GITR signaling regulates ILC2 function

• Project/Area Number: 17K08875
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: Okuyama Yuko 東北大学, 医学系研究科, 助教 (50624475)
• Co-Investigator(Kenkyū-buntansha): 石井 直人 東北大学, 医学系研究科, 教授 (60291267) ; 宗 孝紀 富山大学, 学術研究部薬学・和漢系, 教授 (60294964)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ILC2 / GITR / アレルギー / アレルギー性肺炎症 / IL-9 / NFκB / ILC / TNFRSF / 補助刺激分子 / 自然リンパ球

Outline of Final Research Achievements

Group2 innate lymphoid cells (ILC2) produce large amounts of type 2 effector cytokines such as IL-5 and IL-13 that cause allergy. ILC2 in the lung highly express glucocorticoid-induced TNFR-related protein (GITR), and thus we hypothesized that GITR plays an important role in ILC2.
We here show that GITR-deficiency or blockade of GITR signaling in mice displayed attenuated lung inflammation and that GITR signaling in ILC2 was important for type 2 cytokine production. Ligation of both GITR and IL-33-receptor synergistically activated NF-κB, p38, and Erk signals in ILC2, resulting in IL-9 production, leading to STAT5-driven IL-5 and IL-13 production. Moreover, we found murine ILC2 express both GITR and GITR-L, and autocrine interaction affect ILC2 activation.

Academic Significance and Societal Importance of the Research Achievements

本研究により、GITRシグナルによるILC2の新規活性化制御機構が明らかとなった。従来T細胞の抗原受容体シグナルを補助することが知られてきた補助刺激分子のT細胞以外での機能の発見という点で学術的な意義は大きい。ILC2におけるGITRを標的としたアレルギー性炎症疾患の新規診断・治療法開発への応用に繋がる有用な知見であるという点で社会的な意義が認められる。さらに今後、ヒトPBMC由来のILC2において、GITRの発現とサイトカイン刺激による発現変化について解析を行い、アレルギー性疾患の診断・治療標的としての有用性を検証していく。

Research Products

• [Journal Article] TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells (2020)
  • Author(s): Phung Hai The、Nagashima Hiroyuki、Kobayashi Shuhei、Asano Naoki、Machiyama Tomoaki、Sakurai Tsuyoshi、Tayama Shun-ichi、Asao Atsuko、Imatani Akira、Kawabe Takeshi、Okuyama Yuko、Ishii Naoto、So Takanori
  • Journal Title: ImmunoHorizons Volume: 4 Issue: 3 Pages: 129-139
  • DOI: 10.4049/immunohorizons.2000007
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Fatty Acid Binding Protein 7 in Spinal Cord Astrocytes in a Mouse Model of Experimental Autoimmune Encephalomyelitis (2019)
  • Author(s): Kamizato Kenyu、Sato Sho、Shil Subrata Kumar、Umaru Banlanjo A.、Kagawa Yoshiteru、Yamamoto Yui、Ogata Masaki、Yasumoto Yuki、Okuyama Yuko、Ishii Naoto、Owada Yuji、Miyazaki Hirofumi
  • Journal Title: Neuroscience Volume: - Pages: 120-129
  • DOI: 10.1016/j.neuroscience.2019.03.050
  • Peer Reviewed / Open Access
• [Journal Article] IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s (2019)
  • Author(s): Tayama Shunichi、Okuyama Yuko、Phung Hai The、Asao Atsuko、Kobayashi Shuhei、Musha Tomomi、Machiyama Tomoaki、Sakurai Tsuyoshi、Zhang Chengming、Ushio-Fukai Masuko、Kawabe Takeshi、So Takanori、Ishii Naoto
  • Journal Title: International Immunology Volume: - Issue: 4 Pages: 233-241
  • DOI: 10.1093/intimm/dxz077
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IQGAP1 restrains T‐cell cosignaling mediated by OX40 (2019)
  • Author(s): Okuyama Yuko、Nagashima Hiroyuki、Ushio‐Fukai Masuko、Croft Michael、Ishii Naoto、So Takanori
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 540-554
  • DOI: 10.1096/fj.201900879rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome (2019)
  • Author(s): Niitsuma Sou、Kudo Hiroki、Kikuchi Atsuo、Hayashi Takaya、Kumakura Satoshi、Kobayashi Shuhei、Okuyama Yuko、Kumagai Naonori、Niihori Tetsuya、Aoki Yoko、So Takanori、Funayama Ryo、Nakayama Keiko、Shirota Matsuyuki、Kondo Shuji、Kagami Shoji、Tsukaguchi Hiroyasu、Iijima Kazumoto、Kure Shigeo、Ishii Naoto
  • Journal Title: International Immunology Volume: 32 Issue: 4 Pages: 283-292
  • DOI: 10.1093/intimm/dxz081
  • Peer Reviewed / Open Access
• [Journal Article] GITR (2019)
  • Author(s): 石井直人、奥山祐子
  • Journal Title: アレルギー Volume: 68(3) Pages: 159-160
  • NAID: 130007650857
• [Journal Article] TRAF2 and TRAF5 associated with the signal transducing receptor gp130 limit IL-6-driven transphosphorylation of JAK1 through the inhibition of proximal JAK-JAK interaction. (2018)
  • Author(s): Kimura M, Nagashima H, Okuyama Y, Ishii N, and So T
  • Journal Title: Int. Immunol Volume: - Issue: 7 Pages: 219-299
  • DOI: 10.1093/intimm/dxy029
  • Peer Reviewed
• [Journal Article] Bmi1 Regulates IκBα Degradation via Association with the SCF Complex. (2018)
  • Author(s): Okuyama Y, Tanaka Y, Jiang JJ, Kamimura D, Nakamura A, Ota M, Ohki T, Higo D, Ogura H, Ishii N, Atsumi T, Murakami M.
  • Journal Title: J Immunol. Volume: 201(8) Issue: 8 Pages: 2264-2272
  • DOI: 10.4049/jimmunol.1701223
  • Peer Reviewed
• [Journal Article] GITR cosignal in ILC2s controls allergic lung inflammation. (2018)
  • Author(s): Nagashima H, Okuyama Y, Fujita T, Takeda T, Motomura Y, Moro K, Hidaka T, Omori K, Sakurai T, Machiyama T, Ndhlovu LC, Riccardi C, So T, Ishii N.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 5 Pages: 1939-1943.e8
  • DOI: 10.1016/j.jaci.2018.01.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation. (2018)
  • Author(s): Machiyama T, So T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Harigae H, Ishii N.
  • Journal Title: Biochem Biophys Res Commun. Volume: - Issue: 3 Pages: 544-550
  • DOI: 10.1016/j.bbrc.2018.03.186
  • Peer Reviewed
• [Journal Article] Rbm10 regulates inflammation development via alternative splicing of Dnmt3b. (2017)
  • Author(s): Atsumi T, Suzuki H, Jiang JJ, Okuyama Y, Nakagawa I, Ota M, Tanaka Y, Ohki T, Katsunuma K, Nakajima K, Hasegawa Y, Ohara O, Ogura H, Arima Y, Kamimura D, Murakami M.
  • Journal Title: Int Immunol. Volume: 29(12) Issue: 12 Pages: 581-591
  • DOI: 10.1093/intimm/dxx067
  • Peer Reviewed / Open Access
• [Presentation] GITR co-signaling controls group 2 innate lymphoid cells in allergic lung inflammation. (2019)
  • Author(s): Yuko Okuyama, Hiroyuki Nagashima, Kazuyo Moro, Lishomwa C. Ndhlovu, Carlo Riccardi, Takanori So, Naoto Ishii.
  • Organizer: 第17回国際免疫学会議 (ICI 2019)
  • Int'l Joint Research
• [Presentation] GITR signaling negatively controls DSS-induced intestinal inflammation by regulating NK cells function. (2019)
  • Author(s): Tsuyoshi Sakurai, Yuko Okuyama, Phung The Hai, Takanori So, Naoto Ishii.
  • Organizer: 第48回日本免疫学会学術総会
• [Presentation] TNF receptor-associated factor 5 inhibits IL-27 receptor signaling in CD4+ T-lymphocytes (2019)
  • Author(s): Eigo Kawahara, Yuka Fujimori, Mayu Oishi, Masashi Morita, Yuko Okuyama, Naoto Ishii, Takanori So.
  • Organizer: 第48回日本免疫学会学術総会
• [Presentation] Understanding the role of TRAF family proteins in gp130 signaling (2019)
  • Author(s): Yuka Fujimori, Eigo Kawahara, Masashi Morita, Yuko Okuyama, Naoto Ishii, Takanori So.
  • Organizer: 第48回日本免疫学会学術総会
• [Presentation] TNFR-associated factor (TRAF) 5 expressed by intestinal epithelial cells promotes NF-kB-mediated inflammation via controlling TRAF2 stability in dextran sulfate sodium-induced colitis (2019)
  • Author(s): Hai T Phung, Hiroyuki Nagashima, Shuhei Kobayashi, Tomoaki Machiyama, Tsuyoshi Sakurai, Shun-ichi Tayama, Atsuko Asao, Yuko Okuyama, Naoto Ishii, Takanori So.
  • Organizer: 第48回日本免疫学会学術総会
• [Presentation] IQGAP1 regulates ILC2 apoptosis in the lung (2019)
  • Author(s): Shun-ichi Tayama, Yuko Okuyama, Phung The Hai, Takeshi Kawabe, Takanori So, Naoto Ishii.
  • Organizer: 第48回日本免疫学会学術総会
• [Presentation] GITRによる2型自然リンパ球の活性化を介したアレルギー性肺炎症の制御機構 (2018)
  • Author(s): 奥山 祐子,長島 宏行,宗 孝紀,石井 直人
  • Organizer: 第72回日本細菌学会東北支部総会
• [Presentation] 炎症性腸疾患におけるGITRを介したNK細胞による制御機構 (2018)
  • Author(s): 櫻井 毅,奥山祐子,小林周平,仁尾正記,石井直人
  • Organizer: 第72回日本細菌学会東北支部総会
• [Presentation] GITR co-signaling controls group 2 innate lymphoid cells through IL-9 induction in allergic lung inflammation (2018)
  • Author(s): Yuko Okuyama, Hiroyuki Nagashima, Yasutaka Motomura, Kazuyo Moro, Lishomwa C. Ndhlovu, Carlo Riccardi, Takanori So, Naoto Ishii
  • Organizer: 第47回日本免疫学会学術総会
• [Presentation] GITR signaling regulates intestinal inflammation by suppressing NK cells function in DSS-induced colitis model (2018)
  • Author(s): Tsuyoshi Sakurai, Yuko Okuyama, Shuhei Kobayashi, Masaki Nio, Naoto Ishii
  • Organizer: 第47回日本免疫学会学術総会
• [Presentation] TRAF5 maintains the expression level of TRAF2 in non-hematopoietic cells and exacerbates DSS-colitis in mice (2018)
  • Author(s): Hai The Phung, Hiroyuki Nagashima, Shuhei Kobayashi, Tomoaki Machiyama, Atsuko Asao, Yuko Okuyama, Naoto Ishii, Takanori So
  • Organizer: 第47回日本免疫学会学術総会
• [Presentation] IQGAP1 is essencial for ILC2 maintenance in the lung (2018)
  • Author(s): Shunichi Tayama, Yuko Okuyama, Takanori So, Naoto Ishii
  • Organizer: The 11th Vietnam-Japan Scientific Exchange Meeting
• [Presentation] TNF receptor-associated factor 5 expressed in non-hematopoietic cells augments acute colonic damage induced by dextran sulfate sodium (2018)
  • Author(s): Hai The Phung, Hiroyuki Nagashima, Shuhei Kobayashi, Tomoaki Machiyama, Atsuko Asao, Yuko Okuyama, Naoto Ishii, Takanori So
  • Organizer: The 11th Vietnam-Japan Scientific Exchange Meeting
• [Presentation] アレルギー性肺炎症における 2型自然リンパ球のGITRによる制御機構 (2017)
  • Author(s): 奥山 祐子, 長島 宏行 , 藤田 剛 , 宗 孝紀 , 石井 直人
  • Organizer: 第71回日本細菌学会東北支部総会
• [Presentation] Early activation of group 2 innate lymphoid cells in the lung is critically controlled by the TNFR superfamily molecule GITR (2017)
  • Author(s): Takanori So, Hiroyuki Nagashima, Yuko Okuyama, Yasutaka Motomura, Kazuyo Moro, Lishomwa C. Ndhlovu, Carlo Ricardi, Naoto Ishii
  • Organizer: 第46回日本免疫学会学術総会
• [Presentation] A new regulator of OX40 co-signaling controls autoimmune neuroin ammation mediated by CD4+ T cells (2017)
  • Author(s): Yuko Okuyama, Hiroyuki Nagashima, Masuko Ushio-Fukai, Michael Croft, Naoto Ishii, Takanori So
  • Organizer: 第46回日本免疫学会学術総会
• [Book] アレルギー (2018)
  • Author(s): 石井直人,奥山祐子
  • Total Pages: 89
  • Publisher: 株式会社 杏林舎
• [Remarks] 気管支喘息発症の新しいメカニズムを発見 ‐GITRタンパク質を標的とした新なアレルギー治療戦略‐
  • URL: https://www.tohoku.ac.jp/japanese/newimg/pressimg/tohokuuniv-press20180323_01web.pdf