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

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

  • Clin Epigenetics. 2022 Sep 2;14(1):109. doi: 10.1186/s13148-022-01330-7.
Cong Zeng  # 1 2 3 Ting-Ting Cheng  # 1 2 3 Xia Ma 1 2 3 Yi Liu 1 2 3 Juan Hua 1 2 3 Xu Chen 1 2 3 Shi-Yu Wang 1 2 3 Ya-Jing Xu 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2 National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Changsha, China.
  • 3 Hunan Hematology Oncology Clinical Medical Research Center, Changsha, China.
  • 4 Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China. xyyajingxu@csu.edu.cn.
  • 5 National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Changsha, China. xyyajingxu@csu.edu.cn.
  • 6 Hunan Hematology Oncology Clinical Medical Research Center, Changsha, China. xyyajingxu@csu.edu.cn.
  • 7 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China. xyyajingxu@csu.edu.cn.
  • # Contributed equally.
Abstract

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.

Keywords

AhR; CTCF; EP300; TET2; aGVHD.

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