A Possible Reason to Induce Acute Graft-vs.-Host Disease After Hematopoietic Stem Cell Transplantation: Lack of Sirtuin-1 in CD4+ T Cells

Xu, Yajing; Chen, Fangping; Chen, Yan; Fu, Bin; Liu, Enyi; Zou, Lang; Liu, Linxin

doi:10.3389/fimmu.2018.03078

Cited by 3 publications

(4 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accumulating evidence suggests that the imbalance between Th17 cells and Tregs plays a critical role in aGVHD ( 17 – 19 , 37 – 39 ). Our previous research revealed that STAT3 overexpression and activation in CD4 + T cells from aGVHD cases is one of the causes of Th17/Treg imbalance ( 6 , 22 ). In this study, after CTCF overexpression in CD4 + T cells from aGVHD patients, p53, Foxp3, and IL-10 expression levels were significantly increased, while RORγt and IL-17A were significantly downregulated, thus reversing the Th17/Treg imbalance.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

Hua

Chen

et al. 2020

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Recent evidence indicates that p53 plays a protective role against various systemic autoimmune diseases by suppressing pro-inflammatory cytokine production and reducing the number of pathogenic T cells. However, whether abnormal p53 expression participates in the development of acute graft-versus-host disease (aGVHD) remains unclear. In this study, we demonstrated that p53 was downregulated in CD4 + T cells from patients with aGVHD compared with the non-aGVHD group. Furthermore, we confirmed that low expression of CCCTC-binding factor (CTCF) in CD4 + T cells from aGVHD cases is an important factor affecting histone H3K9/K14 hypoacetylation in the p53 promoter and p53 downregulation. Restoring CTCF expression in CD4 + T cells from aGVHD patients increased p53 amounts and corrected the imbalance of Th17 cells/Tregs. Taken together, these results provide novel insights into p53 downregulation in CD4 + T cells from aGVHD patients.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The median time from transplantation to aGVHD onset was 53 (20–91) days. Conditioning regimens were adopted as described in our previous study ( 22 ). Assessment of aGVHD was based on clinical symptoms in accordance with reported criteria ( 23 , 24 ).…”

Section: Methodsmentioning

confidence: 99%

Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

Hua

Chen

et al. 2020

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The clinical characteristics of the included patients are shown in Table 1 . Conditioning regimens were based on our previous study [ 57 ]. aGVHD was assessed based on clinical symptoms in accordance with commonly accepted criteria [ 58 , 59 ].…”

Section: Methodsmentioning

confidence: 99%

The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression

Zeng

Cheng

et al. 2022

Clin Epigenet

Self Cite

View full text Add to dashboard Cite

Background Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Accumulating evidence suggests that imbalanced Treg/Th17 ratio accelerates the progression of aGVHD. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor activated through cognate ligand binding. Current evidence supports that AhR plays a critical regulatory role in the differentiation of Treg and Th17 cells. However, the relationship between AhR and aGVHD remains unclear. Results Our results showed that AhR expression was downregulated significantly in CD4+ T cells from patients with aGVHD compared with the non-aGVHD group. We also discovered that after activating AhR deficient CD4+ T cells, the expression levels of the activation markers-CD40L, CD134 and CD137 and cell proliferation activity were significantly higher than those of AhR-expressing CD4+ T cells. Restoring the expression of AhR in aGVHD CD4+ T cells resulted in significantly increased percentage of Tregs and associated gene transcripts, including Foxp3, IL-10 and CD39. In contrast, Th17 cell amounts and the transcription of related genes, including RORγt, IL-17A and IL-17F, were significantly reduced. We confirmed that CTCF recruited EP300 and TET2 to bind to the AhR promoter region and promoted AhR expression by mediating histone H3K9/K14 hyperacetylation and DNA demethylation in this region. The low expression of CTCF caused histone hypoacetylation and DNA hypermethylation of the AhR promoter, resulting in insufficient expression in aGVHD CD4+ T cells. Conclusions CTCF is an important inducer of AhR transcription. Insufficient expression of CTCF leads to excessive AhR downregulation, resulting in substantial CD4+ T cell activation and Th17/Treg ratio increase, thereby mediating the occurrence of aGVHD.

show abstract

“…Moreover, conditional SIRT1 KO in T cells was further shown to induce Treg differentiation, thereby prolonging allograft survival 12 , 13 . However, a recent study on patients with acute graft-versus-host disease (aGVHD) revealed contradictory results, as SIRT1 deficiency in CD4 + T cells played a crucial role in upregulating STAT3 phosphorylation, in turn increasing Th17 differentiation and inducing aGVHD 14 . This latter finding was further supported by a study on SIRT1-deficient mice, in which T cells failed to maintain tolerance leading to the development of severe EAE 15 .…”

Section: Introductionmentioning

confidence: 99%

Melatonin ameliorates necrotizing enterocolitis by preventing Th17/Treg imbalance through activation of the AMPK/SIRT1 pathway

Gao

et al. 2020

Theranostics

View full text Add to dashboard Cite

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants. Mounting evidence supports the therapeutic effect of melatonin on NEC, although the underlying mechanisms remain unclear. Methods: NEC was induced in 10-day-old C57BL/6 pups via hypoxia and gavage feeding of formula containing enteric bacteria, and then, mice received melatonin, melatonin + recombinant IL-17, melatonin + anti-CD25 monoclonal antibody, melatonin + Ex-527, or melatonin + Compound C treatment. Control mice were left with their dams to breastfeed and vehicle-treated NEC pups were used as controls for treatment. Ileal tissues were collected from mice and analyzed by histopathology, immunoblotting, and flow cytometry. FITC-labeled dextran was administered to all surviving pups to evaluate gut barrier function by fluorometry. We used molecular biology and cell culture approaches to study the related mechanisms in CD4 + T cells from umbilical cord blood. Results: We demonstrated that melatonin treatment ameliorates disease in an NEC mouse model in a manner dependent on improved intestinal Th17/Treg balance. We also showed that melatonin blocks the differentiation of pathogenic Th17 cells and augments the generation of protective Treg cells in vitro. We further demonstrated that the Th17/Treg balance is influenced by melatonin through activation of AMPK in the intestine, in turn promoting SIRT1 activation and stabilization. Conclusions: These results demonstrate that melatonin-induced activation of AMPK/SIRT1 signaling regulates the balance between Th17 and Treg cells and that therapeutic strategies targeting the Th17/Treg balance via the AMPK/SIRT1 pathway might be beneficial for the treatment of NEC.

show abstract

A Possible Reason to Induce Acute Graft-vs.-Host Disease After Hematopoietic Stem Cell Transplantation: Lack of Sirtuin-1 in CD4+ T Cells

Cited by 3 publications

References 57 publications

Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression

Melatonin ameliorates necrotizing enterocolitis by preventing Th17/Treg imbalance through activation of the AMPK/SIRT1 pathway

Contact Info

Product

Resources

About