Distribution and function of IL-15-producing cells in vivo

• Project/Area Number: 25460589
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kyoto University
• Principal Investigator: IKUTA Koichi 京都大学, ウイルス研究所, 教授 (90193177)
• Co-Investigator(Kenkyū-buntansha): TANI-ICHI Shizue 京都大学, ウイルス研究所, 助教 (50432331) ; HARA Takahiro 京都大学, ウイルス研究所, 助教 (90512301)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 免疫細胞 / 微小環境 / サイトカイン / ストローマ細胞 / IL-15 / 免疫組織

Outline of Final Research Achievements

IL-15 is a cytokine critical for development, maintenance, and response of various immune cells. However, the distribution and function of IL-15-expressing cells in lymphoid organs are not well understood. To address these questions, we first established and analyzed IL-15-CFP knock-in mice. We found that IL-15 was expressed in medullary thymic epithelial cells, CXCL12-abundant reticular cells in bone marrow, fibroblastic reticular cells and blood endothelial cells in lymph nodes. Some IL-15-producing stromal cells were increased as mice aged and in LPS-induced inflammation. Overall, we have identified and characterized IL-15-expressing cells in primary and secondary lymphoid organs, providing a unique perspective of IL-15 niche in immune microenvironment. Next, we established and crossed IL-15-floxed mice with various Cre driver mice. We found unique functions of IL-15 produced by bone marrow endothelial cells, thymic epithelial cells, and intestinal epithelial cells.

Research Products

• [Int'l Joint Research] University of Oxford(英国)
• [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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immunosuppression caused by sepsis-induced osteoblast ablation (2016)
  • Author(s): Terashima, A., Okamoto, K., Nakashima, T., Akira, S., Ikuta, K. and Takayanagi, H.
  • Journal Title: Immunity Volume: ?
  • Peer Reviewed
• [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., 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: ?
  • Peer Reviewed
• [Journal Article] Memory CD8+ T cells colocalize with IL-7+ stromal cells in bone marrow and rest in terms of proliferation and transcription (2015)
  • 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
  • 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
  • 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
  • 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
  • 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 medulla (2015)
  • 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
  • Peer Reviewed / Open Access
• [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] Regulation of IL-7R expression in dendritic cells (2015)
  • 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: 2015-11-20
• [Presentation] Identification and characterization of IL-7 niche in gut-associated lymphoid tissue (2015)
  • 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
• [Presentation] STAT5 and PI3K signals of the IL-7R play differential roles in T cell development and homeostasis revealed by novel IL-7Rα mutant mice (2015)
  • 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
• [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 mice (2015)
  • 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
• [Presentation] Characterization of the IL-15 niche in vivo (2015)
  • 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
  • Int'l Joint Research
• [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] 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
• [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
• [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