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

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.

The effects of thioredoxin peroxidase from Cysticercus cellulosae excretory-secretory antigens on TGF-β signaling pathway and Th17 cells differentiation in Jurkat cells by transcriptomics

“…It is involved in the recruitment of SMAD3, SMAD2, and SMAD4 to form trimeric complexes [48]. The aryl hydrocarbon receptor (AHR), a member of the bHLH-PAS family, is a basic helixloop-helix transcription factor activated through cognate ligand binding [49]. AHR plays a key regulatory role in the differentiation of Treg and Th17 cells.…”

“…AHR plays a key regulatory role in the differentiation of Treg and Th17 cells. Studies have found that the expression of AhR in CD4 + T cells leads to a signi cant increase in the percentage of Treg and related gene transcripts (including Foxp3, IL-10, and CD39), and a signi cant decrease in the transcription of Th17 cells and related genes (including RORγt, IL-17A, and IL-17F), inducing an imbalance between Th17 and Treg cells [49,50].…”