Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4 + T Cells

Wang, Yu; Bi, Yujing; Chen, Xi; Li, Chunxiao; Li, Yan; Zhang, Zhengguo; Wang, Jian; Lu, Yun; Yu, Qing; Su, Huilin; Yang, Hui; Liu, Guangwei

doi:10.1016/j.immuni.2016.05.009

Cited by 151 publications

(166 citation statements)

References 25 publications

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“…Theoretically, mTOR could regulate glycolysis within Th9 cells. In keeping with a recently published finding (63), the glycolytic rate is higher in Th9 cells than in any other Th cell subsets and iTregs. In contrast to Th9 cells, iTregs depend on OXPHOS for their metabolic energy production.…”

Section: Discussionsupporting

confidence: 93%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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CD4؉ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na ؉ /H ؉ exchanger 1 (NHE1; gene name Slc9␣1)) is critically important for regulating intracellular pH (pH i ), cell volume, migration, and cell survival. The pH i influences cytokine secretion, activities of membrane-associated enzymes, ion transport, and other effector signaling molecules such as ATP and Ca 2؉ levels. However, whether NHE1 regulates Th9 cell development or IL-9 secretion has not yet been defined. The present study explored the role of NHE1 in Th9 cell development and function. Th cell subsets were characterized by flow cytometry and pH i was measured using 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) dye. NHE1 functional activity was estimated from the rate of realkalinization following an ammonium pulse. Surprisingly, in Th9 cells pH i and NHE1 activity were significantly higher than in all other Th cell subsets (Th1/Th2/Th17 and induced regulatory T cells (iTregs)). NHE1 transcript levels and protein abundance were significantly higher in Th9 cells than in other Th cell subsets. Inhibition of NHE1 by siRNA-NHE1 or with cariporide in Th9 cells down-regulated IL-9 and ATP production. NHE1 activity, Th9 cell development, and IL-9 production were further blunted by pharmacological inhibition of protein kinase Akt1/Akt2. Our findings reveal that Akt1/Akt2 control of NHE1 could be an important physiological regulator of Th9 cell differentiation, IL-9 secretion, and ATP production. CD4ϩ T cells participate in the regulation of the immune response during infections, autoimmunity, and cancer. CD4 ϩ T cells are an important and essential arm of the adaptive immune system (1). CD4 ϩ T cells can be divided into various subtypes based upon their cytokine secretion: T helper 1 (Th1) 4 cells produce IFN-␥ (1, 2), Th2 cells produce IL-4, IL-5, and IL-13 (3), Th17 cells produce IL-17 (4 -6), Th9 cells produce IL-9 (7-9), and suppressive regulatory T cells (Tregs) produce TGF-␤ and IL-10 (10). A great deal of experimental effort has been dedicated to decipher the development and function of various Th cell subsets. However, Th9 cell development and function remain incompletely understood.Th9 cells are a recently characterized Th cell subset recognized by their potent production of IL-9. Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11, 12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7, 13-23). The development and function of Th9 cells are regulated ...

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Section: Discussionsupporting

confidence: 93%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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“…Whereas Sirt1 deficiency increases glycolytic activity in Th9 cells 32 , we found that RPC increases glycolytic rate in a Sirt1-dependent manner in neurons, demonstrating a cell type-specific function. While the bulk of brain ATP is generated from the oxidation of pyruvate within mitochondria, recent studies highlight the importance of neuronal glycolysis.…”

Section: Discussionmentioning

confidence: 50%

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

Koronowski

Khoury

Saul

et al. 2017

Stroke

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BACKGROUND AND PURPOSE Resveratrol, at least in part via Sirt1 activation, protects against cerebral ischemia when administered 2 days prior to injury. However, it remains unclear if Sirt1 activation must occur, and in which brain cell types, for the induction of neuroprotection. We hypothesized that neuronal Sirt1 is essential for resveratrol-induced ischemic tolerance and sought to characterize the metabolic pathways regulated by neuronal Sirt1 at the cellular level in the brain. METHODS We assessed infarct size and functional outcome following transient 60 minute middle cerebral artery occlusion in control and inducible, neuronal-specific Sirt1 knockout mice. Non-targeted primary metabolomics analysis identified putative Sirt1-regulated pathways in brain. Glycolytic function was evaluated in acute brain slices from adult mice and primary neuronal-enriched cultures under ischemic penumbra-like conditions. RESULTS Resveratrol-induced neuroprotection from stroke was lost in neuronal Sirt1 knockout mice. Metabolomics analysis revealed alterations in glucose metabolism upon deletion of neuronal Sirt1, accompanied by transcriptional changes in glucose metabolism machinery. Furthermore, glycolytic ATP production was impaired in acute brain slices from neuronal Sirt1 knockout mice. Conversely, resveratrol increased glycolytic rate in a Sirt1-dependent manner and under ischemic penumbra-like conditions in vitro. CONCLUSIONS Our data demonstrate that resveratrol requires neuronal Sirt1 to elicit ischemic tolerance and identify a novel role for Sirt1 in the regulation of glycolytic function in brain. Identification of robust neuroprotective mechanisms that underlie ischemia tolerance and the metabolic adaptations mediated by Sirt1 in brain are crucial for the translation of therapies in cerebral ischemia and other neurological disorders.

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“…Of note, the strongest downregulation of mRNA expression levels was detected for IL-9. IL-9 is critical in controlling immune-associated diseases, and T H 9 cells have been reported to inhibit tumour growth [25, 26]. However, further studies are needed to clarify in detail how hypoxia interferes with the generation of T H 9 cells.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

Westendorf

Skibbe

Adamczyk

et al. 2017

Cell Physiol Biochem

164

103

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Background/Aims: Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment. Methods: Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4⁺ effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function. Results: We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4⁺ effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-γ production of T_H1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1α in the modulation of CD4⁺ T cell functions under hypoxic conditions. Conclusion: Our data indicate that oxygen availability can function as a local modulator of CD4⁺ T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer.

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Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4 + T Cells

Cited by 151 publications

References 25 publications

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

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