Downregulation of P53 by Insufficient CTCF in CD4 T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2020 Nov 2

PMID 33133081

Citations 5

Authors

Juan Hua

Yan Chen

Bin Fu

Xu Chen

Xue-Jun Xu

Shuang-Hui Yang

Cong Chen

Ya-Jing Xu

Affiliations

Soon will be listed here.

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 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.

Citing Articles

IFN-γ induces acute graft-versus-host disease by promoting HMGB1-mediated nuclear-to-cytoplasm translocation and autophagic degradation of p53.

Wang S, Cheng T, Chen X, Zeng C, Qin W, Xu Y Clin Sci (Lond). 2024; 138(20):1287-1304.

PMID: 39312196 PMC: 11479981. DOI: 10.1042/CS20241144.

Suppression of P53 Pathway is an Important Factor Inducing Acute Graft-versus-Host Disease Through T Cell Activation Based on Bioinformatics Analysis.

Wang S, Qin W, Cheng T, Zeng C, Chen X, Xu Y J Inflamm Res. 2024; 17:4093-4104.

PMID: 38948198 PMC: 11214571. DOI: 10.2147/JIR.S458860.

Decoding the host-pathogen interspecies molecular crosstalk during oral candidiasis in humans: an analysis.

Kabir A, Chaudhary A, Aladwani M, Podder S Front Genet. 2023; 14:1245445.

PMID: 37900175 PMC: 10603195. DOI: 10.3389/fgene.2023.1245445.

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

Zeng C, Cheng T, Ma X, Liu Y, Hua J, Chen X Clin Epigenetics. 2022; 14(1):109.

PMID: 36056390 PMC: 9440523. DOI: 10.1186/s13148-022-01330-7.

Cohesin-Mediated Chromatin Interactions and Autoimmunity.

Chandrasekaran V, Oparina N, Garcia-Bonete M, Wasen C, Erlandsson M, Malmhall-Bah E Front Immunol. 2022; 13:840002.

PMID: 35222432 PMC: 8866859. DOI: 10.3389/fimmu.2022.840002.

References

Mendez-Catala C, Gretton S, Vostrov A, Pugacheva E, Farrar D, Ito Y . A novel mechanism for CTCF in the epigenetic regulation of Bax in breast cancer cells. Neoplasia. 2013; 15(8):898-912. PMC: 3730042. DOI: 10.1593/neo.121948. View

Simelyte E, Rosengren S, Boyle D, Corr M, Green D, Firestein G . Regulation of arthritis by p53: critical role of adaptive immunity. Arthritis Rheum. 2005; 52(6):1876-84. DOI: 10.1002/art.21099. View

Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y . A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53. Cancer Res. 2018; 78(13):3484-3496. PMC: 8073197. DOI: 10.1158/0008-5472.CAN-17-3454. View

Hou C, Zhao H, Tanimoto K, Dean A . CTCF-dependent enhancer-blocking by alternative chromatin loop formation. Proc Natl Acad Sci U S A. 2008; 105(51):20398-403. PMC: 2629272. DOI: 10.1073/pnas.0808506106. View

Kawashima H, Takatori H, Suzuki K, Iwata A, Yokota M, Suto A . Tumor suppressor p53 inhibits systemic autoimmune diseases by inducing regulatory T cells. J Immunol. 2013; 191(7):3614-23. DOI: 10.4049/jimmunol.1300509. View

Watanabe M, Moon K, Vacchio M, Hathcock K, Hodes R . Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4(+) T cell responses. Immunity. 2014; 40(5):681-91. PMC: 4073799. DOI: 10.1016/j.immuni.2014.04.006. View

Fulton L, Carlson M, Coghill J, Ott L, West M, Panoskaltsis-Mortari A . Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt. J Immunol. 2012; 189(4):1765-72. PMC: 3411855. DOI: 10.4049/jimmunol.1200858. View

Kingsley C, Karim M, Bushell A, Wood K . CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol. 2002; 168(3):1080-6. DOI: 10.4049/jimmunol.168.3.1080. View

Liu Y, Cai Y, Dai L, Chen G, Ma X, Wang Y . The expression of Th17-associated cytokines in human acute graft-versus-host disease. Biol Blood Marrow Transplant. 2013; 19(10):1421-9. DOI: 10.1016/j.bbmt.2013.06.013. View

10.

Zhang S, Zheng M, Kibe R, Huang Y, Marrero L, Warren S . Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. FASEB J. 2011; 25(7):2387-98. PMC: 3114529. DOI: 10.1096/fj.10-175299. View

11.

Wolff D, Ayuk F, Elmaagacli A, Bertz H, Lawitschka A, Schleuning M . Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers. Biol Blood Marrow Transplant. 2013; 19(5):767-76. DOI: 10.1016/j.bbmt.2013.01.018. View

12.

Xu Y, Chen F, Chen Y, Fu B, Liu E, Zou L . A Possible Reason to Induce Acute Graft-vs.-Host Disease After Hematopoietic Stem Cell Transplantation: Lack of Sirtuin-1 in CD4 T Cells. Front Immunol. 2019; 9:3078. PMC: 6308326. DOI: 10.3389/fimmu.2018.03078. View

13.

Fierabracci A, Pellegrino M . The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target. Int J Mol Sci. 2016; 17(12). PMC: 5187775. DOI: 10.3390/ijms17121975. View

14.

Takatori H, Kawashima H, Suzuki K, Nakajima H . Role of p53 in systemic autoimmune diseases. Crit Rev Immunol. 2015; 34(6):509-16. DOI: 10.1615/critrevimmunol.2014012193. View

15.

Schuijers J, Manteiga J, Weintraub A, Day D, Zamudio A, Hnisz D . Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism. Cell Rep. 2018; 23(2):349-360. PMC: 5929158. DOI: 10.1016/j.celrep.2018.03.056. View

16.

Li X, Chen T, Gao Q, Zhang W, Xiao Y, Zhu W . A panel of 4 biomarkers for the early diagnosis and therapeutic efficacy of aGVHD. JCI Insight. 2019; 4(16). PMC: 6777816. DOI: 10.1172/jci.insight.130413. View

17.

Park J, Lim M, Cho M, Ryu J, Moon Y, Jhun J . p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice. Arthritis Rheum. 2013; 65(4):949-59. DOI: 10.1002/art.37841. View

18.

Zeiser R, Socie G, Blazar B . Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol. 2016; 175(2):191-207. DOI: 10.1111/bjh.14295. View

19.

Mustafa M, Lee J, Kim M . CTCF negatively regulates HOXA10 expression in breast cancer cells. Biochem Biophys Res Commun. 2015; 467(4):828-34. DOI: 10.1016/j.bbrc.2015.10.058. View

20.

Majumder P, Gomez J, Chadwick B, Boss J . The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J Exp Med. 2008; 205(4):785-98. PMC: 2292219. DOI: 10.1084/jem.20071843. View