Abstract
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.
Highlights
Allogeneic hematopoietic stem cell transplantation is considered the exclusive treatment option for hematopoietic malignancies, but acute graft-versus-host disease is the primary limitation of this therapy
The pRS-p53 group proliferated strongly in response to IL-2 alone, at a magnitude comparable to their response to anti-CD3/antiCD28 antibodies plus IL-2, whereas the pRS group exhibited a very limited expansion upon stimulation with IL-2 alone (Figures 1E,F). These results indicated that p53 downregulation in CD4+ T cells may lead to an over-reaction to IL-2 and acute graft-versus-host disease (aGVHD) occurrence
This study demonstrated that p53 downregulation significantly enhanced CD4+ T cell response to IL-2 stimulation
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the exclusive treatment option for hematopoietic malignancies, but acute graft-versus-host disease (aGVHD) is the primary limitation of this therapy. Controlling the overactivation of T lymphocytes is the key to preventing aGVHD. The transcription factor p53 is a tumor suppressor gene that plays an important role in regulating cell growth, apoptosis, and DNA repair. Evidence indicates that p53 plays a protective role in inflammatory response by inhibiting the inappropriate expression of pro-inflammatory factors such as IL-1, IL-6, IL-12, and TNF, etc. Recent studies demonstrated that inhibition of autoimmunity by p53 may be related to p53-mediated Foxp transcription in Tregs. P53 plays an important role in regulating Th17 cell/Treg balance. The above findings clearly indicate that p53 is a key factor in inhibiting autoimmune and inflammatory responses; whether abnormal p53 expression participates in the development of aGVHD remains unclear
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