The Transcription Factor Twist1 Limits T Helper 17 and T Follicular Helper Cell Development by Repressing the Gene Encoding the Interleukin-6 Receptor α Chain

Pham, Duy; Walline, Crystal C.; Hollister, Kristin; Dent, Alexander L.; Blum, Janice S.; Firulli, Anthony B.; Kaplan, Mark H.

doi:10.1074/jbc.m113.497248

Cited by 32 publications

(30 citation statements)

References 53 publications

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“…2). Twist1 also inhibits E2A activity, but Th9 differentiation appeared normal in Twist1-deficient T cell cultures [44], suggesting that there is specificity in the ability of Id3 to inhibit IL-9 production.…”

Section: Downstream Of the Tgfβ Activated Kinase Tak1mentioning

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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Section: Downstream Of the Tgfβ Activated Kinase Tak1mentioning

confidence: 99%

The transcription factor network in Th9 cells

Kaplan

2016

Semin Immunopathol

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“…T-cells can be used as a marker of chronic inflammation [17]. Expression of Twist-1 in Th2 cells is in a lower level than Th1 cells and has shown it plays an important role in inhibition of Th17 polarization and inhibition of T follicular helper development [50].…”

Section: Physiological Roles Of Twist In Bm Nichementioning

confidence: 99%

Twist as a new prognostic marker in hematological malignancies

et al. 2015

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Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies.

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“…Moreover, Twist2 −/− mice or Twist1 +/− /Twist2 +/− mice demonstrate increased proinflammatory cytokines associated with increased NFκB pathway signaling and perinatal death, and defects in the type I IFN-mediated suppression of pro-inflammatory cytokines in macrophages (18, 22). In T cells, Twist1 limits Th1, Th17 and T follicular helper cell development (20, 21). However, the role and mechanisms through which Twist1 and Twist2 regulate PRR-induced cytokine outcomes is poorly understood; Twist regulation of NOD2-induced outcomes has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators

Zheng

Hedl

Abraham

2015

The Journal of Immunology

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Proper regulation of microbial-induced cytokines is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn’s disease–associated sensor of bacterial peptidoglycan, induces cytokines. However, chronic NOD2 stimulation in macrophages decreases cytokines upon pattern recognition receptor (PRR) restimulation; cytokine attenuation to PRR stimulation is similarly observed in intestinal macrophages. The role for the transcriptional repressors Twist1 and Twist2 in regulating PRR-induced cytokine outcomes is poorly understood and has not been reported for NOD2. We found that Twist1 and Twist2 were required for optimal cytokine downregulation during acute and, particularly, chronic NOD2 stimulation of human macrophages. Consistently, Twist1 and Twist2 expression was increased after chronic NOD2 stimulation; this increased expression was IL-10 and TGF-β dependent. Although Twist1 and Twist2 did not coregulate each other’s expression, they cooperated to enhance binding to cytokine promoters after chronic NOD2 stimulation. Moreover, Twist1 and Twist2 contributed to enhance expression and promoter binding of the proinflammatory inhibitor c-Maf and the transcriptional repressor Bmi1. Restoring c-Maf and Bmi1 expression in Twist-deficient macrophages restored NOD2-induced cytokine downregulation. Furthermore, with chronic NOD2 stimulation, Twist1 and Twist2 contributed to the decreased expression and cytokine promoter binding of the transcriptional activators activating transcription factor 4, C/EBPα, Runx1, and Runx2. Knockdown of these transcriptional activators in Twist-deficient macrophages restored cytokine downregulation after chronic NOD2 stimulation. Finally, NOD2 synergized with additional PRRs to increase Twist1 and Twist2 expression and Twist-dependent pathways. Therefore, after chronic NOD2 stimulation Twist1 and Twist2 coordinate the regulation of both transcriptional activators and repressors, thereby mediating optimal cytokine downregulation.

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The Transcription Factor Twist1 Limits T Helper 17 and T Follicular Helper Cell Development by Repressing the Gene Encoding the Interleukin-6 Receptor α Chain

Cited by 32 publications

References 53 publications

The transcription factor network in Th9 cells

The transcription factor network in Th9 cells

Twist as a new prognostic marker in hematological malignancies

Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators

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