T Cell Receptor Stimulation-Induced Epigenetic Changes and Foxp3 Expression Are Independent and Complementary Events Required for Treg Cell Development

被引：620

作者：

Ohkura, Naganari ^{[1
,2
]}

Hamaguchi, Masahide ^{[1
,2
]}

Morikawa, Hiromasa ^{[1
,2
]}

Sugimura, Kyoko ^{[2
]}

Tanaka, Atsushi ^{[2
]}

Ito, Yoshinaga ^{[2
]}

Osaki, Motonao ^{[1
,2
]}

Tanaka, Yoshiaki ^{[3
,4
]}

Yamashita, Riu ^{[4
,5
]}

Nakano, Naoko ^{[6
]}

Huehn, Jochen ^{[7
]}

Fehling, Hans Joerg ^{[8
]}

Sparwasser, Tim ^{[9
]}

Nakai, Kenta ^{[3
,4
,10
]}

Sakaguchi, Shimon ^{[1
,2
]}

机构：

[1] Osaka Univ, Dept Expt Immunol, World Premier Int Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan

[2] Kyoto Univ, Dept Expt Pathol, Inst Frontier Med Sci, Kyoto 6068507, Japan

[3] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Tokyo 1088639, Japan

[4] Univ Tokyo, Inst Med Sci, Human Genome Ctr, Tokyo 1088639, Japan

[5] Univ Tokyo, Inst Med Sci, Frontier Res Initiat, Tokyo 1088639, Japan

[6] Tokyo Univ Sci, Res Inst Biol Sci, Chiba 2780022, Japan

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

[8] Univ Clin Ulm, Inst Immunol, D-89081 Ulm, Germany

[9] TWINCORE Ctr Expt & Clin Infect Res, Inst Infect Immunol, D-30625 Hannover, Germany

[10] Japan Sci & Technol Agcy, Inst Bioinformat Res & Dev BIRD, Tokyo 1020081, Japan

来源：

IMMUNITY | 2012年 / 37卷 / 05期

基金：

日本学术振兴会;

关键词：

TRANSCRIPTION FACTOR FOXP3; GENE-EXPRESSION; DNA METHYLATION; GENERATION; PLASTICITY; TOLERANCE; INFLAMMATION; MUTATIONS; PROGRAMS; PEPTIDE;

D O I：

10.1016/j.immuni.2012.09.010

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The transcription factor Foxp3 is essential for the development of regulatory T (Treg) cells, yet its expression is insufficient for establishing the Treg cell lineage. Here we showed that Treg cell development was achieved by the combination of two independent processes, i.e., the expression of Foxp3 and the establishment of Treg cell-specific CpG hypomethylation pattern. Both events were induced by T cell receptor stimulation. The Treg cell-type CpG hypomethylation began in the thymus and continued to proceed in the periphery and could be fully established without Foxp3. The hypomethylation was required for Foxp3(+) T cells to acquire Treg cell-type gene expression, lineage stability, and full suppressive activity. Thus, those T cells in which the two events have concurrently occurred are developmentally set into the Treg cell lineage. This model explains how Treg cell fate and plasticity is controlled and can be exploited to generate functionally stable Treg cells.

引用

页码：785 / 799

页数：15

共 41 条

[21] CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression:: a role for DNA methylation [J].

Kim, Hyoung-Pyo ;

Leonard, Warren J. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (07) :1543-1551

[22] Epigenetic mechanisms in mammals [J].

Kim, J. K. ;

Samaranayake, M. ;

Pradhan, S. .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2009, 66 (04) :596-612

[23] Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease [J].

Lahl, Katharina ;

Loddenkemper, Christoph ;

Drouin, Cathy ;

Freyer, Jennifer ;

Arnason, Jon ;

Eberl, Gerard ;

Hamann, Alf ;

Wagner, Hermann ;

Huehn, Jochen ;

Sparwasser, Tim .

JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (01) :57-63

[24] Nonfunctional Regulatory T Cells and Defective Control of Th2 Cytokine Production in Natural Scurfy Mutant Mice [J].

Lahl, Katharina ;

Mayer, Christian T. ;

Bopp, Tobias ;

Huehn, Jochen ;

Loddenkemper, Christoph ;

Eberl, Gerard ;

Wirnsberger, Gerald ;

Dornmair, Klaus ;

Geffers, Robert ;

Schmitt, Edgar ;

Buer, Jan ;

Sparwasser, Tim .

JOURNAL OF IMMUNOLOGY, 2009, 183 (09) :5662-5672

[25] Ultrafast and memory-efficient alignment of short DNA sequences to the human genome [J].

Langmead, Ben ;

Trapnell, Cole ;

Pop, Mihai ;

Salzberg, Steven L. .

GENOME BIOLOGY, 2009, 10 (03)

[26] Plasticity of Foxp3+ T Cells Reflects Promiscuous Foxp3 Expression in Conventional T Cells but Not Reprogramming of Regulatory T Cells [J].

Miyao, Takahisa ;

Floess, Stefan ;

Setoguchi, Ruka ;

Luche, Herve ;

Fehling, Hans Joerg ;

Waldmann, Herman ;

Huehn, Jochen ;

Hori, Shohei .

IMMUNITY, 2012, 36 (02) :262-275

[27] Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor [J].

Miyara, Makoto ;

Yoshioka, Yumiko ;

Kitoh, Akihiko ;

Shima, Tomoko ;

Wing, Kajsa ;

Niwa, Akira ;

Parizot, Christophe ;

Taflin, Cecile ;

Heike, Toshio ;

Valeyre, Dominique ;

Mathian, Alexis ;

Nakahata, Tatsutoshi ;

Yamaguchi, Tomoyuki ;

Nomura, Takashi ;

Ono, Masahiro ;

Amoura, Zahir ;

Gorochov, Guy ;

Sakaguchi, Shimon .

IMMUNITY, 2009, 30 (06) :899-911

[28] Epigenetic regulation of adipogenesis [J].

Musri, Melina M. ;

Parrizas, Marcelina .

CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE, 2012, 15 (04) :342-349

[29] DNA methylation controls Foxp3 gene expression [J].

Polansky, Julia K. ;

Kretschmer, Karsten ;

Freyer, Jennifer ;

Floess, Stefan ;

Garbe, Annette ;

Baron, Udo ;

Olek, Sven ;

Hamann, Alf ;

von Boehmer, Harald ;

Huehn, Jochen .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2008, 38 (06) :1654-1663

[30] Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells [J].

Polansky, Julia K. ;

Schreiber, Lisa ;

Thelemann, Christoph ;

Ludwig, Leif ;

Krueger, Melanie ;

Baumgrass, Ria ;

Cording, Sascha ;

Floess, Stefan ;

Hamann, Alf ;

Huehn, Jochen .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2010, 88 (10) :1029-1040

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