The Costimulatory Receptor OX40 Inhibits Interleukin-17 Expression through Activation of Repressive Chromatin Remodeling Pathways

Xiao, Xiang; Shi, Xinling; Fan, Yihui; Wu, Chenglin; Zhang, Xiaolong; Minze, Laurie J.; Li, Wentao; Ghobrial, Rafik M.; Lan, Peixiang; Li, Xian Chang

doi:10.1016/j.immuni.2016.05.013

Cited by 57 publications

(60 citation statements)

References 48 publications

(65 reference statements)

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“…Recently, RelB was shown to have an important function in limiting the development of Th17 cells (114). Costimulation of Th17 cells through OX40–OX40L interactions resulted in a significant reduction in IL-17A expression.…”

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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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: 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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“…This transition requires both p50 and STAT6 [74]. Finally, Th17 cells can acquire an IL-9-secreting or mixed phenotype on culture with TGFβ, IL-4, and IL-2, a process that is enhanced by the action of OX40 [72, 78, 79]. This relies on STAT6 and likely the IL-2/STAT5 pathway that both represses Th17 and induces Th9 differentiation [80].…”

Section: Stability and Transitioning To An Il-9-secreting Phenotypementioning

confidence: 99%

The transcription factor network in Th9 cells

Kaplan

2016

Semin Immunopathol

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The development of T helper cell subsets requires activated T cells that respond to a polarizing cytokine environment resulting in the activation and expression of transcription factors. The subset-specific transcription factors bind and induce the production of specific effector cytokines. Th9 cells express IL-9 and develop in the presence of TGFβ, IL-4, and IL-2. Each of these cytokines activates signaling pathways that are required for Th9 differentiation and IL-9 production. In this review I summarize what is currently understood about the signaling pathways and transcription factors that promote the Th9 genetic program, providing some perspective for the integration of the signals in regulating the Il9 gene and dictating the expression of other Th9-associated genes. I highlight how experiments in mouse cells have established a transcriptional network that is conserved in human T cells, and set the stage towards defining the next important questions for a more detailed understanding of Th9 cell development and function.

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“…Unlike other costimulatory molecules, OX40 is not expressed by resting naive T cells, but its expression is rapidly induced upon T cell activation, and OX40 costimulation plays a critical role in cell survival, proliferation, and generation of memory cells (Croft, 2010). We and others have shown that OX40 regulates the induction of multiple T helper (T H ) cell subsets, primarily through triggering chromatin modifications that control accessibility of key transcription factors to target loci (Xiao et al, 2016, 2018). In certain models, OX40 strongly promotes the induction of T H 1, T H 2, and T H 9 cells, whereas in other conditions, it inhibits the generation of T H 17 cells and Foxp3 + Tregs (Ito et al, 2005; Li et al, 2008; Vu et al, 2007; Xiao et al, 2012a).…”

Section: Introductionmentioning

confidence: 99%

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

et al. 2018

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SUMMARY Naive CD4+ T cells can be converted to Foxp3+ T regulatory cells (Tregs) in the periphery (iTregs), where induction of Foxp3 gene expression is central to Treg differentiation. OX40 signaling is known to inhibit Foxp3 expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress Foxp3 expression in freshly activated naive CD4+ T cells. Specifically, OX40 upregulates BATF3 and BATF, which produce a closed chromatin configuration to repress Foxp3 expression in a Sirt1/7-dependent manner. Moreover, OX40 can also activate the AKT-mTOR pathway, especially in the absence of BATF3 and BATF, to inhibit Foxp3 induction, and this is mediated by phos-phorylation and nuclear exclusion of the transcription factor Foxo1. Taken together, our results provide key mechanistic insights into how OX40 inhibits Foxp3 expression and Treg induction in the periphery.

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The Costimulatory Receptor OX40 Inhibits Interleukin-17 Expression through Activation of Repressive Chromatin Remodeling Pathways

Cited by 57 publications

References 48 publications

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

The transcription factor network in Th9 cells

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

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