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Immunity. 2015 Aug 18;43(2):251-63. doi: 10.1016/j.immuni.2015.07.017. Epub 2015 Aug 11.

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

Author information

1
Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China; Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, 240 South 40(th) Street, Philadelphia, PA 19104, USA; Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
2
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
3
Department of Molecular Microbiology and Immunology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
4
National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, MSC 4352 Bethesda, MD 20892, USA.
5
Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Capital Medical University School of Stomatology, #4 Tiantanxili Avenue, Beijing 100050, China.
6
Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, 240 South 40(th) Street, Philadelphia, PA 19104, USA; Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
7
Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China.
8
Norris Medical Library, Keck School of Medicine, University of Southern California, 2003 Zonal Avenue, Los Angeles, CA 90033, USA.
9
Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China. Electronic address: yanhengzhou@gmail.com.
10
Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, 240 South 40(th) Street, Philadelphia, PA 19104, USA; Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA. Electronic address: songtaos@dental.upenn.edu.

Abstract

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-β (TGF-β)-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-hydroxymethylcytosine (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-β and IL-2 signaling to maintain Foxp3 demethylation and Treg-cell-associated immune homeostasis.

PMID:
26275994
PMCID:
PMC4731232
DOI:
10.1016/j.immuni.2015.07.017
[Indexed for MEDLINE]
Free PMC Article

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