Mechanisms of regulatory T cell-mediated immune regulation

• Project/Area Number: 15H04747
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokyo (2016-2017); Institute of Physical and Chemical Research (2015)
• Principal Investigator: Hori Shohei 東京大学, 大学院薬学系研究科(薬学部), 教授 (50392113)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 免疫寛容 / 自己免疫疾患 / 制御性T細胞 / 遺伝子発現制御 / Foxp3 / BATF / 自己免疫寛容 / 転写因子

Outline of Final Research Achievements

Foxp3+ regulatory T cells (Treg) are essential for the regulation of deleterious immune responses. Recent studies have shown that Treg cells change their gene expression in order to adapt to inflammatory or tissue environments to regulate immune responses. However, the molecular basis of this ability -adaptability- remains elusive. By generating mouse models harboring Foxp3 mutations identified in patients with the autoimmune disease IPEX, we have found that one mutation, A384T, induces tissue inflammation by specifically impairing the ability of Treg cells to accumulate in certain non-lymphoid tissues. Mechanistically, repressed expression of the transcription factor BATF contributed to the impaired adaptability of tissue Treg cells in the mutant mice. At the molecular level, the A384T mutation acted as a gain-of-function mutation in that it broadened the DNA-binding specificity of Foxp3. Our findings identify BATF as a critical regulator of Treg cell adaptability.

Research Products

• [Journal Article] Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+T Cells in Human Colorectal Cancer (2018)
  • Author(s): Fujimoto Hanae、Saito Yoriko、Ohuchida Kenoki、Kawakami Eiryo、Fujiki Saera、Watanabe Takashi、Ono Rintaro、Kaneko Akiko、Takagi Shinsuke、Najima Yuho、Hijikata Atsushi、Cui Lin、Ueki Takashi、Oda Yoshinao、Hori Shohei、Ohara Osamu、Nakamura Masafumi、Saito Takashi、Ishikawa Fumihiko
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 9 Pages: 3291-3303
  • DOI: 10.4049/jimmunol.1701222
  • Peer Reviewed
• [Journal Article] Analyses of a Mutant Foxp3 Allele Reveal BATF as a Critical Transcription Factor in the Differentiation and Accumulation of Tissue Regulatory T Cells (2017)
  • Author(s): Hayatsu Norihito、Miyao Takahisa、Tachibana Masashi、Murakami Ryuichi、Kimura Akihiko、Kato Takako、Kawakami Eiryo、Endo Takaho A.、Setoguchi Ruka、Watarai Hiroshi、Nishikawa Takeshi、Yasuda Takuwa、Yoshida Hisahiro、Hori Shohei
  • Journal Title: Immunity Volume: 47 Issue: 2 Pages: 268-283.e9
  • DOI: 10.1016/j.immuni.2017.07.008
  • 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] T follicular helper and T follicular regulatory cells have different TCR specificity (2017)
  • Author(s): Maceiras, A. R. Almeida, S. C. P. Mariotti-Ferrandiz, E. Chaara, W. Jebbawi, F. Six, A. Hori, S. Klatzmann, D. Faro, J. Graca, L.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 15067-15067
  • DOI: 10.1038/ncomms15067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maternal High Fiber Diet during Pregnancy and Lactation Influences Regulatory T Cell Differentiation in Offspring in Mice (2017)
  • Author(s): Nakajima, A. Kaga, N. Nakanishi, Y. Ohno, H. Miyamoto, J. Kimura, I. Hori, S. Sasaki, T. Hiramatsu, K. Okumura, K. Miyake, S. Habu, S. Watanabe, S.
  • Journal Title: J Immunol Volume: 199 Issue: 10 Pages: 3516-3524
  • DOI: 10.4049/jimmunol.1700248
  • Peer Reviewed / Open Access
• [Journal Article] Attenuation of CD4+CD25+regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug (2017)
  • Author(s): Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, Furusawa Y, Hase K, Sasaki A, Udono H.
  • Journal Title: EBioMedicine Volume: 25 Pages: 154-164
  • DOI: 10.1016/j.ebiom.2017.10.009
  • NAID: 120006767320
  • Peer Reviewed / Open Access
• [Journal Article] Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. (2016)
  • Author(s): Zhang B, Chikuma S, Hori S, Fagarasan S, and Honjo T.
  • Journal Title: Proc Natl Acad Sci USA Volume: 113 Issue: 30 Pages: 8490-8495
  • DOI: 10.1073/pnas.1608873113
  • NAID: 120005819493
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-17-producing γδ T cells enhance bone regeneration (2016)
  • Author(s): Ono T, et al.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 10928-10928
  • DOI: 10.1038/ncomms10928
  • Peer Reviewed / Open Access
• [Journal Article] Helios enhances regulatory T cell function in cooperation with Foxp3 (2015)
  • Author(s): Takatori H, Kawashima H, Matsuki A, Meguro K, Tanaka S, Iwamoto T, Sanayama Y, Nishikawa N, Tamachi T, Ikeda K, Suto A, Suzuki K, Kagami S, Hirose K, Kubo M, Hori S, Nakajima H
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 6 Pages: 1491-502
  • DOI: 10.1002/art.39091
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis (2015)
  • Author(s): Nishio J, et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 112 Issue: 41 Pages: 12770-12775
  • DOI: 10.1073/pnas.1516617112
  • Peer Reviewed / Open Access
• [Presentation] 制御性T細胞による免疫制御 (2017)
  • Author(s): 堀昌平
  • Organizer: 第53回日本移植学会
  • Invited
• [Presentation] 免疫寛容とアレルギー (2017)
  • Author(s): 堀昌平
  • Organizer: 日本アレルギー学会 第4回総合アレルギー講習会
  • Invited
• [Presentation] 制御性T細胞とアレルギー (2016)
  • Author(s): 堀昌平
  • Organizer: 日本アレルギー学会 第3回総合アレルギー講習会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-17
  • Invited
• [Presentation] Functional dissection of the Foxp3-centered molecular network in regulatory T cells (2016)
  • Author(s): Hori, S
  • Organizer: The 45th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
  • Int'l Joint Research / Invited
• [Presentation] 制御性T細胞の多様性とその意義 (2016)
  • Author(s): 堀昌平
  • Organizer: 第16回LEGEND seminar 2016
  • Place of Presentation: ANAクラウンプラザホテル沖縄（沖縄県那覇市）
  • Year and Date: 2016-12-04
  • Invited
• [Presentation] Dissecting Foxp3-dependent mechanisms of regulatory T cell function (2016)
  • Author(s): Hori, S
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] 制御性T細胞による自己免疫寛容のメカニズムとその破綻 (2016)
  • Author(s): 堀昌平
  • Organizer: 千里ライフサイエンスセミナー
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2016-11-15
  • Invited
• [Presentation] 制御性T細胞の機能発現と制御 (2015)
  • Author(s): 堀昌平
  • Organizer: 日本アレルギー学会 第２回総合アレルギー講習会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-12-12
  • Invited
• [Presentation] Foxp3 changes its partners and genomic binding regions in regulatory T cells in response to IL-4 stimulation (2015)
  • Author(s): Hayatsu N and Hori S
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-20
• [Presentation] Foxp3-dependent control of Treg cell function and homeostasis in tissues (2015)
  • Author(s): Hori S
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-19
  • Invited
• [Presentation] Foxp3はサイトカイン刺激に応答してダイナミックに制御性T細胞の遺伝子発現を制御する (2015)
  • Author(s): 早津徳人、堀昌平
  • Organizer: 第25回 Kyoto T Cell Conference
  • Place of Presentation: 京都大学芝蘭会館（京都府京都市）
  • Year and Date: 2015-05-16