p53 promotes the expansion of regulatory T cells via DNMT3a- and TET2- mediated Foxp3 expression in sepsis

Hui Zhang; Tiantian Wu; Chao Ren; Ning Dong; Yao Wu; Yongming Yao

doi:10.1093/burnst/tkad021

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p53 promotes the expansion of regulatory T cells via DNMT3a- and TET2- mediated Foxp3 expression in sepsis

更新时间：2023-08-29

- p53 promotes the expansion of regulatory T cells via DNMT3a- and TET2- mediated Foxp3 expression in sepsis
- Burns & Trauma Vol. 11, Issue 1, (2023)
- 作者机构：
  
  1. Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital
  2. Department of Hepatobiliary Surgery, Peking University International Hospital
  3. Department of Respiratory and Critical Care Medicine
  4. Capital Medical University
  5. Translational Medicine Research Center
- 作者简介：
- 基金信息：
- DOI：10.1093/burnst/tkad021
  CLC：
- Published：2023，
  
  Published Online：8 August 2023，
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Hui Zhang, Tiantian Wu, Chao Ren, Ning Dong, Yao Wu, Yongming Yao, p53 promotes the expansion of regulatory T cells via DNMT3a- and TET2- mediated Foxp3 expression in sepsis, Burns & Trauma, Volume 11, 2023, tkad021, https://doi.org/10.1093/burnst/tkad021
DOI：

Hui Zhang, Tiantian Wu, Chao Ren, Ning Dong, Yao Wu, Yongming Yao, p53 promotes the expansion of regulatory T cells via DNMT3a- and TET2- mediated Foxp3 expression in sepsis, Burns & Trauma, Volume 11, 2023, tkad021, https://doi.org/10.1093/burnst/tkad021 DOI：

摘要

Abstract

BackgroundImmunosuppression is an important characteristic of sepsis and is closely related to poor outcomes. Regulatory T cells (Tregs) contribute to immune suppression by inhibiting effector T cell (Teff) proliferation and differentiation. We aimed to investigate the role of p53 in Treg expansion after sepsis.MethodsWe constructed a sepsis model in wild-type (WT) and p53f/f/CD4-Cre+ mice by cecal ligation and puncture (CLP) and evaluated the proportions of CD4+CD25+ Foxp3+ Tregs by flow cytometry. The expression levels of forkhead/winged helix transcription factor p3 (Foxp3)

DNA methyltransferase enzyme (DMNT)3a and ten–eleven translocation (TET)2 were examined using quantitative real-time PCR and Western blot analysis. Treg-specific demethylation region (TSDR) methylation sites in cells were analyzed by bisulfite-sequencing PCR. Furthermore

the direct binding of p53 to the Dnmt3a and TET2 promoters was illustrated using a luciferase assay. The suppressive ability of Tregs was indicated by enzyme-linked immunosorbent assay analysis of cytokine levels and the proliferation of cocultured Teffs. Finally

mortality rates after CLP were compared among WT and p53f/f/CD4-Cre+ mice.ResultsThe proportion of CD4+CD25+ Foxp3+ Tregs was significantly reduced in p53f/f/CD4-Cre+ mice compared to WT mice after CLP. The enhanced expression of Foxp3 in WT mice was downregulated in the p53f/f/CD4-Cre+ group. We found decreased DMNT3a and increased TET2 levels after CLP. However

the dysregulation of DNMT3a and TET2 was significantly reversed in p53f/f/CD4-Cre+ mice. TSDR underwent increased demethylation in p53f/f/CD4-Cre+ mice. Luciferase activity indicated direct binding of p53 to the promoter regions of DNMT3a and TET2 to regulate their transcription. Consequently

Tregs from p53f/f/CD4-Cre+ CLP mice exhibited limited suppressive ability

as indicated by the reduced production of transforming growth factor-β and interleukin 10 (IL-10). In the coculture system

Teffs showed preserved production of IL-2

differentiation into Th1 cells and proliferation in the presence of Tregs isolated from p53f/f/CD4-Cre+ CLP mice. Finally

the mortality rate of the p53f/f/CD4-Cre+ group after CLP was significantly reduced in comparison to that of the WT group.Conclusionp53 appears to be critical for Foxp3 expression and consequent Treg expansion by regulating the induction of DNMT3a and TET2

thereby resulting in Foxp3-TSDR demethylation in the context of sepsis.

关键词

Keywords

SepsisImmunosuppressionp53Regulatory T cellsFoxp3DNMT3aTET2

references

1.Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801–10.

2.Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study. Lancet. 2020;395:200–11.

3.Prescott HC, Angus DC. Enhancing recovery from sepsis: a review. JAMA. 2018;319:62–75.

4.Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.

5.Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016;126:23–31.

6.Martin MD, Badovinac VP, Griffith TS. CD4 T cell responses and the sepsis-induced immunoparalysis state. Front Immunol. 2020;11:1364.

7.Cabrera-Perez J, Condotta SA, Badovinac VP, Griffith TS. Impact of sepsis on CD4 T cell immunity. J Leukoc Biol. 2014;96:767–77.

8.Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.

9.Monneret G, Debard AL, Venet F, Bohe J, Hequet O, Bienvenu J, et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med. 2003;31:2068–71.

10.Leng FY, Liu JL, Liu ZJ, Yin JY, Qu HP. Increased proportion of CD4+CD25+Foxp3+ regulatory T cells during early-stage sepsis in ICU patients. J Microbiol Immunol Infect. 2013;46:338–44.

11.Guo G, Marrero L, Rodriguez P, Del Valle L, Ochoa A, Cui Y. Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res. 2013;73:1668–75.

12.Won KY, Kim HS, Sung JY, Kim GY, Lee J, Park YK, et al. Tumoral FOXP3 has potential oncogenic function in conjunction with the p53 tumor suppressor protein and infiltrated Tregs in human breast carcinomas. Pathol Res Pract. 2013;209:767–73.

13.Park JS, Lim MA, Cho ML, Ryu JG, Moon YM, Jhun JY, et al. p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice. Arthritis Rheum. 2013;65:949–59.

14.Zhang H, Xu CF, Ren C, Wu TT, Dong N, Yao YM. Novel role of p53 in septic immunosuppression: involvement in loss and dysfunction of CD4+ T lymphocytes. Cell Physiol Biochem. 2018;51:452–69.

15.Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008;38:1654–63.

16.Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, et al. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res. 2022;9:56.

17.Li E, Zhang Y. DNA methylation in mammals. Cold Spring Harb Perspect Biol. 2014;6:a019133.

18.Cao C, Ma T, Chai YF, Shou ST. The role of regulatory T cells in immune dysfunction during sepsis. World J Emerg Med. 2015;6:5–9.

19.Yoon SJ, Kim SJ, Lee SM. Overexpression of HO-1 contributes to sepsis-induced immunosuppression by modulating the Th1/Th2 balance and regulatory T-cell function. J Infect Dis. 2017;215:1608–18.

20.Hu ZQ, Yao YM, Chen W, Bian JL, Zhao LJ, Chen LW, et al. Partial depletion of regulatory T cells enhances host inflammatory response against acute Pseudomonas aeruginosa infection after sepsis. Inflammation. 2018;41:1780–90.

21.Gupta DL, Bhoi S, Mohan T, Galwnkar S, Rao DN. Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with post traumatic sepsis. Cytokine. 2016;88:214–21.

22.Venet F, Pachot A, Debard AL, Bohé J, Bienvenu J, Lepape A, et al. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit Care Med. 2004;32:2329–31.

23.Venet F, Chung CS, Kherouf H, Geeraert A, Malcus C, Poitevin F, et al. Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (−)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med. 2009;35:678–86.

24.Pokhrel RH, Acharya S, Ahn JH, Gu Y, Pandit M, Kim JO, et al. AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway. Mol Cancer. 2021;20:133.

25.Wu D, Luo Y, Guo W, Niu Q, Xue T, Yang F, et al. Lkb1 maintains Treg cell lineage identity. Nat Commun. 2017;8:15876.

26.Lee HM, Bautista JL, Hsieh CS. Thymic and peripheral differentiation of regulatory T cells. Adv Immunol. 2011;112:25–71.

27.Kawashima H, Takatori H, Suzuki K, Iwata A, Yokota M, Suto A, et al. Tumor suppressor p53 inhibits systemic autoimmune diseases by inducing regulatory T cells. J Immunol. 2013;191:3614–23.

28.Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.

29.Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4:337–42.

30.Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky AY. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell. 2014;158:749–63.

31.Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012;36:262–75.

32.Kressler C, Gasparoni G, Nordström K, Hamo D, Salhab A, Dimitropoulos C, et al. Targeted de-methylation of the FOXP3-TSDR is sufficient to induce physiological FOXP3 expression but not a functional Treg phenotype. Front Immunol. 2021;11:609891.

33.Wu SC, Zhang Y. Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 2010;11:607–20.

34.Lio CJ, Rao A. TET enzymes and 5hmC in adaptive and innate immune systems. Front Immunol. 2019;10:210.

35.Loaeza-Loaeza J, Beltran AS, Hernández-Sotelo D. DNMTs and impact of CpG content, transcription factors, consensus motifs, lncRNAs, and histone marks on DNA methylation. Genes (Basel). 2020;11:1336.

36.Wang L, Liu Y, Beier UH, Han R, Bhatti TR, Akimova T, et al. Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood. 2013;121:3631–9.

37.Sasidharan Nair V, Song MH, Oh KI. Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J Immunol. 2016;196:2119–31.

38.Chen LL, Morcelle C, Cheng ZL, Chen X, Xu Y, Gao Y, et al. Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses. Nat Cell Biol. 2022;24:353–63.

39.Tovy A, Spiro A, McCarthy R, Shipony Z, Aylon Y, Allton K, et al. p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity. Genes Dev. 2017;31:959–72.

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