HIF-2α is indispensable for regulatory T cell function

Hsu, Tzu-Sheng; Lin, Yen-Lin; Wang, Yuan; Mo, Shu-Ting; Chi, Po‐Yu; Lai, Alan Chuan‐Ying; Pan, Hsuan-Yin; Chang, Ya‐Jen; Lai, Ming-Zong

doi:10.1038/s41467-020-18731-y

Cited by 94 publications

(78 citation statements)

References 65 publications

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“…The present manuscript adds additional arguments in favor of an important role of hypoxia-induced factors in the control of regulatory T cell function. A recent manuscript by Tzu-Sheng Hsu and colleagues 46 provides an elegant hypothesis to reconcile some of key findings concerning the role of HIF1α in Treg biology. Most experimental evidence concurs with a dual role of HIF1α in Treg differentiation and stability.…”

Section: Discussionmentioning

confidence: 99%

“…As discussed for HIF1α, HIF2α also appears to regulate Treg stability, albeit in a different direction. Despite a normal phenotype at rest, mice displaying HIF2α-deficient Tregs are largely defective in suppressing inflammation in the gut and in the lungs 46 . Noteworthy, this pro-inflammatory phenotype was largely explained by the HIF1α-dependent reprogramming of HIF2α-deficient Tregs into IL-17 secreting cells.…”

Section: Discussionmentioning

confidence: 99%

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The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

Ajouaou

Azouz

Taquin

et al. 2021

Preprint

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The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing an effector/Th1-like phenotype. Concomitantly, the expression of innate-type cytokines such as IL1-β, IL-12p40, IL-12p35 and TNF-α was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs do not efficiently control inflammatory response in vivo, in particular immune responses characterized by IFN-γ production. Further analysis revealed that Treg dysregulation is largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs revealed an altered expression of several chemokine receptors including CXCR3, a finding corroborated by the altered in vivo localization of PHD2-deficient Tregs in splenic tissues. Collectively, these findings uncover an important role of the PHD2-HIF2α axis in regulatory T cell positioning and trafficking.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

Ajouaou

Azouz

Taquin

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The role of Treg cells in cancer is also ambiguous, as they are critical inhibitory regulators in solid tumors; whereas during inflammation-induced tumorigenesis, they prevent cancer initiation by restraining inflammation [ 211 , 212 ]. Moreover, during the severity of allergic airway inflammation and tumor, Treg cells adapt to the local environmental changes through functional and phenotypic reprogramming [ 213 , 214 ]. High-grade gliomas have more regions under chronic hypoxia than lower-grade tumors [ 215 ].…”

Section: Discussionmentioning

confidence: 99%

Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

Huang

Dong

2021

Journal of Immunology Research

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CD4+T helper (Th) cells are important mediators of immune responses in asthma and cancer. When counteracted by different classes of pathogens, naïve CD4+T cells undergo programmed differentiation into distinct types of Th cells. Th cells orchestrate antigen-specific immune responses upon their clonal T-cell receptor (TCR) interaction with the appropriate peptide antigen presented on MHC class II molecules expressed by antigen-presenting cells (APCs). T helper 9 (Th9) cells and regulatory T (Treg) cells and their corresponding cytokines have critical roles in tumor and allergic immunity. In the context of asthma and cancer, the dynamic internal microenvironment, along with chronic inflammatory stimuli, influences development, differentiation, and function of Th9 cells and Treg cells. Furthermore, the dysregulation of the balance between Th9 cells and Treg cells might trigger aberrant immune responses, resulting in development and exacerbation of asthma and cancer. In this review, the development, differentiation, and function of Th9 cells and Treg cells, which are synergistically regulated by various factors including cytokine signals, transcriptional factors (TFs), costimulatory signals, microenvironment cues, metabolic pathways, and different signal pathways, will be discussed. In addition, we focus on the recent progress that has helped to achieve a better understanding of the roles of Th9 cells and Treg cells in allergic airway inflammation and tumor immunity. We also discuss how various factors moderate their responses in asthma and cancer. Finally, we summarize the recent findings regarding potential mechanisms for regulating the balance between Th9 and Treg cells in asthma and cancer. These advances provide opportunities for novel therapeutic strategies that are aimed at reestablishing the balance of these cells in the diseases.

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“…Specifically, HIF-1α has been shown to activate transcription of Th17 genes and flag FoxP3 for protein degradation (Dang et al, 2011). In contrast, the expression of HIF-2α, which supports Treg cell function (Hsu et al, 2020), is slightly elevated with treatment ( Supplementary Figure 2E). The contrasting expression changes for HIF-1α and HIF-2α suggest that this response was not due to hypoxia and support the FoxP3 upregulation phenotype observed in Th17 cells in response to MTHFD2i.…”

Section: Mthfd2 Activity Regulates Mtorc1 Activity In Th1 and Treg Cementioning

confidence: 98%

MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

Sugiura

Andrejeva

Voss

et al. 2021

Preprint

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Antigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.

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HIF-2α is indispensable for regulatory T cell function

Cited by 94 publications

References 65 publications

The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

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