Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells

Jain, Renu; Chen, Yi; Kanno, Yuka; Joyce-Shaikh, Barbara; Vahedi, Golnaz; Hirahara, Kiyoshi; Blumenschein, Wendy M.; Sukumar, Selvakumar; Haines, Christopher J.; Sadekova, Svetlana; McClanahan, Terrill K.; McGeachy, Mandy J.; O’Shea, John J.; Daniel, J.

doi:10.1016/j.immuni.2015.11.009

Cited by 136 publications

(128 citation statements)

References 36 publications

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“…For example, both Blimp-1 and G9a are required to limit Th17 cell development in a cell-intrinsic manner (15, 123). However, the increased frequency of Th17 cells does not result in enhanced pathogenicity of inflammatory diseases such as EAE or intestinal inflammation (15, 124), demonstrating that reducing the activity of Blimp-1 or G9a, or by inhibiting their interaction, may be a viable method to reduce the development of pathogenic Th17 cells. Future studies will define the precise role of G9a in immune cell development, differentiation, and function and determine the relevance of G9a as a drug target to treat inflammatory disease.…”

Section: Discussionmentioning

confidence: 99%

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The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

Scheer

Zaph

2017

Front. Immunol.

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G9a (KMT1C, EHMT2) is a lysine methyltransferase (KMT) whose primary function is to di-methylate lysine 9 of histone H3 (H3K9me2). G9a-dependent H3K9me2 is associated with gene silencing and acts primarily through the recruitment of H3K9me2-binding proteins that prevent transcriptional activation. Gene repression via G9a-dependent H3K9me2 is critically required in embryonic stem (ES) cells for the development of cellular lineages by repressing expression of pluripotency factors. In the immune system, lymphoid cells such as T cells and innate lymphoid cells (ILCs) can differentiate from a naïve state into one of several effector lineages that require both activating and repressive mechanisms to maintain the correct gene expression program. Furthermore, the long-term immunity to re-infection is mediated by memory T cells, which also require specific gene expression and repression to maintain a quiescent state. In this review, we examine the molecular machinery of G9a-dependent functions, address the role of G9a in lymphoid cell differentiation and function, and identify potential functions of T cells and ILCs that may be controlled by G9a. Together, this review will highlight the dynamic nature of G9a-dependent H3K9me2 in the immune system and shed light on the nature of repressive epigenetic modifications in cellular lineage choice.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, IL-23-induced Blimp-1 has been shown to be critical for the development of inflammatory Th17 cells that are required for the pathogenesis of EAE (124). Thus, mice lacking Blimp-1 in T cells fail to develop EAE.…”

Section: Interactions and Potential Roles Of G9amentioning

confidence: 99%

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

Scheer

Zaph

2017

Front. Immunol.

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“…Ndfip1-deficient Th17 cells do not show increased levels of IL-23R mRNA compared to WT cells, however we have not explored IL23R protein levels or protein levels of Blimp1. Blimp1 can also increase the production of IFNγ, GM-CSF, and IL-17A from Th17 cells817. Interestingly, Blimp1, like RORγT, contains an LPXY motif that would allow binding to Itch.…”

Section: Discussionmentioning

confidence: 99%

“…Such exposure results in the formation of a complex that contains the transcription factors Blimp1, RORγT, STAT3, p300, HIF1α, BATF and IRF4. Together, these factors cooperate to drive the expression of genes such as il17a, il23r and csf2 817. Furthermore, pathogenic Th17s have been reported to show a gene profile that includes tbx21, csf2 and ccl5 (Rantes), among others18.…”

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confidence: 99%

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Layman¹,

Sprout²,

Phillips³

et al. 2017

Sci Rep

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While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.

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“…Th17 cells differentiate from naïve Th0 cells under conditions of inflammation, driven by signals from TGFβ, IL-6, IL-1 and IL-21 [5]. During differentiation, Th17 cells express the IL-23 receptor (IL-23R), and signals from IL-23 are necessary for these cells to be pathogenic [6–9]. Indeed, antibodies against IL-17A and IL-23 are effective in treating autoimmunity, particularly plaque psoriasis [10, 11].…”

Section: Introductionmentioning

confidence: 99%

CCAAT/Enhancer-binding protein β promotes pathogenesis of EAE

et al. 2017

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The CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPβ itself regulates numerous genes involved in inflammation. However, the role of C/EBPβ in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb−/− mice are resistant to EAE. Cebpb−/− mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPβ in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPβ in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPβ binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPβ as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPβ in regulation of IL-23R expression.

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Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells

Cited by 136 publications

References 36 publications

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

CCAAT/Enhancer-binding protein β promotes pathogenesis of EAE

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