Orphan Nuclear Receptor NR2F6 Suppresses T Follicular Helper Cell Accumulation through Regulation of IL-21

Olson, William J.; Jakic, Bojana; Labi, Verena; Schoeler, Katia; Kind, Michaela; Klepsch, Victoria; Baier, Gottfried; Hermann-Kleiter, Natascha

doi:10.1016/j.celrep.2019.08.024

Cited by 24 publications

(24 citation statements)

References 62 publications

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“…Additionally, NRs have been shown to regulate the inflammatory process, which is an important component in the development of NAFLD/NASH and insulin resistance. Given that NR2F6 is a critical regulator of immune response and cytokine production, [ 32,33 ] we speculate that the role of NR2F6 in the hepatic inflammation and lipid metabolism might be partially interdependent.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated the NR2F-specific binding oligonucleotide sequence contains a TGACCT motif. [32,33] We analyzed the promoter region of mouse CD36 gene (−2000 bp from the transcriptional start site) and found a potential NR2F6 binding site at −1916 bp ( Figure 3G). It is of interest that this binding site also exists in the promoter region of human CD36 gene (Figure 3G).…”

Section: Nr2f6 Promotes Cd36 Expression Through Directly Binding To Tmentioning

confidence: 99%

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The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

et al. 2020

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Nuclear receptors (NRs) are a superfamily of transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic triglyceride (TG) homeostasis and causal factor in the development of non‐alcoholic fatty liver disease (NAFLD). Adeno‐associated virus (AAV)‐mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic‐specific suppression of NR2F6 improves obesity‐associated hepatosteatosis, insulin resistance, and methionine and choline‐deficient (MCD) diet‐induced non‐alcoholic steatohepatitis (NASH). Mechanistically, the fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of nuclear receptor coactivator 1 (SRC‐1) and histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating NAFLD/NASH pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Nr2f6 Promotes Cd36 Expression Through Directly Binding To Tmentioning

confidence: 99%

The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

et al. 2020

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“…Memory CD8 + T-cell precursors form early in the antibacterial effector phase and can be characterized by effector functions, tissue localization, and cell surface determined [14][15][16][17][18] . Using germ-line knockout mice, we have identified functions of the orphan NR, NR2F6 in effector CD4 + and CD8 + T-lymphocytes during cancer progression, autoimmune responses, and immunization [19][20][21][22][23][24] . Mechanistically, NR2F6 suppresses the transcription of cytokine genes directly (Il21) or via blocking the binding of activating transcription factors such as NFAT/AP-1 to the promoter and/or other conserved regulatory sequences (Il2, Ifng, Il17), thus acting as a brake on inflammatory cytokine responses 19,20,22,24 .…”

Section: Introductionmentioning

confidence: 99%

“…Using germ-line knockout mice, we have identified functions of the orphan NR, NR2F6 in effector CD4 + and CD8 + T-lymphocytes during cancer progression, autoimmune responses, and immunization [19][20][21][22][23][24] . Mechanistically, NR2F6 suppresses the transcription of cytokine genes directly (Il21) or via blocking the binding of activating transcription factors such as NFAT/AP-1 to the promoter and/or other conserved regulatory sequences (Il2, Ifng, Il17), thus acting as a brake on inflammatory cytokine responses 19,20,22,24 . Our previous tumor experiments demonstrated that Nr2f6-deficient mice have superior protective memory responses 19 .…”

Section: Introductionmentioning

confidence: 99%

Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ

et al. 2021

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Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127−KLRG1+) or memory precursors cells (MPECs, CD127+KLRG1−) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8+ memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-γ, TNFα, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6−/− OT-I T-cells showed that the augmented memory formation is CD8+ T-cell intrinsic. Although the relative difference between the Nr2f6+/+ and Nr2f6−/− OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-γ responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8+ T-cell responses. Following a secondary adoptive transfer into naïve congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-γ mediated. IFN-γ blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8+ T cells may have therapeutic potential for enhancing early IFN-γ production and consequently the functionality of memory CD8+ T cells in vivo.

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“…It is also known for its functions as a transcription factor, coactivator, and repressor for the expression of various genes, including hormones, hormone receptors, and apolipoproteins [ 12 , 13 , 14 , 15 , 16 , 17 ]. In immune cells, it helps to regulate the expression of cytokines like Interleukin-21 (IL-21) or Interferon-γ (IFN-γ) [ 18 , 19 ], and it is also a negative regulator of T-cell development [ 20 ]. NR2F6 was defined as an intracellular immune checkpoint in tumor-infiltrating T-cells.…”

Section: Introductionmentioning

confidence: 99%

NR2F6 as a Prognostic Biomarker in HNSCC

Klapper

Ribbat‐Idel

Kuppler

et al. 2020

IJMS

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Head and neck squamous cell carcinoma (HNSCC)is the 6th most common cancer in humans worldwide and is associated with a poor prognosis for patients. NR2F6 has been identified as an immune checkpoint molecule in tumor-infiltrating T lymphocytes and is associated with a poor prognostic outcome in various cancers. The prognostic value of NR2F6 in HNSCC has not been described yet. We used a large, representative and clinically well-characterized cohort of 383 HNSCC patients, of which 22.4% developed a local recurrence. The NR2F6 expression was analyzed by using immunohistochemistry and was afterward correlated with clinical characteristics and clinicopathological features of HNSCC patients. Primary tumors from patients who develop a local recurrence have a higher NR2F6 expression than primary tumors which do not develop a local recurrence. Furthermore, a high NR2F6 expression is associated with poorer recurrence-free survival, although there is no correlation with overall survival. NR2F6 expression is independent of the T stage and UICC stage. NR2F6 might be a new prognostic biomarker for the early detection of local recurrences in HNSCC patients. Therefore, it may help to improve the recognition of patients who would benefit from more frequent follow-up examinations.

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Orphan Nuclear Receptor NR2F6 Suppresses T Follicular Helper Cell Accumulation through Regulation of IL-21

Cited by 24 publications

References 62 publications

The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ

NR2F6 as a Prognostic Biomarker in HNSCC

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