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サイトカイン産生性免疫微小環境の機能解析

Publicly Offered Research

Project AreaAnalysis and synthesis of multi-dimensional immune organ network
Project/Area Number 15H01153
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKyoto University

Principal Investigator

生田 宏一  京都大学, ウイルス・再生医科学研究所, 教授 (90193177)

Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Keywordsサイトカイン / リンパ組織 / Tリンパ球 / Bリンパ球 / NK細胞 / 自然リンパ球 / ストローマ細胞 / 骨芽細胞 / 免疫学 / 感染症 / 生体分子 / 発生・分化
Outline of Annual Research Achievements

骨髄において、CAR細胞でIL-7遺伝子が破壊されるLepr-Cre IL-15cKOマウスを解析し、CAR細胞が多能性幹細胞からリンパ球までの分化を担うニッチとして働くことを明らかにした(Gomes, Hara et al, Immunity 45:1219, 2016)。CAR細胞、血管内皮細胞、血液細胞でIL-15遺伝子が破壊されるLepr-Cre、Tie2-Cre、Vav-Cre IL-15cKOマウスを解析し、血液細胞由来のIL-15がNK細胞、NKT細胞、メモリーCD8 T細胞の分化、成熟、維持に、血管内皮細胞由来のIL-15がNK細胞の成熟に関与していることを明らかにした。
胸腺において、胸腺上皮細胞と血管内皮細胞でIL-15遺伝子が破壊されるFoxn1-Cre、Tie2-Cre IL-15cKOマウスを解析し、胸腺髄質上皮細胞由来のIL-15がiNKT細胞の成熟に重要であり、特に新たに分画した2B4+ iNKT細胞の分化に必須であることを明らかにした。一方、血管内皮細胞由来のIL-15がCD8 T細胞とiNKT細胞の胸腺外移出を制御している可能性を示した。
リンパ節およびパイエル板において、細網線維芽細胞と血管内皮細胞でIL-15遺伝子が破壊されるCCL19-Cre、Tie2-Cre IL-15cKOマウスを解析し、細網線維芽細胞由来のIL-15が1型自然リンパ球の維持に必須であることを明らかにした(Gil-Cruz et al, Nat. Immunol. 17:1388, 2016)。また、血管内皮細胞、特に高内皮細静脈由来のIL-15が、T細胞の遊走に関与している可能性を示した。
肝臓において、肝細胞でIL-15遺伝子が破壊されるAlb-Cre IL-15cKOマウスを解析し、T細胞、NK細胞、NKT細胞の維持に関与していることを明らかにした。

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。

Report

(2 results)
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (26 results)

All 2017 2016 2015 Other

All Int'l Joint Research (3 results) Journal Article (10 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 10 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results) Presentation (10 results) (of which Int'l Joint Research: 2 results) Remarks (3 results)

  • [Int'l Joint Research] Kantonsspital St. Gallen/Heinrich Heine University/University of Bern, Bern(スイス、ドイツ)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Yale University/German Cancer Research Center/University of Leuven(米国、ドイツ、ベルギー)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Sepsis-induced osteoblast ablation causes immunodeficiency2016

    • 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

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • 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 inflammation2016

    • 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

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fibroblastic reticular cells regulate intestinal inflammation through IL-15-mediated control of group 1 ILCs2016

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Hematopoietic stem cell niches produce lineage-instructive signals to control multipotent progenitor differentiation2016

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] γδ T cells shape pre-immune peripheral B cell populations.2016

    • Author(s)
      Huang, Y., Getahun, A., Heiser, R. A., Detanico, T. O., Kirchenbaum, G. A., Casper, T. L., Huang, C., Aydintug, M. K., Carding, S. R., Ikuta, K., Huang, H., Wysocki, L. J., Cambier, J. C., O’Brien, R. L., and Born, W. K.
    • Journal Title

      J. Immunol.

      Volume: 196 Issue: 1 Pages: 217-231

    • DOI

      10.4049/jimmunol.1501064

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Memory CD8+ T cells colocalize with IL-7+ stromal cells in bone marrow and rest in terms of proliferation and transcription2015

    • Author(s)
      Alp, O. S., Durlanik, S., Schulz, D., McGrath, M., Grun, J. R., Bardua, M., Ikuta, K., Sgouroudis, E., Riedel, R., Zehentmeier, S., Hauser, A. E., Tsuneto, M., Melchers, F., Tokoyoda, K., Chang, H-D., Thiel, A., and Radbruch, A.
    • Journal Title

      Eur. J. Immunol.

      Volume: 45 Issue: 4 Pages: 975-987

    • DOI

      10.1002/eji.201445295

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] STAT5 Orchestrates Local Epigenetic Changes for Chromatin Accessibility and Rearrangements by Direct Binding to the TCRγ Locus.2015

    • Author(s)
      Wagatsuma K, Tani-Ichi S, Liang B, Shitara S, Ishihara K, Abe M, Miyachi H, Kitano S, Hara T, Nanno M, Ishikawa H, Sakimura K, Nakao M, Kimura H, Ikuta K.
    • Journal Title

      J Immunol.

      Volume: 195 Issue: 4 Pages: 1804-14

    • DOI

      10.4049/jimmunol.1302456

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] An Enhancer of the IL-7 Receptor α-Chain Locus Controls IL-7 Receptor Expression and Maintenance of Peripheral T Cells.2015

    • Author(s)
      Abe A, Tani-ichi S, Shitara S, Cui G, Yamada H, Miyachi H, Kitano S, Hara T, Abe R, Yoshikai Y, Ikuta K.
    • Journal Title

      J. Immunol.

      Volume: 195 Issue: 7 Pages: 3129-3138

    • DOI

      10.4049/jimmunol.1302447

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma.2015

    • Author(s)
      Adachi T, Kobayashi T, Sugihara E, Yamada T, Ikuta K, Pittaluga S, Saya H, Amagai M, Nagao K.
    • Journal Title

      Nature Med.

      Volume: 21 Issue: 11 Pages: 1272-1279

    • DOI

      10.1038/nm.3962

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Ectopic Aire expression in 1 the thymic cortex reveals inherent properties of Aire as a tolerogenic factor within the medulla2015

    • Author(s)
      Nishijima H, Kitano S, Miyachi H, Morimoto J, Kawano H, Hirota F, Morita R, Mouri Y, Masuda K, Imoto I, Ikuta K, Matsumoto M.
    • Journal Title

      J Immunol

      Volume: 195 Issue: 10 Pages: 4641-4649

    • DOI

      10.4049/jimmunol.1501026

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Identification of bone marrow IL-7 niche critical for B lymphopoesis2017

    • 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
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [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
    • Related Report
      2016 Annual Research Report
  • [Presentation] Local function of the IL-15 niche in thymus2016

    • 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
    • Related Report
      2016 Annual Research Report
  • [Presentation] Identification of IL-15 niche for NK cells in bone marrow2016

    • 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
    • Related Report
      2016 Annual Research Report
  • [Presentation] Immunodeficiency caused by sepsis-induced osteoblast ablation2016

    • 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
    • Related Report
      2016 Annual Research Report
  • [Presentation] Regulation of IL-7R expression in dendritic cells2015

    • Author(s)
      谷一靖江、生田宏一
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Identification and characterization of IL-7 niche in gut-associated lymphoid tissue2015

    • Author(s)
      原崇裕、生田宏一
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-11-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] STAT5 and PI3K signals of the IL-7R play differential roles in T cell development and homeostasis revealed by novel IL-7Rα mutant mice2015

    • Author(s)
      崔広為、榛葉旭恒、谷一靖江、小川真、阿部真也、原崇裕、生田宏一
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-11-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] Differential roles of IL-7 and IL-2 receptor signals in lymphocyte differentiation and development revealed by IL-7Rα/IL-2Rβ chimera knock-in mice2015

    • Author(s)
      榛葉旭恒、谷一靖江、増田喬子、崔広為、小川真、阿部真也、原崇裕、河本宏、生田宏一
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-11-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] Characterization of the IL-15 niche in vivo2015

    • Author(s)
      Cui, G., Hara, T., Simmons, S., Ishii, M., Tani-ichi, S., Ikuta, K.
    • Organizer
      The 6th FIMSA Congress
    • Place of Presentation
      Singapore
    • Year and Date
      2015-07-01
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [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/

    • Related Report
      2016 Annual Research Report
  • [Remarks] STAT5はT細胞受容体遺伝子座に直接結合することでクロマチンのアクセシビリティと再編成を制御する

    • URL

      http://www.virus.kyoto-u.ac.jp/about/y2015/ikuta201508.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] IL-7レセプターα鎖遺伝子座のエンハンサーは末梢T細胞のIL-7レセプターの発現と維持を制御する

    • URL

      http://www.virus.kyoto-u.ac.jp/about/y2015/ikuta201510.html

    • Related Report
      2015 Annual Research Report

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Published: 2015-04-16   Modified: 2018-03-28  

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