Differentiation and function of Foxp3-negative IL-10-producing regulatory T cells on mucosal bacterial infection

• Project/Area Number: 26293400
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Nagai Shigenori 東京医科歯科大学, 医歯(薬)学総合研究科, 准教授 (50348801)
• Co-Investigator(Kenkyū-buntansha): 東 みゆき 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (90255654)
• Co-Investigator(Renkei-kenkyūsha): YOSHIMURA Akihiko 慶應義塾大学, 医学部, 教授 (90182815)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: IL-10 / ヘルパーT細胞 / PI3K / 免疫学 / 細菌感染 / 粘膜免疫

Outline of Final Research Achievements

Since Foxp3-negative, IL-10-producing regulatory T (Tr1) cells are quite important for the suppression of chronic inflammation, I tried to investigate the regulatory mechanisms of Tr1 differentiation. When I added the inhibitor of PI3K, a kind of lipid kinases, in Tr1 differentiation by IL-27, I was able to suppress Tr1 differentiation. In contrast, Tr1 differentiation was enhanced when the PI3K pathway was augmented. These results suggest that PI3K pathway positively regulates the differentiation of IL-27-induced Tr1 cells.

Research Products

• [Journal Article] TGF-β-induced phosphorylation of Akt and Foxo transcription factors negatively regulates induced regulatory T cell differentiation. (2016)
  • Author(s): Kurebayashi Y, Baba Y, Minowa A, Nadya NA, Azuma M, Yoshimura A, Koyasu S, Nagai S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 480 Issue: 1 Pages: 114-119
  • DOI: 10.1016/j.bbrc.2016.09.153
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Delayed Propionibacterium acnes surgical site infections occur only in the presence of an implant (2016)
  • Author(s): Y. Shiono, K. Ishii, S. Nagai, H. Kakinuma, A. Sasaki, H. Funao, T. Kuramoto1, K. Yoshioka, H. Ishihama, N. Isogai, K. Takeshima, T. Tsuji, Y. Okada, S. Koyasu, M. Nakamura, Yoshiaki Toyama, M. Aizawa, and M. Matsumoto
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 32758-32758
  • DOI: 10.1038/srep32758
  • Peer Reviewed / Open Access
• [Journal Article] The RNA Binding Protein Mex-3B Is Required for IL-33 Induction in the Development of Allergic Airway Inflammation. (2016)
  • Author(s): Yamazumi Y, Sasaki O, Imamura M, Oda T, Ohno Y, Shiozaki-Sato Y, Nagai S, Suyama S, Kamoshida Y, Funato K, Yasui T, Kikutani H, Yamamoto K, Dohi M, Koyasu S, Akiyama T.
  • Journal Title: Cell Rep. Volume: 16 Issue: 9 Pages: 2456-2471
  • DOI: 10.1016/j.celrep.2016.07.062
  • Peer Reviewed / Open Access
• [Journal Article] A novel hydroxyapatite film coated with ionic silver via inositol hexaphosphate chelation prevents implant-associated infection. (2016)
  • Author(s): Funao H, Nagai S, Sasaki A, Hoshikawa T, Tsuji T, Okada Y, Koyasu S, Toyama Y, Nakamura M, Aizawa M, Matsumoto M, Ishii K.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 23238-23238
  • DOI: 10.1038/srep23238
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel mouse model of soft-tissue infection using bioluminescence imaging allows noninvasive, real-time monitoring of bacterial growth. (2014)
  • Author(s): Yoshioka K, Ishii K, Kuramoto T, Nagai S, Funao H, Ishihama H, Shiono Y, Sasaki A, Aizawa M, Okada Y, Koyasu S, Toyama Y, Matsumoto M
  • Journal Title: PLoS One Volume: 9 Issue: 9 Pages: e106367-e106367
  • DOI: 10.1371/journal.pone.0106367
  • Peer Reviewed / Open Access
• [Presentation] CELLULAR RESPONSES OF IMMUNE CELLS TO GLASS CERAMICS IN THE CaO-P2O5-SiO2-B2O3 SYSTEM. (2016)
  • Author(s): Rihoko Kizukuri, Kiyotaka Yamada, Michiyo Honda, Shigenori Nagai and Mamoru Aizawa.
  • Organizer: 16th Australasian BioCeramics Symposium.
  • Place of Presentation: Brisbane, Australia.
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Regulation of IL-10 production from IL-27-induced Tr1 cells by PI3K-Akt pathway. (2016)
  • Author(s): Adiba Nadya Niken, Miyuki Azuma, Shigenori Nagai
  • Organizer: 第45回日本免疫学会総会・学術集会
  • 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
• [Presentation] Features of oral mucosal inflammation -comparative studies with skin inflammation-. (2016)
  • Author(s): Worawalun Hirunwidchayarat, Tatsukuni Ohno, Siwen Kang, Shigenori Nagai, Michio Tomura, Miyuki Azuma
  • Organizer: 第45回日本免疫学会総会・学術集会
  • 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
• [Presentation] Tr1分化におけるPI3Kの役割． (2016)
  • Author(s): Niken Adiba Nadya, 東 みゆき，永井 重徳
  • Organizer: 第58回歯科基礎医学会学術大会
  • 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: 2016-08-24
• [Presentation] 口腔粘膜炎症において局所に集積するT細胞の解析． (2016)
  • Author(s): Hirunwidchayarat Worawalun，大野 建州，Kang Siwen，永井 重徳，東 みゆき
  • Organizer: 第58回歯科基礎医学会学術大会
  • 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: 2016-08-24
• [Presentation] Phosphorylation of Akt and Foxos induced by TGF-β negatively regulates the differentiation of induced regulatory T cells. (2016)
  • Author(s): Shigenori Nagai, Yutaka Kurebayashi, Yukiko Baba, Akiko Minowa, Miyuki Azuma, Akihiko Yoshimura, Shigeo Koyasu.
  • Organizer: 16th International Congress of Immunology
  • Place of Presentation: Melbourne, Australia.
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] CaO-P2O5-SiO2-B2O3系ガラスセラミックスの免疫細胞応答性． (2016)
  • Author(s): 木造理萌子，山田清貴，本田みちよ，永井重徳，相澤守．
  • Organizer: 無機マテリアル学会第132回講演会．
  • Place of Presentation: 船橋市民文化創造館 千葉県船橋市
  • Year and Date: 2016-06-02
• [Presentation] Role of PI3K in Tr1 cell differentiation. (2015)
  • Author(s): Adiba Nadya Niken, Miyuki Azuma, Shigenori Nagai
  • Organizer: 第44回日本免疫学会総会・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: 2015-11-18
• [Presentation] Masticatory mucosa-associated B7-H1 limits mucosal tissue damage. (2015)
  • Author(s): Siwen Kang, Tatsukuni Ohno, Shigenori Nagai, Miyuki Azuma
  • Organizer: 第44回日本免疫学会総会・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: 2015-11-18
• [Presentation] Recruiting T cells to the oral mucosa under the inflammatory condition. (2015)
  • Author(s): Worawalun Hirunwidchayarat, Tatsukuni Ohno, Siwen Kang, Shigenori Nagai, Miyuki Azuma
  • Organizer: 第44回日本免疫学会総会・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: 2015-11-18
• [Presentation] Morphological Observation of Immune Cells Derived from Mouse Spleen to Hydroxyapatite Ceramics Surface-Modified with Inositol Phosphate. (2015)
  • Author(s): Kiyotaka Yamada, Mariko Nakamura, Shigenori Nagai, Michiyo Honda, Mamoru Aizawa
  • Organizer: Bioceramics 27th Symphosium and Annual Meeting of the International Society for Ceramics in Medicine
  • Place of Presentation: Bali, Indonesia.
  • Year and Date: 2015-10-27
  • Int'l Joint Research
• [Presentation] 合成樹脂製インプラントにおける新規抗菌加工の安全性評価―細胞毒性とバイオメカニクス的検討―． (2015)
  • Author(s): 石濱 寛子, 石井 賢, 柿沼 祐亮, 塩野 雄太, 蔵本 哲也, 吉岡 研之, 船尾 陽生, 永井 重徳, 佐々木 文, 相澤 守, 岡田 保典, 小安 重夫, 松本 守雄, 中村 雅也
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] 合成樹脂製インプラントにおける新規抗菌開発法の開発． (2015)
  • Author(s): 石濱 寛子, 石井 賢, 柿沼 祐亮, 塩野 雄太, 蔵本 哲也, 吉岡 研之, 船尾 陽生, 永井 重徳, 佐々木 文, 相澤 守, 岡田 保典, 小安 重夫, 松本 守雄, 中村 雅也
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2015-10-22
• [Presentation] イノシトールリン酸を表面修飾した水酸アパタイトセラミックスに対するマウス脾臓由来免疫細胞の応答性． (2015)
  • Author(s): 山田 清貴，中村 まり子，永井 重徳，本田 みちよ，相澤 守
  • Organizer: セラミックス協会第28回秋季シンポジウム
  • Place of Presentation: 富山大学（富山県富山市）
  • Year and Date: 2015-09-16
• [Presentation] Phosphorylation of Akt and Foxos induced by TGF-β negatively controls the differentiation of Induced Regulatory T Cells. (2014)
  • Author(s): Shigenori Nagai, Yutaka Kurebayashi, Miyuki Azuma, Akihiro Yoshimura, Shigeo Koyasu
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] TGF-βによるAktおよびFoxoのリン酸化はiTreg分化を負に制御する (2014)
  • Author(s): 永井 重徳，紅林 泰，東 みゆき，吉村 昭彦，小安 重夫．
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Cellular Responses of Immune Cells Derived from Mouse Spleen to Hydroxyapatite Ceramics Surface-modified with Inositol Phosphate. (2014)
  • Author(s): Kiyotaka Yamada, Mariko Nakamura, Shigenori Nagai, Michiyo Honda, Mamoru Aizawa
  • Organizer: 26th Symphosium and Annual Meeting of the International Society for Ceramics in Medicine
  • Place of Presentation: Barcelona, Italy.
  • Year and Date: 2014-11-06 – 2014-11-08
• [Presentation] イノシトールリン酸を表面修飾した水酸アパタイトセラミックスに対するマウス脾臓由来免疫細胞の応答性． (2014)
  • Author(s): 山田 清貴，中村 まり子，永井 重徳，本田 みちよ，相澤 守
  • Organizer: 第24回無機リン化学討論会
  • Place of Presentation: 高知
  • Year and Date: 2014-09-25 – 2014-09-26
• [Book] アバス－リックマン－ピレ「分子細胞免疫学」第7版（第12章） (2014)
  • Author(s): 白木 文子，永井 重徳．（監訳：松島 綱治，山田 幸宏）
  • Total Pages: 627
  • Publisher: エルゼビア・ジャパン
• [Remarks] 東京医科歯科大学 分子免疫学分野
  • URL: http://www.tmd.ac.jp/mim/
• [Patent(Industrial Property Rights)] 細胞培養基材、細胞培養基材の製造方法、細胞培養方法、及び細胞培養装置 (2014)
  • Inventor(s): 相澤守，中村まり子，山田清貴，永井重徳
  • Industrial Property Rights Holder: 相澤守，中村まり子，山田清貴
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-09-22