時計遺伝子NFIL3によるリンパ組織形成メカニズムの解明

• Project Area: Analysis and synthesis of multi-dimensional immune organ network
• Project/Area Number: 15H01162
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo University of Science
• Principal Investigator: 久保 允人 東京理科大学, 研究推進機構生命医科学研究所, 教授 (40277281)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: リンパ組織形成 / 免疫システム / 発生・分化

Outline of Annual Research Achievements

我々はこれまでのT細胞に焦点を当てた研究から、時計遺伝子として知られる転写因子E4BP4/NFIL-3が、過剰な免疫反応を沈静化する働きを持つことを報告した(Nature Immunology　2011)。この分子を欠くマウスは、腸管内に存在するリンパ組織であるパイエル板の数が激減していた。このパイエル板に与える影響は、Lymphoid tissue inducer ('LTi')の発生過程に障害があることを明らかにした。また、E4BP4/NFIL-3の欠損は腸管内に主に分布する3型自然リンパ球（ILC3）の発生過程でも鍵となる分子として働いていることが分かった。ILCはサイトカインの産生パターンの違いによって、ILC1, ILC2, ILC3に分類できる。E4BP4/NFIL-3は、NK細胞の分化に加え、ILC1とILC2の分化過程，特に初期分化過程において必須の分子であることを見いだした。さらに、エピジェネティックな解析から、E4BP4/NFIL-3はId2遺伝子に結合することで、その発現制御によりILCの初期分化課程を制御していることを明らかにした(Cell Report　2015)。
一方、肺などの末梢組織では、E4BP4欠損下でもILC2細胞が存在していたことから、E4BP4に依存しない分化経路の存在が浮き彫りにされた。しかしながら、E4BP4非依存的ILC2細胞が存在する環境下でも、E4BP4欠損マウスはシステインプロテアーゼで誘導される急性期アレルギー性気道炎症が減弱しているとともに、それに伴うTh2細胞の集積も顕著に減弱した。この炎症後期に集積するTh2細胞は慢性期の反応系を構成しており、その集積にはILC2細胞あるいは好酸球球からのIL-13の産生が必要とされる。E4BP4は、急性期気道炎症時に起こるIL-13の産生を制御することにより、気道炎症の慢性化を制御するE4BP4の新しい役割が、本計画研究から明らかにされることになった。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Innate and adaptive type 2 immunity in lung allergic inflammation (2017)
  • Author(s): Kubo, M
  • Journal Title: Immunolgical Review Volume: - Issue: 1 Pages: 162-172
  • DOI: 10.1111/imr.12557
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Basophil-derived interleukin-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy (2017)
  • Author(s): Hussain M, Borcard L, Walsh KP, Pena Rodriguez M, Mueller C, Kim BS, Kubo M, Artis D, Noti M
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 1 Pages: 223-234.e5
  • DOI: 10.1016/j.jaci.2017.02.035
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] E3 ubiquitin ligases SIAH1/2 regulates hypoxia-inducible factor 1(HIF1)-mediated TH17 cell differentiation (2017)
  • Author(s): Matsui-Hasumi A, Sato Y, Uto-Konomi A, Yamashita S, Uehori J, Yoshimura A, Yamashita M, Asahara H, Suzuki S, Kubo M
  • Journal Title: Int.Immunol Volume: - Issue: 3 Pages: 133-143
  • DOI: 10.1093/intimm/dxx014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Differences in the importance of mast cells, basophils, IgE and IgG, versus CD4+ T cells and ILC2 cells, in primary and secondary immunity to Strongyloides venezuelensis (2017)
  • Author(s): Mukai K, Karasuyama H, Kabashima K, Kubo M, Galli SJ
  • Journal Title: Infect Immun Volume: - Issue: 5
  • DOI: 10.1128/iai.00053-17
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] IL4 from T Follicular Helper Cells Downregulates Antitumor Immunity (2017)
  • Author(s): Shirota H, Klinman DM, Ito SE, Ito H, Kubo M, Ishioka C
  • Journal Title: Cancer Immunology Research Volume: 5(1) Pages: 61-71
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Allergin-1 inhibits TLR2-mediated mast cell activation and suppresses dermatitis (2016)
  • Author(s): Tsurusaki S, Tahara-Hanaoka S, Shibagaki S, Miyake S, Imai M, Shibayama S, Kubo M, Shibuya A
  • Journal Title: International Immunology Volume: 28(12) Issue: 12 Pages: 605-609
  • DOI: 10.1093/intimm/dxw046
  • NAID: 120007135029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mathematical modeling of atopic dermatitis reveals “double switch” mechanisms underlying 4 common disease phenotypes (2016)
  • Author(s): Domínguez-Hüttinger E, Christodoulides P, Miyauchi K, Irvine AD, Okada-Hatakeyama M, Kubo M, Tanaka RJ
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 6 Pages: 1861-1872.e7
  • DOI: 10.1016/j.jaci.2016.10.026
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protective neutralizing influenza antibody response in the absence of T follicular helper cells (2016)
  • Author(s): Miyauchi K, Sugimoto-Ishige A, Harada Y, Adachi Y, Usami Y, Kaji T, Inoue K, Hasegawa H, Watanabe T, Hijikata A, Fukuyama S, Maemura T, Okada-Hatakeyama M, Ohara O, Kawaoka Y, Takahashi Y, Takemori T, Kubo M
  • Journal Title: Nature Immunology Volume: 17(12) Issue: 12 Pages: 1447-1458
  • DOI: 10.1038/ni.3563
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis (2016)
  • Author(s): Yasuda T, Fukada T, Nishida K, Nakayama M, Matsuda M, Miura I, Dainichi T, Fukuda S, Kabashima K, Nakaoka S, Bin BH, Kubo M, Ohno H, Hasegawa T, Ohara O, Koseki H, Wakana S, Yoshida H
  • Journal Title: J. Clin. Invest Volume: 126(6) Issue: 6 Pages: 2064-76
  • DOI: 10.1172/jci82887
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. (2016)
  • Author(s): Takeuchi, A., Badr Mel, S., Miyauchi, K., Ishihara, C., Onishi, R., Guo, Z., Sasaki. Y., Ike, H., Takumi, A., Tsuji, NM., Murakami, Y., Katakai, T., Kubo, M. and Saito, T.
  • Journal Title: J. Exp. Med. Volume: 213 Issue: 1 Pages: 123-138
  • DOI: 10.1084/jem.20150519
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncolytic reovirus synergizes with chemotherapeutic agents to promote cell death in canine mammary gland tumor (2016)
  • Author(s): Igase M, Hwang CC, Kambayashi S, Kubo M, Coffey M, Miyama TS, Baba K, Okuda M, Noguchi S, Mizuno T
  • Journal Title: Can J Vet Res Volume: 80(1) Pages: 21-31
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway (2015)
  • Author(s): Hara Y, Tashiro Y, Murakami A, Nishimura M, Shimizu T, Kubo M, Burrows PD, Azuma T
  • Journal Title: Mol Immunol Volume: 68(2 Pt C) Issue: 2 Pages: 617-27
  • DOI: 10.1016/j.molimm.2015.10.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PU.1 Suppresses Th2 Cytokine Expression via Silencing of GATA3 Transcription in Dendritic Cells (2015)
  • Author(s): Yashiro T, Kubo M, Ogawa H, Okumura K, Nishiyama C
  • Journal Title: PLoS One Volume: 10(9) Issue: 9 Pages: e0137699-e0137699
  • DOI: 10.1371/journal.pone.0137699
  • Peer Reviewed / Open Access
• [Journal Article] TCF-1 and LEF-1 help launch the T(FH) program (2015)
  • Author(s): Kubo M
  • Journal Title: Nat Immunol Volume: 16(9) Issue: 9 Pages: 900-1
  • DOI: 10.1038/ni.3254
  • Peer Reviewed
• [Journal Article] An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers. (2015)
  • Author(s): Morita H, Arae K, Unno H, Miyauchi K, Toyama S, Nambu A, Oboki K, Ohno T, Motomura K, Matsuda A, Yamaguchi S, Narushima S, Kajiwara N, Iikura M, Suto H, McKenzie AN, Takahashi T, Karasuyama H, Okumura K, Azuma M, Moro K, Akdis CA, Galli SJ, Koyasu S, Kubo M, Sudo K, Saito H, Matsumoto K, Nakae S.
  • Journal Title: Immunity Volume: 43 Issue: 1 Pages: 175-86
  • DOI: 10.1016/j.immuni.2015.06.021
  • NAID: 40020962854
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Notch signaling enhances FceRI-mediated cytokine production by mast cells through direct and indirect mechanisms (2015)
  • Author(s): Nakano, N., Nishiyama, C., Yagita, H., Hara, M., Motomura, Y., Kubo, M., Okumura, K., and Ogawa, H
  • Journal Title: J. Immunol Volume: 194(9) Issue: 9 Pages: 4535-44
  • DOI: 10.4049/jimmunol.1301850
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zinc-binding metallothioneins are key modulators of IL-4 production by basophils (2015)
  • Author(s): Ugajin T, Nishida K, Yamasaki S, Suzuki J, Mita M, Kubo M, Yokozeki H, Hirano T
  • Journal Title: Mol Immunol Volume: 66 Issue: 2 Pages: 180-188
  • DOI: 10.1016/j.molimm.2015.03.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors (2015)
  • Author(s): Wei Xu, Rita G. Domingues, Diogo Fonseca-Pereira, Manuela Ferreira, Hélder Ribeiro, Silvia Lopez-Lastra, Yasutaka Motomura, Lara Moreira-Santos, Franck Bihl4, Véronique Braud, Barbara Kee, Hugh Brady, Mark C.Coles, Christian Vosshenrich, Kubo, M., James P. Di Santo and Henrique Veiga-Fernandes
  • Journal Title: Cell Report Volume: 10(12) Issue: 12 Pages: 2043-54
  • DOI: 10.1016/j.celrep.2015.02.057
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 新たなアレルギー発症メカニズム (2015)
  • Author(s): 久保允人
  • Journal Title: ファルマシア Volume: 51（6） Pages: 526-531
  • NAID: 130007448190
• [Journal Article] 好塩基球による免疫応答制御 (2015)
  • Author(s): 久保允人
  • Journal Title: 感染・炎症・免疫 Volume: 45-2 Pages: 63-67
• [Presentation] Role of T follicular helper (Tfh) and Th1 cells in anti-viral immunity (2017)
  • Author(s): Kubo Masato
  • Organizer: 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: Shiran Kaikan, Kyoto University(Kyoto City, Kyoto)
  • Year and Date: 2017-03-13
  • Int'l Joint Research
• [Presentation] New therapeutic approach for atopic dermatitis (AD) using comprehensive analysis and system biology (2017)
  • Author(s): Kubo Masato
  • Organizer: 2017 INTERNATIONAL BIOMEDICAL INTERFACE SYMPOSIUM
  • Place of Presentation: Taipei Medical University(Taipei, Taiwan)
  • Year and Date: 2017-03-04
  • Int'l Joint Research / Invited
• [Presentation] 皮膚恒常性制御機構とアトピー性皮膚炎 (2017)
  • Author(s): 久保允人
  • Organizer: アトピー疾患研究センター学術セミナー
  • Place of Presentation: 順天堂大学（東京都・文京区）
  • Invited
• [Presentation] Essential role of E4BP4 in effector function of lung ILC2 (2016)
  • Author(s): SUZUKI Narumi, OMI Ai, MIYAUCHI Kosuke, KUBO Masato
  • Organizer: The 45th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Okinawa Convention Center, Laguna Garden Hotel(Ginowan City, Okinawa)
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] IFNg and IL-6-dependent production of influenza virus specific IgA (2016)
  • Author(s): MIYAUCHI Kosuke, TAKEMORI Toshitada, KUBO Masato
  • Organizer: 45th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Okinawa Convention Center, Laguna Garden Hotel(Ginowan City, Okinawa)
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Role of T follicular helper (TFH) in humoral immunity (2016)
  • Author(s): Kubo Masato
  • Organizer: The 13th International Workshop on Autoantibodies and Autoimmunity (IWAA2016)
  • Place of Presentation: The Westin Miyako Kyoto(Kyoto City, Kyoto)
  • Year and Date: 2016-10-11
  • Int'l Joint Research / Invited
• [Presentation] サイトカインシグナルと皮膚恒常性 (2016)
  • Author(s): 久保允人
  • Organizer: NEXT Lecture Meeting in Chiba
  • Place of Presentation: 千葉大学(千葉県・千葉市)
  • Invited
• [Presentation] 免疫疾患における細胞内シグナル伝達・サイトカインの基礎から応用へ (2016)
  • Author(s): 久保允人
  • Organizer: Cytokine Network Seminar ～免疫シグナル伝達の解明・進展～
  • Place of Presentation: 大阪大学（大阪府・吹田市）
  • Invited
• [Presentation] アレルギーにおける自然免疫と獲得免疫のクロストーク (2016)
  • Author(s): 久保允人
  • Organizer: 第65回日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム （東京都・千代田区）
  • Invited
• [Presentation] Humoral Immunity against Influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • 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
  • Int'l Joint Research / Invited
• [Presentation] Most of the CD8＋TIL are tumor-reactive in spontaneously regressing or progressing murine gastric cancer (2015)
  • Author(s): NAGAOKA Koji, HOSOI Akihiro, MATSUSHITA Hirokazu, KUBO Masato, TAKEDA Kazuyoshi, KAKIMI Kazuhiro
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • 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
  • Int'l Joint Research
• [Presentation] Germinal centers and follicular helper T cells are dispensable for a protective antibody response to acute influenza A virus infection (2015)
  • Author(s): MIYAUCHI Kosuke, SUGIMOTO-ISHIGE Akiko, TAKAHASHI Yoshimasa, HASEGAWA Hideki, TAKEMORI Toshitada, KUBO Masato
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • 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
  • Int'l Joint Research
• [Presentation] Pathogenic effect of PM2.5 and nanoparticle in Lung inflammation (2015)
  • Author(s): THARMALINGAM Jayaraman, MIYAUCHI Kosuke, KUBO Masato
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • 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
  • Int'l Joint Research
• [Presentation] Innate and acquired immunity in influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: 2015 Fall Conference of The Korean Association of the Immunologists
  • Place of Presentation: Sejong University Convention Center（Soul, Korea）
  • Year and Date: 2015-11-12
  • Int'l Joint Research / Invited
• [Presentation] Innate and acquired immunity in influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: International Symposium on Allergy and Inflammation 2015
  • Place of Presentation: 大洗パークホテル（茨城県東茨城郡）
  • Year and Date: 2015-10-29
  • Int'l Joint Research / Invited
• [Presentation] アレルギーにおける白血球・リンパ球の役割 (2015)
  • Author(s): 久保允人
  • Organizer: 鹿児島呼吸器セミナー
  • Place of Presentation: 鹿児島大学（鹿児島県鹿児島市）
  • Year and Date: 2015-09-15
  • Invited
• [Presentation] Host defense mechanisms against Influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: International Symposium of Center for Animal Disease Model (CADMIS) 2015
  • Place of Presentation: 学士会館（東京都千代田区）
  • Year and Date: 2015-07-21
  • Int'l Joint Research / Invited
• [Presentation] 転写因子E4BP4と自然リンパ球によるアレルギー性気道炎症の制御 (2015)
  • Author(s): KUBO Masato
  • Organizer: 第80回日本インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 東京工業大学（東京都目黒区）
  • Year and Date: 2015-07-17
  • Invited
• [Presentation] 皮膚の恒常と炎症の制御 (2015)
  • Author(s): 久保允人
  • Organizer: 第22回四国四大学皮膚科研究会
  • Place of Presentation: ザ クラウンパレス新阪急高知（高知県高知市）
  • Year and Date: 2015-07-11
  • Invited
• [Presentation] インフルエンザ感染における気道炎症制御と抗体産生制御について (2015)
  • Author(s): 久保允人
  • Organizer: ヘルスバイオサイエンス研究部 免疫学セミナー
  • Place of Presentation: 徳島大学（徳島県徳島市）
  • Year and Date: 2015-07-10
  • Invited
• [Presentation] マスト細胞・好塩基球欠損マウスシステムの構築とサイトカイン産生能 (2015)
  • Author(s): 久保允人
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2015-05-28
  • Invited
• [Presentation] 転写因子E4BP4 と自然リンパ球によるアレルギー性気道炎症の制御 (2015)
  • Author(s): 久保允人
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪(東京都港区）
  • Year and Date: 2015-05-26
  • Invited
• [Presentation] アレルギー性気道炎症における自然免疫細胞 (2015)
  • Author(s): 久保允人
  • Organizer: SCIENCE in Shinagawa
  • Place of Presentation: ガーデンシティ品川（東京都港区）
  • Year and Date: 2015-04-18
  • Invited