サイトカイン産生性免疫微小環境の可視化と機能解析

• Project Area: Analysis and synthesis of multi-dimensional immune organ network
• Project/Area Number: 25111504
• 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: Kyoto University
• Principal Investigator: 生田 宏一 京都大学, ウイルス研究所, 教授 (90193177)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
• Keywords: 免疫学 / 免疫組織 / 微小環境 / サイトカイン / ストローマ細胞 / IL-15

Outline of Annual Research Achievements

IL-15遺伝子座にCFP cDNAを挿入したIL-15-CFPノックインマウスを作製し、生体内におけるIL-15産生細胞の分布を解析した。その結果、骨髄では主に血管周囲に存在するVCAM-1陽性の間葉系ストローマ細胞にIL-15の発現が見られた。胸腺ではMHCクラスIIを強く発現する成熟した胸腺髄質上皮細胞にIL-15の発現が検出された。リンパ節ではＴ細胞領域の細網線維芽細胞や樹状細胞がIL-15を産生していた。さらに、高内皮性細静脈とすべての血管内皮細胞でIL-15が検出された。以上の結果から、生体内のIL-15産生性ストローマ細胞を初めて同定し、その特徴的な分布と発現様式を明らかにした。
IL-15cKOマウスの作製については、Foxn1-Cre、Villin-Cre、Alb-Cre、Tie2-Cre、CD11c-Cre、MuCre-A、LysM-Cre、Prx1-Cre、Adipoq-CreなどのCreマウスとの交配が順調に進んでいる。Villin-Cre、Alb-Cre、Tie2-Cre、Adipoq-CreマウスについてはIL-7-floxマウスとも交配し、IL-15/IL-7ダブルcKOマウスも作製中である。IL-15cKO解析については、Foxn1-Cre、Alb-Creについての解析が進行中である。Foxn1-Cre IL-15cKOマウスの胸腺では、NKT細胞とγδ T細胞が減少していた。特にNKT細胞についてはより成熟した段階のものの減少が大きかった。これらの結果はIL-15欠損マウスの表現型とよく一致しており、胸腺の中では胸腺上皮細胞が産生するIL-15が主要な働きをしていることが示された。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A genome-wide analysis identifies a Notch-RBP-Jκ-IL-7Rα axis that controls IL-17-producing γδ T cell homeostasis in mice. (2015)
  • Author(s): Nakamura M, Shibata K, Hatano S, Sato T, Ohkawa Y, Yamada H, Ikuta K, Yoshikai Y.
  • Journal Title: J Immunol. Volume: 194 Issue: 1 Pages: 243-251
  • DOI: 10.4049/jimmunol.1401619
  • Peer Reviewed
• [Journal Article] γδ T cells affect IL-4 production and B cell tolerance (2015)
  • Author(s): Huang, Y., Heiser, R. A., Detanico, T. O., Getahun, A., Kirchenbaum, G. A., Aydintug, M. K., Smith, C. W., Carding, S. R., Ikuta, K., Huang, H., Wysocki, L. J., Cambier, J. C., O’Brien, R. L., and Born, W. K.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 112 Issue: 1
  • DOI: 10.1073/pnas.1415107111
  • Peer Reviewed
• [Journal Article] Environments of B cell development. (2014)
  • Author(s): Tsuneto M, Kajikhina E, Seiler K, Reimer A, Tornack J, Bouquet C, Simmons S, Knoll M, Wolf I, Tokoyoda K, Hauser A, Hara T, Tani-Ichi S, Ikuta K, Grun J. R, Grutzkau A, Engels N, Wienands J, Yanagisawa Y, Ohnishi K , Melchers F.
  • Journal Title: Immunol Lett. Volume: 157 Issue: 1-2 Pages: 60-63
  • DOI: 10.1016/j.imlet.2013.11.011
  • Peer Reviewed
• [Journal Article] Characterization of the interleukin-15 niche in primary and secondary lymphoid organs in vivo. (2014)
  • Author(s): Cui G, Hara T, Simmons S, Wagatsuma K, Abe A, Miyachi H, Kitano S, Ishii M, Tani-ichi S, Ikuta K.
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 5 Pages: 1915-1920
  • DOI: 10.1073/pnas.1318281111
  • Peer Reviewed
• [Journal Article] Lymphocyte-stromal cell interaction induces IL-7 expression by interferon regulatory factors. (2013)
  • Author(s): Sekai M, Tani-ichi S, Yoneyama M, Fujita T, Kina T, Ikuta K.
  • Journal Title: Mol Immunol Volume: 54 Issue: 3-4 Pages: 378-385
  • DOI: 10.1016/j.molimm.2013.01.002
  • Peer Reviewed
• [Journal Article] Interleukin-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRγδ+ intraepithelial lymphocytes. (2013)
  • Author(s): Shitara S, Hara T, Liang B, Wagatsuma K, Zuklys S, Hollander GA, Nakase H, Chiba T, Tani-ichi S, Ikuta K.
  • Journal Title: J Immunol Volume: 190 Issue: 12 Pages: 6173-6179
  • DOI: 10.4049/jimmunol.1202573
  • Peer Reviewed
• [Journal Article] Signal transducer and activator of transcription 3 (Stat3) contributes to T-cell homeostasis by regulating pro-survival Bcl-2 family genes. (2013)
  • Author(s): Lee JK, Won C, Yi EH, Seok SH, Kim MH, Kim SJ, Chung MH, Lee HG, Ikuta K, Ye SK.
  • Journal Title: Immunology Volume: 140 Issue: 3 Pages: 288-300
  • DOI: 10.1111/imm.12133
  • Peer Reviewed
• [Journal Article] CD49b-dependent estabhshment of T helper cell memory. (2013)
  • Author(s): Hanazawa, A., Hayashizaki, K.,Shinoda, K., Yagita, H., Okumura, K., Löhning, M., Hara, T., Tani-ichi, S., Ikuta, K., Eckes, B.,Radbruch, A., Tokoyoda, K, and Nakayama, T.
  • Journal Title: Immuno1. Cell Bio1 Volume: 91 Issue: 8 Pages: 524-531
  • DOI: 10.1038/icb.2013.36
  • Peer Reviewed
• [Journal Article] B cell progenitors and precursors change their microenvironment in fetal liver during early development. (2013)
  • Author(s): Tsuneto M, Tokoyoda K, Kajikhina E, Hauser AE, Hara T, Tani-ichi S, Ikuta K, Melchers F.
  • Journal Title: Stem Cells Volume: 31 Issue: 12 Pages: 2800-2812
  • DOI: 10.1002/stem.1421
  • Peer Reviewed
• [Presentation] Distribution and function of IL-7- and IL-15-expressing cells in intestines (2014)
  • Author(s): 原崇裕、崔広為、生田宏一
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-12
• [Presentation] Differential roles of IL-7 and IL-2 receptor signals in lymphocyte development and maintenance revealed by IL-7Rα/IL-2Rβ chimera knock-in mice (2014)
  • Author(s): 榛葉旭恒、谷一靖江、増田喬子、原崇裕、河本宏、生田宏一
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10
• [Presentation] Approaches to identify Aire-regulated non-tissue-restricted antigen genes by the ectopic expression of Aire in thymic cortex (2014)
  • Author(s): 西嶋仁、森本純子、毛利安宏、河野弘、生田宏一、松本満
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10
• [Presentation] 末梢組織でのガンマデルタT細胞維持におけるTCRシグナルの必要性 (2014)
  • Author(s): 谷一靖江、生田宏一
  • Organizer: 第24回Kyoto T Cell Conference
  • Place of Presentation: 京都
  • Year and Date: 2014-05-17
• [Presentation] Visualization of the immune microenvironment by reporter mice (2013)
  • Author(s): Ikuta, K., Cui, G., Shitara, S., Liang, B., Tani-ichi, S., and Hara, T.
  • Organizer: The 6th International Workshop of Kyoto T Cell Conference 2013
  • Place of Presentation: Kyoto
• [Presentation] Visualization and characterization of IL-7- and IL-15-expressing cells in vivo (2013)
  • Author(s): Hara, T., Cui, G., Shitara, S., Tani-ichi, S. and Ikuta, K.
  • Organizer: The 6th International Workshop of Kyoto T Cell Conference 2013
  • Place of Presentation: Kyoto
• [Presentation] Distribution and function of IL-7-expressing cells in the intestinal tissues (2013)
  • Author(s): Hara, T. and Ikuta, K.
  • Organizer: The 8th International Symposium of the Institute Network
  • Place of Presentation: Kyoto
• [Presentation] Visualizing the immune microenvironment by reporter mice (2013)
  • Author(s): Ikuta, K., Cui, G., Shitara, S., Liang, B., Tani-ichi, S., and Hara, T.
  • Organizer: The 20th East Asia Joint Symposium on Global Medical Science for the 22th Century
  • Place of Presentation: Tokyo
• [Presentation] Identification and characterization of the IL-15-expressing cells in vivo (2013)
  • Author(s): Cui, G., Hara, T., Simmons, S., Wagatsuma, K., Tani-ichi, S., Ishii, M., and Ikuta, K.
  • Organizer: The 20th East Asia Joint Symposium on Global Medical Science for the 22th Century
  • Place of Presentation: Tokyo
• [Presentation] Distribution and function of IL-7-expressing cells in large intestine (2013)
  • Author(s): Hara, T. and Ikuta, K.
  • Organizer: The 4th Workshop on Synthetic Immunology
  • Place of Presentation: Kyoto
• [Presentation] Distribution and function of IL-7-expressing cells in intestines (2013)
  • Author(s): 原崇裕、崔広為、設楽宗一朗、生田宏一
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Remarks] 生体内リンパ器官におけるインターロイキン15ニッチの解明
  • URL: http://www.virus.kyoto-u.ac.jp/about/y2014/ikuta20140326.html
• [Remarks] 論文リスト
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/ikuta_folder/publication/publication.html
• [Remarks] サイトカインIL-15を産生する細胞の可視化に成功 －免疫系の微小環境の解明に期待－
  • URL: http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2013_1/140121_1.htm