Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis.
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.
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.
Ruili
R
Yang
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Cunye
C
Qu
Department of Molecular Microbiology and Immunology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Yu
Y
Zhou
National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, MSC 4352 Bethesda, MD 20892, USA.
Joanne E
JE
Konkel
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Shihong
S
Shi
Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Capital Medical University School of Stomatology, #4 Tiantanxili Avenue, Beijing 100050, China.
Yi
Y
Liu
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.
Chider
C
Chen
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Shiyu
S
Liu
Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China.
Dawei
D
Liu
Norris Medical Library, Keck School of Medicine, University of Southern California, 2003 Zonal Avenue, Los Angeles, CA 90033, USA.
Yibu
Y
Chen
Department of Molecular Microbiology and Immunology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Ebrahim
E
Zandi
National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, MSC 4352 Bethesda, MD 20892, USA.
Wanjun
W
Chen
Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China. Electronic address: yanhengzhou@gmail.com.
Yanheng
Y
Zhou
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.
Songtao
S
Shi
D019264:Adoptive Transfer; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000276:immunology
D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; C492062:Nfyb protein, mouse; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D051900:Smad3 Protein; C540839:TET1 protein, mouse; D016212:Transforming Growth Factor beta; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D006862:Hydrogen Sulfide