A Role for IL-27 in Limiting T Regulatory Cell Populations

Wojno, Elia D. Tait; Hosken, Nancy; Stumhofer, Jason S.; O'Hara, Aisling; Mauldin, Elizabeth A.; Fang, Qun; Turka, Laurence A.; Levin, Steven D.; Hunter, Christopher A.

doi:10.4049/jimmunol.1004182

Cited by 87 publications

(33 citation statements)

References 59 publications

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“…Another notable observation in this study is that EBI3 −/− T cells had enhanced IL-2 production and proliferation. Enhanced IL-2 production by T cells from EBI3 −/− mice is consistent with the known anti-IL-2 effect of IL-27 (32–34) and could explain the stronger proliferation of EBI3 −/− T cells.…”

Section: Discussionsupporting

confidence: 79%

Increased Th17 and Regulatory T Cell Responses in EBV-Induced Gene 3-Deficient Mice Lead to Marginally Enhanced Development of Autoimmune Encephalomyelitis

Liu

Zhang

et al. 2012

The Journal of Immunology

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Epstein-Barr virus-induced gene 3 (EBI3) encoded protein can form heterodimers with IL-27P28 and IL-12P35 to form IL-27 and IL-35. IL-27 and IL-35 may influence autoimmunity through inhibiting Th17 differentiation, and facilitating the inhibitory roles of Foxp3+ Treg cells, respectively. In this study we have evaluated the development of experimental autoimmune encephalomyelitis (EAE) in EBI3-deficient mice that lack both IL-27 and IL-35. We found that MOG peptide immunization resulted in marginally enhanced EAE development in EBI3-deficient C57BL6 and 2D2 TCR transgenic mice. EBI3-deficiency resulted in significantly increased Th17 and Th1 responses in the central nervous system (CNS) and increased T cell production of IL-2 and IL-17 in the peripheral lymphoid organs. EBI3-deficient and -sufficient 2D2 T cells had equal ability in inducing EAE in Rag1−/− mice, however more severe disease was induced in EBI3−/−Rag1−/− mice than in Rag1−/− mice by 2D2 T cells. EBI3-deficient mice had increased numbers of CD4+FoxP3+ Treg cells in peripheral lymphoid organs. More strikingly, EBI3-deficient Treg cells had more potent suppressive functions in vitro and in vivo. Thus, our data support an inhibitory role for EBI3 in Th17, Th1, IL-2 and Treg responses. While these observations are consistent with the known functions of IL-27, the IL-35 contribution to the suppressive functions of Treg cells is not evident in this model. Enhanced Treg responses in EBI3−/− mice may explain why the EAE development is only modestly enhanced compared to WT mice.

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Section: Discussionsupporting

confidence: 79%

Increased Th17 and Regulatory T Cell Responses in EBV-Induced Gene 3-Deficient Mice Lead to Marginally Enhanced Development of Autoimmune Encephalomyelitis

Liu

Zhang

et al. 2012

The Journal of Immunology

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“…IL-27 signaling, unlike IL-6 signaling [57], did not cause Treg to downregulate Foxp3; however, when IL-27 was present during the generation of the Treg pool, Treg reconstitution was inhibited. Associated with the lack of Treg, IL-27 tg mice had a marked defect in their capacity to produce IL-2, suggesting that IL-27 may influence differentiating Treg indirectly through IL-2 modulation [58]. …”

Section: Il-27 Regulates Tregmentioning

confidence: 99%

“…For example, it is unknown whether IL-27 influences CD4 + T cells converting or differentiating to the Treg fate directly or indirectly. The report using Il27ra −/− T cells in the setting of colitis proposed that IL-2 is not involved [56]; however, the study of IL-27 tg mice provides evidence for an indirect mechanism, in which the loss of Treg in an IL-27-rich environment is associated with reduced IL-2 [58]. Additionally, how IL-27 influences inducible versus natural Treg populations remains unknown, though Il27ra −/− mice have normal Treg frequencies [3].…”

Section: Il-27 Regulates Tregmentioning

confidence: 99%

New directions in the basic and translational biology of interleukin-27

Wojno

Hunter

2012

Trends in Immunology

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102

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Interleukin(IL)-27 is a member of the IL-6 and IL-12 family composed of the IL-27p28 and Epstein Barr-induced virus 1 subunits. While IL-27 was originally identified as a pro-inflammatory factor, subsequent studies have revealed the pleotropic nature of this cytokine. This review discusses recent work that explores the effect of IL-27 on CD4+ T cell subsets, including T regulatory type 1 cells, T follicular helper cells, and Foxp3+ T regulatory cells. Additionally, we highlight studies that identify a role for the IL-27p28 subunit as a cytokine receptor antagonist. Much of the recent work on IL-27 has been relevant to human disease states characterized by inappropriate or excessive inflammation, and this review will discuss potential opportunities to use IL-27 as a therapeutic.

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“…IL-27 impacts Foxp3 + Treg development and function in vivo . Indeed mice that overexpress both IL-27 subunits, IL-27p28 and EBI3, have decreased number of Foxp3 + Tregs and developed spontaneous inflammation similar to mice that lack Foxp3 + Tregs such as the scurfy Foxp3 mutant mice or IL-2 −/− mice[73]. Interestingly, IL-27 transgenic mice are deficient in IL-2.…”

Section: Molecular Pathways Involved In Il-27 Biologymentioning

confidence: 99%

Induction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27

Pot

Apétoh

Awasthi

et al. 2011

Seminars in Immunology

143

123

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Accumulating evidence indicates that IL-27, a member of the IL-12 family of cytokines, alleviates the severity of autoimmune diseases in both mice and men. The IL-27-induced activation of Signal transducer and activator of transcription (Stat)1 and Stat3 promotes the generation of IL-10-producing type 1 regulatory T (Tr1) cells that inhibit effector T cells. In addition, IL-27 also suppresses the development of pathogenic IL-17-producing CD4+ T cells (TH17) cells, suggesting that pharmacological manipulations of IL-27 signaling pathway could be exploited therapeutically in regulating tissue inflammation. Here, we review how IL-27 controls inflammation through the regulation of Tr1 and TH17 responses.

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A Role for IL-27 in Limiting T Regulatory Cell Populations

Cited by 87 publications

References 59 publications

Increased Th17 and Regulatory T Cell Responses in EBV-Induced Gene 3-Deficient Mice Lead to Marginally Enhanced Development of Autoimmune Encephalomyelitis

Increased Th17 and Regulatory T Cell Responses in EBV-Induced Gene 3-Deficient Mice Lead to Marginally Enhanced Development of Autoimmune Encephalomyelitis

New directions in the basic and translational biology of interleukin-27

Induction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27

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