Control of innate immune cells, chronic inflammation and infection by cytokine-producing immune microenvironment

• Project/Area Number: 16H05172
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kyoto University
• Principal Investigator: IKUTA Koichi 京都大学, ウイルス・再生医科学研究所, 教授 (90193177)
• Co-Investigator(Kenkyū-buntansha): 谷一 靖江 京都大学, 医学研究科, 助教 (50432331)
• Research Collaborator: CUI Guangwei ; MUKOHIRA Hisa ; Zhu Yuanbo ; OGAWA Makoto
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: リンパ球 / 生体分子 / 発生・分化 / サイトカイン / ストローマ細胞 / NK細胞 / 自然リンパ球 / 免疫学 / 感染症 / リンパ組織 / Tリンパ球 / Bリンパ球 / 骨芽細胞

Outline of Final Research Achievements

Innate immune cells, such as innate lymphoid cells and NK cells, play important roles in allergy and infection. Although the cytokines IL-7 and IL-15 are essential for development and maintenance of innate immune cells, the cells producing these cytokines are not well characterized. By using cell-type specific conditional knockout mice, we revealed the functions of the cytokines produced by each type of stromal cells in bone marrow, thymus, liver and intestines, in development, maintenance and pathogenesis of innate immune cells.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、自然免疫系細胞をサイトカインIL-7とIL-15によって助ける組織内の細胞が同定された。そのため、今後は、アレルギーや自己免疫疾患などの慢性炎症ならびに寄生虫などに対する感染防御などの病態における、自然免疫系細胞の役割の総合的な理解が進むと考えられる。また、将来、IL-7とIL-15を用いて自然免疫系細胞を介して、これらの病態を人為的にコントロールすることにも貢献するであろう。

Research Products

• [Int'l Joint Research] ETH Zurich/Helmholtz Centre for Infection Research(スイス)
• [Int'l Joint Research] Parque Tecnologico de Ciencias(スペイン)
• [Int'l Joint Research] Kantonsspital St. Gallen/Heinrich Heine University/University of Bern, Bern(スイス、ドイツ)
• [Int'l Joint Research] Yale University/German Cancer Research Center/University of Leuven(米国、ドイツ、ベルギー)
• [Journal Article] Notch signaling controls transcription via the recruitment of RUNX1 and MYB to enhancers during T cell development (2019)
  • Author(s): Rodriguez-Caparros, A., Garcia, V., Casal, A, Lopez-Ros, J., Garcia-Mariscal, A., Tani-ichi, S., Ikuta, K., and Hernandez-Munain, C.
  • Journal Title: J. Immunol. Volume: 202 Issue: 8 Pages: 2460-2472
  • DOI: 10.4049/jimmunol.1801650
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tissue maintenance of CMV-specific inflationary memory T cells by IL-15 (2018)
  • Author(s): Baumann, N., Torti, N., Welten, S. P. M., Barnstorf, I., Borsa, M., Pallmer, K., Oduro, J. D., Cicin-Sain, L., Ikuta, K., Ludewig, B., and Oxenius, A.
  • Journal Title: PLoS Pathog. Volume: 14 Issue: 4 Pages: e1006993-e1006993
  • DOI: 10.1371/journal.ppat.1006993
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4 (2018)
  • Author(s): Shimba A, Cui G, Tani-Ichi S, Ogawa M, Abe S, Okazaki F, Kitano S, Miyachi H, Yamada H, Hara T, Yoshikai Y, Nagasawa T, Schütz G, Ikuta K.
  • Journal Title: Immunity Volume: 48 Issue: 2 Pages: 286-298
  • DOI: 10.1016/j.immuni.2018.01.004
  • NAID: 120006401712
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing γδ T cells (2017)
  • Author(s): Nakamizo Satoshi、Honda Tetsuya、Adachi Akimasa、Nagatake Takahiro、Kunisawa Jun、Kitoh Akihiko、Otsuka Atsushi、Dainichi Teruki、Nomura Takashi、Ginhoux Florent、Ikuta Koichi、Egawa Gyohei、Kabashima Kenji
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 999-999
  • DOI: 10.1038/s41598-017-14292-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sepsis-induced osteoblast ablation causes immunodeficiency (2016)
  • Author(s): Terashima, A., Okamoto, K., Nakashima, T., Akira, S., Ikuta, K. and Takayanagi, H.
  • Journal Title: Immunity Volume: 44 Issue: 6 Pages: 1434-1443
  • DOI: 10.1016/j.immuni.2016.05.012
  • Peer Reviewed / Open Access
• [Journal Article] Thy-1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation (2016)
  • Author(s): Shinoda, K., Hirahara, K., Iinuma, T., Ichikawa, T., Suzuki, A. S., Sugaya, K., Tumes, D. J., Yamamoto, H., Hara, T., Tani-ichi, S., Ikuta, K., Okamoto, Y., and Nakayama, T.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 113 Issue: 20
  • DOI: 10.1073/pnas.1512600113
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblastic reticular cells regulate intestinal inflammation through IL-15-mediated control of group 1 ILCs (2016)
  • Author(s): Gil-Cruz, C., Perez-Shibayama, C., Onder, L., Chai, Q., Cupovic, J., Cheng, H., Novkovic, M., Lang, P. A., Geuking, M. B., McCoy, K. D., Abe, S., Cui, G., Ikuta, K., Scandella, E., and Ludewig, B.
  • Journal Title: Nat. Immunol. Volume: 17 Issue: 12 Pages: 1388-1396
  • DOI: 10.1038/ni.3566
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hematopoietic stem cell niches produce lineage-instructive signals to control multipotent progenitor differentiation (2016)
  • Author(s): Gomes, A. C., Hara, T., Lim, V. Y., Herndler-Brandstetter, D., Nevius, E., Sugiyama, T., Tani-ichi, S., Schlenner, S., Richie, E., Rodewald, H., Flavell, R. A., Nagasawa, T., Ikuta, K., and Pereira, J. P.
  • Journal Title: Immunity Volume: 45 Issue: 6 Pages: 1219-1231
  • DOI: 10.1016/j.immuni.2016.11.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Intestinal epithelial cell-derived IL-15 supports the homeostasis of intraepithelial lymphocytes (2018)
  • Author(s): Zhu, Y., Cui, G., and Ikuta, K.
  • Organizer: The 25th East Asia Joint Symposium on Biomedical Research
  • Int'l Joint Research
• [Presentation] 胸腺内IL-15産生性免疫微小環境の機能解析 (2018)
  • Author(s): 崔広為、生田宏一
  • Organizer: Kyoto T Cell Conference 第28回学術集会
• [Presentation] Local IL-15 dependency of liver-resident ILC1 (2018)
  • Author(s): Asahi, T., Shimba, A., Cui, G., Abe, S., Zhu, Y., Ejima, A., Takami, D., Tani-ichi, S., Hara, T., and Ikuta, K.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Hematopoietic cell-derived IL-15 supports the development and maintenance of NK, NKT and memory CD8 T cells in bone marrow (2018)
  • Author(s): Abe, S., Hara, T., Cui, G., Asahi, T., and Ikuta, K.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] CXCL12-expressing bone marrow stromal cells express adiponectin and are targeted by Adipoq-Cre transgene (2018)
  • Author(s): Mukohira, H., Hara, T., Tani-ichi, S., and Ikuta, K.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Intestinal epithelial cell-derived IL-15 supports the homeostasis of intraepithelial lymphocytes (2018)
  • Author(s): Zhu, Y., Cui, G., Shimba, A., Abe, S., Hara, T., Tani-ichi, S., and Ikuta, K.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Identification of bone marrow IL-7 niche critical for B lymphopoesis (2017)
  • Author(s): 原崇裕、生田宏一
  • Organizer: The 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 芝蘭会館、京都市
  • Year and Date: 2017-03-13
  • Int'l Joint Research
• [Presentation] Glucocorticoids drive circadian changes in T-cell homing and response via IL-7 receptor (2017)
  • Author(s): Shimba, A., and Ikuta, K.
  • Organizer: Immunology 2017 (AAI)
  • Int'l Joint Research
• [Presentation] IL-7Rα signaling upregulates growth hormone signaling-related gene in naive T cells (2017)
  • Author(s): Tani-ichi, S., and Ikuta, K.
  • Organizer: Keystone Symposium: Integrating Metabolism and Immunity
  • Int'l Joint Research
• [Presentation] Osteoblasts mediate immunosuppression during sepsis by regulating lymphopoiesis (2017)
  • Author(s): Terashima, A., Okamoto, K., Nakashima, T., Ikuta, K., and Takayanagi, H.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] グルココルチコイドはIL-7受容体の発現を介してT細胞の体内分布および活性化の日内変動を制御する (2017)
  • Author(s): 岡崎史恵、榛葉旭恒、崔広為、生田宏一
  • Organizer: ConBio2017（生命科学系学会合同年次大会）
• [Presentation] Glucocorticoids drive diurnal changes in distribution and response of T cells via IL-7 receptor expression (2017)
  • Author(s): Shimba, A., Cui, G., and Ikuta, K.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Competition between STAT5 and PI3K of the IL-7R modulates T cell and type 2 ILC development in vivo (2017)
  • Author(s): Cui, G., Shimba, A., Zhu, Y., Tani-ichi, S., Hara, T., and Ikuta, K.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Exploring the signals upregulating IL-7Rα expression via NFκB activation in T cells (2017)
  • Author(s): Tani-ichi, S., and Ikuta, K.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 骨髄におけるリンパ球分化を制御するIL-7産生ストローマ細胞の同定 (2016)
  • Author(s): 原崇裕、生田宏一
  • Organizer: 第26回Kyoto T Cell Conference
  • Place of Presentation: 延暦寺会館、大津市
• [Presentation] Local function of the IL-15 niche in thymus (2016)
  • Author(s): 崔広為、榛葉旭恒、阿部真也、朱媛博、向平妃沙、谷一靖江、原崇裕、生田宏一
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター、宜野湾市、沖縄
• [Presentation] Identification of IL-15 niche for NK cells in bone marrow (2016)
  • Author(s): 阿部真也、原崇裕、崔広為、生田宏一
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター、宜野湾市、沖縄
• [Presentation] Immunodeficiency caused by sepsis-induced osteoblast ablation (2016)
  • Author(s): 寺島明日香、岡本一男、審良静男、生田宏一、高柳広
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター、宜野湾市、沖縄
• [Remarks] ステロイドが免疫力を高める？！ －免疫の新たな昼夜サイクルを解明－
  • URL: http://www.infront.kyoto-u.ac.jp/achievements/post-2986/
• [Remarks] ステロイドが免疫力を高める －免疫の新たな昼夜サイクルを解明－
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2017/180124_1.html
• [Remarks] 多能性造血前駆細胞からリンパ球までの分化を方向付ける骨髄ニッチの同定
  • URL: http://www.infront.kyoto-u.ac.jp/achievements/post-1160/