Active Demethylation of the Foxp3 Locus Leads to the Generation of Stable Regulatory T Cells within the Thymus

被引：203

作者：

Toker, Aras ^{[1
]}

Engelbert, Dirk ^{[2
]}

Garg, Garima ^{[1
]}

Polansky, Julia K. ^{[1
]}

Floess, Stefan ^{[1
]}

Miyao, Takahisa ^{[3
]}

Baron, Udo ^{[4
]}

Dueber, Sandra ^{[1
]}

Geffers, Robert ^{[1
]}

Giehr, Pascal ^{[5
]}

Schallenberg, Sonja ^{[6
]}

Kretschmer, Karsten ^{[6
]}

Olek, Sven ^{[4
]}

Walter, Joern ^{[5
]}

Weiss, Siegfried ^{[1
]}

Hori, Shohei ^{[3
]}

Hamann, Alf ^{[2
]}

Huehn, Jochen ^{[1
]}

机构：

[1] Helmholtz Ctr Infect Res, D-38124 Braunschweig, Germany

[2] Charite, Med Clin Rheumatol & Clin Immunol, D-10117 Berlin, Germany

[3] RIKEN Res Ctr Allergy & Immunol, Res Unit Immune Homeostasis, Yokohama, Kanagawa 2300045, Japan

[4] Epiontis GmbH, D-12489 Berlin, Germany

[5] Univ Saarland, Dept Genet Epigenet, D-66123 Saarbrucken, Germany

[6] Deutsch Forsch Gemeinschaft, Ctr Regenerat Therapies Dresden, D-01307 Dresden, Germany

来源：

JOURNAL OF IMMUNOLOGY | 2013年 / 190卷 / 07期

关键词：

TRANSCRIPTION FACTOR FOXP3; HEMATOPOIETIC STEM-CELLS; DNA DEMETHYLATION; IN-VIVO; MAMMALIAN DNA; EXPRESSION; LINEAGE; GENE; SELECTION; MICE;

D O I：

10.4049/jimmunol.1203473

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Stable expression of Foxp3 in regulatory T cells (Tregs) depends on DNA demethylation at the Treg-specific demethylated region (TSDR), a conserved, CpG-rich region within the Foxp3 locus. The TSDR is selectively demethylated in ex vivo Tregs purified from secondary lymphoid organs, but it is unclear at which stage of Treg development demethylation takes place. In this study, we show that commitment to a stable lineage occurred during early stages of murine thymic Treg development by engraving of lineage-specific epigenetic marks in parallel with establishment of a Treg-specific gene expression profile. TSDR demethylation was achieved through an active mechanism and involved enzymes of the ten-eleven-translocation family and hydroxylation of methylated cytosines, a modification that is implicated as an initiating step of mitosis-independent DNA demethylation pathways and has not yet been observed at specific loci during immune cell differentiation. Together, our results demonstrate that initiating TSDR demethylation during early stages of thymic Treg development commences stabilization of Foxp3 expression and guarantees full functionality and long-term lineage stability of Tregs. The Journal of Immunology, 2013, 190: 3180-3188.

引用

页码：3180 / 3188

页数：9

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