Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression

Hiroko Nakatsukasa, Mayumi Oda, Jinghua Yin, Shunsuke Chikuma, Minako Ito, Mana Koga-Iizuka, Kazue Someya, Yohko Kitagawa, Naganari Ohkura, Shimon Sakaguchi, Ikuko Koya, Tsukasa Sanosaka, Jun Kohyama, Yuichi Tsukada, Soichiro Yamanaka, Takeji Takamura-Enya, Qianjin Lu, Akihiko Yoshimura

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Although Tet2/Tet3 deficiency has been reported to lead to myeloid cell, B-cell and invariant natural killer T (iNKT) cell malignancy, the effect of TET on regulatory T cells (Tregs) has not been elucidated. We found that Tet2/Tet3 deficiency in Tregs led to lethal hyperproliferation of CD4+Foxp3+ T cells in the spleen and mesenteric lymph nodes after 5 months of age. Additionally, in aged Treg-specific Tet2/Tet3-deficient mice, serum IgG1, IgG3, IgM and IgE levels were markedly elevated. High IL-17 expression was observed in both Foxp3+ and Fopx3- CD4+ T cells, and adoptive transfer of Tet2/Tet3-deficient Tregs into lymphopenic mice inhibited Foxp3 expression and caused conversion into IL-17-producing cells. However, the conserved non-coding DNA sequence-2 (CNS2) region of the Foxp3 gene locus, which has been shown to be particularly important for stable Foxp3 expression, was only partly methylated. We identified novel TET-dependent demethylation sites in the Foxp3 upstream enhancer, which may contribute to stable Foxp3 expression. Together, these data indicate that Tet2 and Tet3 are involved in Treg stability and immune homeostasis in mice.

Original languageEnglish
Pages (from-to)335-347
Number of pages13
JournalInternational Immunology
Volume31
Issue number5
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Interleukin-17
Protein Transport
Regulatory T-Lymphocytes
Immunoglobulin G
5-Methylcytosine
T-Lymphocytes
Natural Killer T-Cells
Adoptive Transfer
Myeloid Cells
DNA Methylation
Immunoglobulin E
Immunoglobulin M
Homeostasis
B-Lymphocytes
Spleen
Lymph Nodes
Gene Expression
Serum
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Nakatsukasa, H., Oda, M., Yin, J., Chikuma, S., Ito, M., Koga-Iizuka, M., ... Yoshimura, A. (2019). Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. International Immunology, 31(5), 335-347. https://doi.org/10.1093/intimm/dxz008

Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. / Nakatsukasa, Hiroko; Oda, Mayumi; Yin, Jinghua; Chikuma, Shunsuke; Ito, Minako; Koga-Iizuka, Mana; Someya, Kazue; Kitagawa, Yohko; Ohkura, Naganari; Sakaguchi, Shimon; Koya, Ikuko; Sanosaka, Tsukasa; Kohyama, Jun; Tsukada, Yuichi; Yamanaka, Soichiro; Takamura-Enya, Takeji; Lu, Qianjin; Yoshimura, Akihiko.

In: International Immunology, Vol. 31, No. 5, 01.01.2019, p. 335-347.

Research output: Contribution to journalArticle

Nakatsukasa, H, Oda, M, Yin, J, Chikuma, S, Ito, M, Koga-Iizuka, M, Someya, K, Kitagawa, Y, Ohkura, N, Sakaguchi, S, Koya, I, Sanosaka, T, Kohyama, J, Tsukada, Y, Yamanaka, S, Takamura-Enya, T, Lu, Q & Yoshimura, A 2019, 'Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression', International Immunology, vol. 31, no. 5, pp. 335-347. https://doi.org/10.1093/intimm/dxz008
Nakatsukasa, Hiroko ; Oda, Mayumi ; Yin, Jinghua ; Chikuma, Shunsuke ; Ito, Minako ; Koga-Iizuka, Mana ; Someya, Kazue ; Kitagawa, Yohko ; Ohkura, Naganari ; Sakaguchi, Shimon ; Koya, Ikuko ; Sanosaka, Tsukasa ; Kohyama, Jun ; Tsukada, Yuichi ; Yamanaka, Soichiro ; Takamura-Enya, Takeji ; Lu, Qianjin ; Yoshimura, Akihiko. / Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. In: International Immunology. 2019 ; Vol. 31, No. 5. pp. 335-347.
@article{160626b65a11405dba15ddcf8dbee362,
title = "Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression",
abstract = "Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Although Tet2/Tet3 deficiency has been reported to lead to myeloid cell, B-cell and invariant natural killer T (iNKT) cell malignancy, the effect of TET on regulatory T cells (Tregs) has not been elucidated. We found that Tet2/Tet3 deficiency in Tregs led to lethal hyperproliferation of CD4+Foxp3+ T cells in the spleen and mesenteric lymph nodes after 5 months of age. Additionally, in aged Treg-specific Tet2/Tet3-deficient mice, serum IgG1, IgG3, IgM and IgE levels were markedly elevated. High IL-17 expression was observed in both Foxp3+ and Fopx3- CD4+ T cells, and adoptive transfer of Tet2/Tet3-deficient Tregs into lymphopenic mice inhibited Foxp3 expression and caused conversion into IL-17-producing cells. However, the conserved non-coding DNA sequence-2 (CNS2) region of the Foxp3 gene locus, which has been shown to be particularly important for stable Foxp3 expression, was only partly methylated. We identified novel TET-dependent demethylation sites in the Foxp3 upstream enhancer, which may contribute to stable Foxp3 expression. Together, these data indicate that Tet2 and Tet3 are involved in Treg stability and immune homeostasis in mice.",
author = "Hiroko Nakatsukasa and Mayumi Oda and Jinghua Yin and Shunsuke Chikuma and Minako Ito and Mana Koga-Iizuka and Kazue Someya and Yohko Kitagawa and Naganari Ohkura and Shimon Sakaguchi and Ikuko Koya and Tsukasa Sanosaka and Jun Kohyama and Yuichi Tsukada and Soichiro Yamanaka and Takeji Takamura-Enya and Qianjin Lu and Akihiko Yoshimura",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/intimm/dxz008",
language = "English",
volume = "31",
pages = "335--347",
journal = "International Immunology",
issn = "0953-8178",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression

AU - Nakatsukasa, Hiroko

AU - Oda, Mayumi

AU - Yin, Jinghua

AU - Chikuma, Shunsuke

AU - Ito, Minako

AU - Koga-Iizuka, Mana

AU - Someya, Kazue

AU - Kitagawa, Yohko

AU - Ohkura, Naganari

AU - Sakaguchi, Shimon

AU - Koya, Ikuko

AU - Sanosaka, Tsukasa

AU - Kohyama, Jun

AU - Tsukada, Yuichi

AU - Yamanaka, Soichiro

AU - Takamura-Enya, Takeji

AU - Lu, Qianjin

AU - Yoshimura, Akihiko

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Although Tet2/Tet3 deficiency has been reported to lead to myeloid cell, B-cell and invariant natural killer T (iNKT) cell malignancy, the effect of TET on regulatory T cells (Tregs) has not been elucidated. We found that Tet2/Tet3 deficiency in Tregs led to lethal hyperproliferation of CD4+Foxp3+ T cells in the spleen and mesenteric lymph nodes after 5 months of age. Additionally, in aged Treg-specific Tet2/Tet3-deficient mice, serum IgG1, IgG3, IgM and IgE levels were markedly elevated. High IL-17 expression was observed in both Foxp3+ and Fopx3- CD4+ T cells, and adoptive transfer of Tet2/Tet3-deficient Tregs into lymphopenic mice inhibited Foxp3 expression and caused conversion into IL-17-producing cells. However, the conserved non-coding DNA sequence-2 (CNS2) region of the Foxp3 gene locus, which has been shown to be particularly important for stable Foxp3 expression, was only partly methylated. We identified novel TET-dependent demethylation sites in the Foxp3 upstream enhancer, which may contribute to stable Foxp3 expression. Together, these data indicate that Tet2 and Tet3 are involved in Treg stability and immune homeostasis in mice.

AB - Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Although Tet2/Tet3 deficiency has been reported to lead to myeloid cell, B-cell and invariant natural killer T (iNKT) cell malignancy, the effect of TET on regulatory T cells (Tregs) has not been elucidated. We found that Tet2/Tet3 deficiency in Tregs led to lethal hyperproliferation of CD4+Foxp3+ T cells in the spleen and mesenteric lymph nodes after 5 months of age. Additionally, in aged Treg-specific Tet2/Tet3-deficient mice, serum IgG1, IgG3, IgM and IgE levels were markedly elevated. High IL-17 expression was observed in both Foxp3+ and Fopx3- CD4+ T cells, and adoptive transfer of Tet2/Tet3-deficient Tregs into lymphopenic mice inhibited Foxp3 expression and caused conversion into IL-17-producing cells. However, the conserved non-coding DNA sequence-2 (CNS2) region of the Foxp3 gene locus, which has been shown to be particularly important for stable Foxp3 expression, was only partly methylated. We identified novel TET-dependent demethylation sites in the Foxp3 upstream enhancer, which may contribute to stable Foxp3 expression. Together, these data indicate that Tet2 and Tet3 are involved in Treg stability and immune homeostasis in mice.

UR - http://www.scopus.com/inward/record.url?scp=85067560189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067560189&partnerID=8YFLogxK

U2 - 10.1093/intimm/dxz008

DO - 10.1093/intimm/dxz008

M3 - Article

AN - SCOPUS:85067560189

VL - 31

SP - 335

EP - 347

JO - International Immunology

JF - International Immunology

SN - 0953-8178

IS - 5

ER -