Clarification of regulatory T cell-specific epigenome

• Project/Area Number: 15H04744
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Kyoto University (2018); Osaka University (2015-2017)
• Principal Investigator: Ohkura Naganari 京都大学, ウイルス・再生医科学研究所, 特定研究員 (20300949)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 制御性T細胞 / エピゲノム / DNA脱メチル化 / DNAメチル化 / エピジェネティクス / regulatory T cells / 発生分化

Outline of Final Research Achievements

To reveal the mechanisms for Treg differentiation, we determined Treg-specific DNA hypomethylated regions using whole genome bisulfite sequencing, and examined the association between the regions and Treg-specific characteristics. Treg-hypomethylated regions were highly associated with Treg-specific gene expression, H3K27ac modification, and open chromatin status. In addition, autoimmune disease-associated SNPs were highly accumulated within the regions, but not in the T cell activation-specific hypomethylated regions. These results suggest that autoimmune disease susceptibility would be largely affected by the changes in Treg function rather than those in T cell activation. By single cell analysis of thymic T cells, we also found the path and factors for Treg development, which are different from those of conventional T cells. This information would be useful for the development of therapies or drugs for autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究により、自己免疫疾患感受性は、活性化T細胞の機能亢進よりむしろTreg機能の低下が要因となっていることが示された。本研究結果は、エピジェネテック変化に関与する遺伝子やクロマチン構造変化をもたらす遺伝子の変異、多型が、自己免疫疾患ひいては慢性炎症の感受性に影響する可能性を示しており、新たな治療法開発の基礎となる成果である。
加えて、胸腺細胞群のsingle cell解析では、Treg分化の最初期に関わる因子を同定した。本因子群は、Tregの人工的誘導等や分化抑制に応用可能であり、自己免疫疾患や悪性腫瘍の新たな治療法への展開が期待できる。

Research Products

• [Journal Article] Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization, and IL-17 expression. (2019)
  • Author(s): 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 YI, Yamanaka S, Takamura-Enya T, Lu Q, Yoshimura A
  • Journal Title: International immunology Volume: 31 Issue: 5 Pages: 335-347
  • DOI: 10.1093/intimm/dxz008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer. (2019)
  • Author(s): Matoba T, Imai M, Ohkura N, Kawakita D, Ijichi K, Toyama T, Morita A, Murakami S, Sakaguchi S, Yamazaki S.
  • Journal Title: International Journal of Cancer Volume: 144(11) Issue: 11 Pages: 2811-2822
  • DOI: 10.1002/ijc.32024
  • Peer Reviewed / Open Access
• [Journal Article] Innate Myeloid Cell Subset-Specific Gene Expression Patterns in the Human Colon are Altered in Crohn's Disease Patients. (2018)
  • Author(s): Sekido Y, Yasumizu Y, Nishimura J, Kayama H, Matsuno H, Ogino T, Miyoshi N, Takahashi H, Haraguchi N, Hata T, Matsuda C, Doki Y, Mori M, Takeda K, Ohkura N, Sakaguchi S, Mizushima T.
  • Journal Title: Digestion Volume: 19: Issue: 3 Pages: 1-11
  • DOI: 10.1159/000490890
  • Peer Reviewed / Open Access
• [Journal Article] Ultraviolet B?Induced Maturation of CD11b-Type Langerin?Dendritic Cells Controls the Expansion of Foxp3+Regulatory T Cells in the Skin (2017)
  • Author(s): Yamazaki Sayuri、Odanaka Mizuyu、Nishioka Akiko、Kasuya Saori、Shime Hiroaki、Hemmi Hiroaki、Imai Masaki、Riethmacher Dieter、Kaisho Tsuneyasu、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 1 Pages: 119-129
  • DOI: 10.4049/jimmunol.1701056
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FANTOM5 CAGE profiles of human and mouse samples (2017)
  • Author(s): Noguchi Shuhei、Arakawa Takahiro、Ogishima Soichi、ほか
  • Journal Title: Sci Data Volume: 4 Issue: 1 Pages: 170112-170112
  • DOI: 10.1038/sdata.2017.112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lamtor1 Is Critically Required for CD4+ T Cell Proliferation and Regulatory T Cell Suppressive Function. (2017)
  • Author(s): Hosokawa T, Kimura T, Nada S, Okuno T, Ito D, Kang S, Nojima S, Yamashita K, Nakatani T, Hayama Y, Kato Y, Kinehara Y, Nishide M, Mikami N, Koyama S, Takamatsu H, Okuzaki D, Ohkura N, Sakaguchi S, Okada M, Kumanogoh A.
  • Journal Title: J Immunol. Volume: 199 Issue: 6 Pages: 2008-2019
  • DOI: 10.4049/jimmunol.1700157
  • Peer Reviewed / Open Access
• [Journal Article] A distinct subpopulation of CD25－ T-follicular regulatory cells localizes in the germinal centers (2017)
  • Author(s): James Badger Wing, Yohko Kitagawa, Michela Locci, Hannah Hume, Christopher Tay, Takayoshi Morita, Yujiro Kidani, Kyoko Matsuda, Takeshi Inoue, Tomohiro Kurosaki, Shane Crotty, Cevayir Coban, Naganari Ohkura, and Shimon Sakaguchi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 31 Pages: 6400-6400
  • DOI: 10.1073/pnas.1705551114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells. (2017)
  • Author(s): Garg G, Nikolouli E, Hardtke-Wolenski M, Toker A, Ohkura N, Beckstette M, Miyao T, Geffers R, Floess S, Gerdes N, Lutgens E, Osterloh A, Hori S, Sakaguchi S, Jaeckel E, Huehn J.
  • Journal Title: Oncotarget. Volume: 8(22) Issue: 22 Pages: 35542-35557
  • DOI: 10.18632/oncotarget.16221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. (2017)
  • Author(s): Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, Yasuda K, Motooka D, Nakamura S, Kondo M, Taniuchi I, Kohwi-Shigematsu T, Sakaguchi S.
  • Journal Title: Nat Immunol. Volume: 18(2) Issue: 2 Pages: 173-183
  • DOI: 10.1038/ni.3646
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system. (2016)
  • Author(s): Vandenbon A, Dinh VH, Mikami N, Kitagawa Y, Teraguchi S, Ohkura N, Sakaguchi S.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 113(17) Issue: 17
  • DOI: 10.1073/pnas.1604351113
  • Peer Reviewed / Open Access
• [Journal Article] Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. (2016)
  • Author(s): Saito, T., Nishikawa, H., Wada, H., Nagano, Y., Sugiyama, D., Atarashi, K., Maeda, Y., Hamaguchi, M., Ohkura, N., Sato, E., Nagase, H., Nishimura, J., Yamamoto, H., Takiguchi, S., Tanoue, T., Suda, W., Morita, H., Hattori, M., Honda, K., Mori, M., Doki, Y., Sakaguchi, S.
  • Journal Title: Nat. Med Volume: 22 Issue: 6 Pages: 679-684
  • DOI: 10.1038/nm.4086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Significance of naive Treg-specific DNA hypomethylation in autoimmune disease susceptibility (2018)
  • Author(s): Naganari Ohkura
  • Organizer: 日本免疫学会
  • Invited
• [Presentation] Dendritic cells expressing a unique set of genes associated with immunological tolerance are specialized to expand thymus-derived Foxp3+ regulatory T cells in the ultraviolet B-exposed skin (2018)
  • Author(s): Sayuri Yamazaki, Naganari Ohkura, Akimichi Morita et. al.
  • Organizer: 日本免疫学会
• [Presentation] A new feature of regulatory T cells in human head and neck cancer (2018)
  • Author(s): Takuma Matoba, Naganari Ohkura, Sayuri Yamazaki et al.
  • Organizer: 日本免疫学会
• [Presentation] Distinct transcriptional regulation in tumor-infiltrating regulatory T cells (2018)
  • Author(s): Yujiro Kidani, Naganari Ohkura et al.
  • Organizer: 日本免疫学会
• [Presentation] Consecutive transcriptional regulation for the development of regulatory T cells (2018)
  • Author(s): Naganari Ohkura
  • Organizer: 日本免疫学会
• [Presentation] Significance of naive Treg-specific DNA hypomethylation in autoimmune disease susceptibility (2018)
  • Author(s): Naganari Ohkura
  • Organizer: Immune profiling symposium in Tokyo
  • Invited
• [Presentation] Significance of the regulatory T cell-specific epigenetics for autoimmune disease susceptibility (2018)
  • Author(s): Ohkura N, Yasumizu Y, Sakaguchi S.
  • Organizer: 9th International Symposium with a theme of Cutting-edge Immunology Research.
  • Int'l Joint Research / Invited
• [Presentation] Epigenomic signatures of extrathymic-derived regulatory T cells (2017)
  • Author(s): Kawakami R, Mikami N, Sugimoto A, Ohkura N, Sakaguchi S.
  • Organizer: The 46th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Significance of the regulatory T cell-specific epigenetics in autoimmune disease susceptibility (2017)
  • Author(s): Yasumizu Y, Ohkura N, Kitagawa Y, Sakaguchi S.
  • Organizer: The 46th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Epigenetic control for the development of regulatory T cells (2016)
  • Author(s): Naganari Ohkura, Yohko Kitagawa, Shimon Sakaguchi
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] Epigenetic control of regulatory T cell identity and its association with autoimmune diseases in human (2016)
  • Author(s): Yohko Kitagawa, Naganari Ohkura, Yujiro Kidani, Shimon Sakaguchi
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] Specific transcriptional regulation of tutor-infiltrating regulatory T cells (2016)
  • Author(s): Yujiro Kidani, Yohko Kitagawa, Naganari Ohkura, Shimon Sakaguchi
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] Epigenetic priming for the development of regulatory T cells (2016)
  • Author(s): Naganari Ohkura, Yohko Kitagawa, Shimon Sakaguchi
  • Organizer: IMS-JSI International Symposium
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-06-14
  • Int'l Joint Research / Invited
• [Presentation] Specific characteristics of tutor infiltrating regulatory T cells (2015)
  • Author(s): Yujiro Kidani, Shimon Sakaguchi, Naganari Ohkura
  • Organizer: 日本免疫学会総会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Establishment of regulatory T cell-specific super-enhancers (2015)
  • Author(s): Yohko Kitagawa, Naganari Ohkura, Shimon Sakaguchi
  • Organizer: 日本免疫学会総会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] ヒト末梢血由来T細胞分画の全ゲノムDNAメチル化解析 (2015)
  • Author(s): 大倉永也、中村やまみ
  • Organizer: NGS現場の会 第4回研究会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2015-07-01
• [Patent(Industrial Property Rights)] 癌治療用医薬組成物 (2018)
  • Inventor(s): 大倉永也 他
  • Industrial Property Rights Holder: 大倉永也 他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas
• [Patent(Industrial Property Rights)] 非公開 (2017)
  • Inventor(s): 大倉永也, 坂口志文 他
  • Industrial Property Rights Holder: 大倉永也, 坂口志文 他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-065603
  • Filing Date: 2017-03-29
• [Patent(Industrial Property Rights)] DNAメチル化パターンに基づく免疫状態解析法 (2016)
  • Inventor(s): 大倉永也
  • Industrial Property Rights Holder: 大倉永也
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-02-17