IL-9 as a mediator of Th17-driven inflammatory disease

Nowak, Elizabeth C.; Weaver, Casey T.; Turner, Henrietta; Begum-Haque, Sakhina; Schreiner, Bettina; Coyle, Anthony J.; Kasper, Lloyd H.; Noelle, Randolph J.

doi:10.1084/jem.20090246

Cited by 333 publications

(342 citation statements)

References 28 publications

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“…These results changed our perception of the IL-9 stimulating activity of TGF-b/IL-4 reported by Schmitt [11]. More recently, still, IL-9 production by CD4 1 T cells stimulated in the presence of TGF-b/IL-6, the canonical Th17 combination [12][13][14], was also reported [15,16].…”

Section: Introductionmentioning

confidence: 62%

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TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

2010

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TGF-b and IL-4 were recently shown to selectively upregulate IL-9 production by naïve CD4 1 T cells. We report here that TGF-b interactions with IL-1a, IL-1b, IL-18, and IL-33 have equivalent IL-9-stimulating activities that function even in IL-4-deficient animals. This was observed after in vitro antigenic stimulation of immunized or unprimed mice and after polyclonal T-cell activation. Based on intracellular IL-9 staining, all IL-9-producing cells were CD4 1 and 80-90% had proliferated, as indicated by reduced CFSE staining. In contrast to IL-9, IL-13 and IL-17 were strongly stimulated by IL-1 and either inhibited (IL-13) or were unaffected (IL-17) by addition of TGF-b. IL-9 and IL-17 production also differed in their dependence on IL-2 and regulation by IL-1/IL-23. As IL-9 levels were much lower in Th2 and Th17 cultures, our results identify TGF-b/IL-1 and TGF-b/IL-4 as the main control points of IL-9 synthesis.

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Section: Introductionmentioning

confidence: 62%

“…Several publications have reported IL-9 production by purified Th17 CD4 1 T cells activated with anti-CD3/CD28 [15,16]. We carefully tested this condition in antigen recall responses of mice immunized with OVA.…”

Section: Introductionmentioning

confidence: 99%

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

2010

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“…18 The cytokine IL-9, produced by Th17 cells in the lymph nodes of MOG -primed mice, has been recently identified to recruit MCs in lymphoid organs and to promote EAE development and progression. 65 We have shown in vitro that activated MCs inhibit Treg suppression and promote the differentiation of Th17 effector cells. 19 In vivo, MCs colocalized with Th17 cells and Treg in draining lymph nodes of MOG -immunized mice, thus potentially engaging multiple interactions with cells participating to adaptive immune response.…”

Section: Discussionmentioning

confidence: 95%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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Mast cell (MC)-deficient c-Kit mutant Kit W/W-v mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit W-sh/W-sh . Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced chronic EAE was exacerbated in Kit W-sh/W-sh compared with Kit þ / þ mice. Kit W-sh/W-sh mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit W-sh/W-sh and in Kit W/W-v mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG and adjuvants. Although Kit W-sh/W-sh mice exhibited exacerbated EAE under all immunization protocols, Kit W/W-v mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit W-sh/W-sh mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit W-sh/W-sh mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols. MCs are key factors in IgE-associated immediate hypersensitivity reactions, during which they release a wide spectrum of inflammatory mediators in response to IgE and antigen (Ag) stimulation. 1 However, recent findings have pointed out that MCs may exert also important effector and/or immunomodulatory functions in other physiopathological conditions as venom detoxification, pathogen clearance, tumor growth, contact hypersensitivity, allograft acceptance and autoimmunity. 2 Most of these studies have assessed the in vivo role of MCs by the use of mouse models carrying spontaneous mutations in c-Kit receptor (WBB6F 1 -Kit W/W-v or C57BL/6-Kit W-sh/W-sh mice) or c-Kit ligand (WCB6F 1 -Kitl Sl /Kitl Sl-d ), which show severe deficiency of MC populations. 3,4 MCs may either enhance or suppress the inflammation associated to different types of autoimmune diseases. MC-deficient Kit W/W-v and Kitl Sl/Sl-d mice are protected from autoantibodymediated models of rheumatoid arthritis and bullous pemphigoid, inflammatory disorders affecting, respectively, the joint and the skin. Reconstitution of Kit W/W-v mice with bone marrow derived, in vitro cultured MCs (BMMCs) restores complete disease susceptibility in both conditions, thus indicating a proinflammatory role of these cells in such diseases. 5,6 Conversely, MCs seem to exert a protective function in experimental autoimmune glomerulonephritis, by limiting clinical and histological glomerular pathology and mortality. 7,8 However, recent work has shown that, unlike Kit W/W-v , Ki...

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“…Notably, it has been demonstrated that IL-27 functions as the key regulator of IL-10 and IL-17 production in human CD4 + T cells. 36 Nowak and colleagues 37 also identified IL-9 as a mediator of Th17-driven inflammatory disease. Moreover, it has also been shown that IL-9 synergizes with TGF-beta1 to differentiate naive CD4 + T cells into Th17 cells and postulated an additional role for IL-9 in mediating the suppressive function of Tregs in experimental autoimmune encephalomyelitis.…”

Section: Discussionmentioning

confidence: 99%

Case report: type 1 diabetes in monozygotic quadruplets

et al. 2011

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Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-a further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity is 'fertilized' and precipitated by a viral infection leading to a fully blown T1D.

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IL-9 as a mediator of Th17-driven inflammatory disease

Cited by 333 publications

References 28 publications

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Case report: type 1 diabetes in monozygotic quadruplets

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IL-9 as a mediator of Th17-driven inflammatory disease

Cited by 333 publications

References 28 publications

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4+ T cells

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4+ T cells

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Case report: type 1 diabetes in monozygotic quadruplets

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TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells