Data were collected with a Cyan flow cytometer (Dako) and analysed using FlowJo software (Tree star).…”

Section: Isolation Of Leukocytes and Flow Cytometry Analysismentioning

confidence: 99%

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Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

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Intestinal CD103 1 DC promote the differentiation of Foxp3 1 Treg from naïve CD4 1 T cells through mechanisms involving TGF-b and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103 1 DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103 1 DC, which is associated with lower expression of tgfb2 and aldh1a2. Accordingly, CD103 1 DC taken from colitic mice are impaired in their ability to induce Foxp3 1 Treg and instead favour the emergence of IFN-c-producing CD4 1 T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103 1 DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103 1 DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103 1 DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.Key words: Colitis . DC . Intestinal immunity . Ontogeny . Treg IntroductionThe intestinal immune system must maintain a fine balance between harmless responses to food and commensal bacteria and protective immunity to invading pathogens. It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known. One possibility is that these activities are mediated by distinct DC populations and indeed many subtypes of DC have been identified in the gut [4]. It has been proposed that resident gutconditioned DC may favour tolerogenic responses, whereas newly recruited inflammatory DC may drive host protective immunity.Alternatively, tissue-resident DC may adopt distinct functions under homeostatic and inflammatory conditions [4,5].We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10]. Under homeostatic conditions, CD103 1 DC in MLN promote the development of Foxp3 1 Treg. By contrast, the reciprocal CD103 À MLN DC population displays a more pro-inflammatory phenotype and appears to represent a developmentally distinct DC population [9].In intestinal inflammation, immune regulatory pathways that normally promote tolerance in the intestine break down. Whether this is attributable to changes in DC populations or their function in the MLN is not known. Here, we show that in colitic mice, the tolerogenic properties of CD103 1 MLN DC are lost and that this APC population now drives inflammatory T-cell responses that may c...

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“…Les choses ne sont toutefois peut-être pas si simples. Ainsi, si il est maintenant acquis que l'IL-23 joue un rôle déterminant dans le développement des maladies inflammatoires du tube digestif chez l'homme comme chez l'animal [8], une étude récente mené chez la souris a montré que cette cytokine exercerait son effet délétère, non pas en favorisant l'expansion ou l'activité des lymphocytes Th17, mais plutôt en exerçant un effet inhibiteur sur les lymphocytes T régulateurs [9].…”

Section: Un Rôle Encore Incertain Des Lymphocytes Th17 Dans Les Maladunclassified

Une nouvelle vision de l’auto-immunité

Glaichenhaus

2008

Med Sci (Paris)

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Interleukin-23 Restrains Regulatory T Cell Activity to Drive T Cell-Dependent Colitis

Cited by 367 publications

References 55 publications

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

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

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Une nouvelle vision de l’auto-immunité

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Interleukin-23 Restrains Regulatory T Cell Activity to Drive T Cell-Dependent Colitis

Cited by 367 publications

References 55 publications

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

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

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

Une nouvelle vision de l’auto-immunité

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Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells