Hydrogen Sulfide Promotes Tet1-and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis

被引：369

作者：

Yang, Ruili ^{[1
,2
,3
]}

Qu, Cunye ^{[3
]}

Zhou, Yu ^{[4
]}

Konkel, Joanne E. ^{[5
]}

Shi, Shihong ^{[3
]}

Liu, Yi ^{[6
,7
]}

Chen, Chider ^{[2
,3
]}

Liu, Shiyu ^{[3
]}

Liu, Dawei ^{[1
]}

Chen, Yibu ^{[8
]}

Zandi, Ebrahim ^{[4
]}

Chen, Wanjun ^{[5
]}

Zhou, Yanheng ^{[1
]}

Shi, Songtao ^{[2
,3
]}

机构：

[1] Peking Univ, Sch & Hosp Stomatol, Dept Orthodont, Beijing 100081, Peoples R China

[2] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA

[3] Univ So Calif, Ostrow Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA

[4] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA

[5] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA

[6] Capital Med Univ, Sch Stomatol, Lab Tissue Regenerat & Immunol, Beijing 100050, Peoples R China

[7] Capital Med Univ, Sch Stomatol, Dept Periodont, Beijing 100050, Peoples R China

[8] Univ So Calif, Keck Sch Med, Norris Med Lib, Los Angeles, CA 90033 USA

来源：

IMMUNITY | 2015年 / 43卷 / 02期

关键词：

CYSTATHIONINE-BETA-SYNTHASE; GENE-EXPRESSION; TARGET GENES; CIS-ELEMENT; MOUSE MODEL; TRANSCRIPTION; TET2; 5-HYDROXYMETHYLCYTOSINE; PROLIFERATION; GENERATION;

D O I：

10.1016/j.immuni.2015.07.017

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Regulatory T (Treg) cells are essential for maintenance of immune homeostasis. Here we found that hydrogen sulfide (H2S) was required for Foxp3(+) Treg cell differentiation and function and that H2S deficiency led to systemic autoimmune disease. H2S maintained expression of methylcytosine dioxygenases Tet1 and Tet2 by sulfhydrating nuclear transcription factor Y subunit beta (NFYB) to facilitate its binding to Tet1 and Tet2 promoters. Transforming growth factor-beta (TGF-beta)-activated Smad3 and interleukin-2 (IL-2)-activated Stat5 facilitated Tet1 and Tet2 binding to Foxp3. Tet1 and Tet2 catalyzed conversion of 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) in Foxp3 to establish a Treg-cell-specific hypomethylation pattern and stable Foxp3 expression. Consequently, Tet1 and Tet2 deletion led to Foxp3 hypermethylation, impaired Treg cell differentiation and function, and autoimmune disease. Thus, H2S promotes Tet1 and Tet2 expression, which are recruited to Foxp3 by TGF-beta and IL-2 signaling to maintain Foxp3 demethylation and Treg-cell-associated immune homeostasis.

引用

页码：251 / 263

页数：13

共 42 条

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