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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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CCAAT-Binding Factor / metabolism
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Cell Differentiation / genetics
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Colitis / genetics
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Colitis / immunology*
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DNA Methylation / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dioxygenases
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Homeostasis / genetics
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Homeostasis / immunology
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Humans
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Hydrogen Sulfide / metabolism*
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Interleukin-2 / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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STAT5 Transcription Factor / metabolism
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Smad3 Protein / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / transplantation
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Transforming Growth Factor beta / immunology
Substances
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CCAAT-Binding Factor
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2
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Nfyb protein, mouse
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Proto-Oncogene Proteins
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STAT5 Transcription Factor
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Smad3 Protein
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TET1 protein, mouse
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Transforming Growth Factor beta
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Dioxygenases
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Tet2 protein, mouse
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Hydrogen Sulfide