Contribution of imperfect elimination of self-reactive T cells in the thymus to tumor immune surveillance

• Project/Area Number: 26670234
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: AKIYAMA TAISHIN 東京大学, 医科学研究所, 准教授 (50327665)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌免疫 / 自己免疫 / T細胞 / 胸腺 / 癌 / 免疫 / TNFレセプターファミリー

Outline of Final Research Achievements

Immune system efficiently responses to various pathogens and tumors as non-self, but not against self-tissues. T lymphocytes (T cells) play a pivotal role on such discrimination between self and no-self. Epithelial cells in the thymic medulla (mTECs) eliminate self-tissue reactive T cells and also can delete T cells responsive to tumors in the thymus, thereby playing critical roles on discrimination between self and non-self by T cells. In this study, we investigated how fine tuning of the mTEC function contributes to the self- and non-self discrimination. We found that a negative feedback regulation of mTEC function ensures efficient immune responses to tumors. This study would provide some important information regarding tumor immune surveillance and contributes to developing efficient tumor immune therapies.

Research Products

• [Int'l Joint Research] University of Cincinnati/Cincinnati Children’s Hospital/Taussig Cancer Institute(米国)
• [Journal Article] Catalytic subunits of the phosphatase calcineurin interact with NF-B-inducing kinase (NIK) and attenuate NIK-dependent gene expression. (2015)
  • Author(s): Shinzawa. M., Konno, H., Qin, J., Akiyama, N., Miyauchi, M., Ohashi, H., Miyamoto-Sato, E., Yanagawa, H., Akiyama, T.* and Inoue, J.
  • Journal Title: Sci. Rep Volume: 5 Issue: 1 Pages: 10758-10758
  • DOI: 10.1038/srep10758
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of RelB expression and activation at the single-cell level during dendritic cell maturation in Relb-Venus knock-in mice (2015)
  • Author(s): Takao Seki, Mami Yamamoto, Yuu Taguchi, Maki Miyauchi, Noritaka Yamaguchi, Jin Gohda, Taishin Akiyama, Jun-ichiro Inoue
  • Journal Title: Journal of Biochemistry Volume: 158 Pages: 485-495
  • DOI: 10.1093/jb/mvv064
  • NAID: 40020683863
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling (2015)
  • Author(s): Varney, M.E., Niederkorn, M., Konno, H., Matsumura, T., Gohda, J., Yoshida, N., Akiyama, T., Christie, S., Fang, J., Miller, D., Jerez, A., Karsan, A., Maciejewski, J.P., Inoue, J. and Starczynowski, D.T
  • Journal Title: J. Exp. Med Volume: 212 Issue: 11 Pages: 1967-1985
  • DOI: 10.1084/jem.20141898
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypergravity provokes a temporary reduction in CD4+CD8+ thymocyte number and a persistent decrease in medullary thymic epithelial cell frequency in mice. (2015)
  • Author(s): Tateishi R, Akiyama N, Miyauchi M, Yoshinaga R, Sasanuma H, Kudo T, Shimbo M, Shinohara M, Obata K, Inoue J, Shirakawa M, Shiba D, Asahara H, Yoshida N, Takahashi S, Morita H, Akiyama T
  • Journal Title: PLOS ONE Volume: 10 Issue: 10 Pages: 1-17
  • DOI: 10.1371/journal.pone.0141650
  • Peer Reviewed / Open Access
• [Journal Article] Positive and negative regulatory mechanisms for fine-tuning cellularity and functions of medullary thymic epithelial cells (2015)
  • Author(s): Taishin Akiyama, Ryosuke Tateishi, Nobuko Akiyama, Riko Yoshinaga, Tetsuya J. Kobayashi
  • Journal Title: Frontier Immunology Volume: 6 Pages: 1-6
  • DOI: 10.3389/fimmu.2015.00461
  • Peer Reviewed / Open Access
• [Journal Article] 転写因子Spi-Bによる免疫寛容制御機構 (2015)
  • Author(s): 秋山泰身、良永理子、秋山伸子
  • Journal Title: 臨床免疫・アレルギー科 Volume: 65 Pages: 185-190
• [Journal Article] 胸腺髄質上皮細胞と確率論的な自己寛容誘導 (2015)
  • Author(s): 秋山泰身、秋山伸子
  • Journal Title: 感染 炎症 免疫 Volume: 45-4 Pages: 66-67
• [Journal Article] 胸腺髄質上皮細胞分化のネガティブフィードバック制御 (2015)
  • Author(s): 秋山伸子、秋山泰身
  • Journal Title: 医学のあゆみ Volume: 255 Pages: 1119-1120
• [Journal Article] 胸腺依存的な自己寛容にかかわる遺伝子発現 (2015)
  • Author(s): 秋山泰身、 立石涼介、良永理子、秋山伸子
  • Journal Title: 臨床免疫・アレルギー科 Volume: 64 Pages: 404-409
• [Journal Article] 自己免疫疾患と胸腺髄質上皮細胞 (2015)
  • Author(s): 秋山泰身、 立石涼介、秋山伸子
  • Journal Title: 病理と臨床 Volume: 33 Pages: 703-707
• [Journal Article] Excess NF-kB induces ectopic odontogenesis in embryonic incisor epithelium. (2015)
  • Author(s): Blackburn, J., Kawasaki, K., Porntaveetus, T., Kawasaki, M., Otsuka-Tanaka, Y., Miake, Y., Ota, M.S., Watanabe, M., Hishinuma, M., Nomoto, T., Oommen, S., Ghafoor, S., Harada, F., Nozawa-Inoue, K., Maeda, T., Peterková, R., Lesot, H., Inoue, J., Akiyama, T.,
  • Journal Title: J. Dent. Res Volume: 94 Issue: 1 Pages: 121-128
  • DOI: 10.1177/0022034514556707
  • Peer Reviewed / Open Access
• [Journal Article] Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. (2014)
  • Author(s): Akiyama, N., Shinzawa, M., Miyauchi, M., Yanai, H., Tateishi, R., Shimo, Y., Ohshima, D., Matsuo, M., Sasaki. I., Hoshino, K., Wu, G., Yagi, S., Inoue, J., Kaisho, T. and Akiyama, T.
  • Journal Title: J. Exp. Med. Volume: 211 Issue: 12 Pages: 2425-2438
  • DOI: 10.1084/jem.20141207
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN (2014)
  • Author(s): Akiyama, T., Shiraishi, T., Qin, J., Konno, H., Akiyama, N., Shinzawa, M., Miyauchi, M., Takizawa, N., Yanai, H., Ohashi, H., Miyamoto-Sato, E., Yanagawa, H., Yong, W., Shou, W. and Inoue, J.
  • Journal Title: PLoS ONE Volume: 9(5) Issue: 5 Pages: e95992-e95992
  • DOI: 10.1371/journal.pone.0095992
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of transcription factors activated in thymic epithelial cells during embryonic thymus development. (2014)
  • Author(s): Akiyama, T., Qin, J., Ohshima, D. and Inoue, J.
  • Journal Title: Methods Mol. Biol. Volume: 1164 Pages: 163-170
  • DOI: 10.1007/978-1-4939-0805-9_13
  • ISBN: 9781493908042, 9781493908059
  • Peer Reviewed
• [Presentation] Induction of Thymic Epithelial-like cells from human iPSC by ectopically expression of FoxN1 in stepwise culture system (2015)
  • Author(s): Kotaro Kitagawa, Hisako Akatsuka, Taishin Akiyama, Shin Kaneko, Tetsuro Tamaki, Masato Ohtsuka, Masafumi Tanaka, Minoru Kimura and Takehito Sato
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: コンベンションセンター（札幌）
  • Year and Date: 2015-11-20
• [Presentation] Analysis of the molecular mechanism regulating regeneration of medullay Thymic Epithelial Cells (2015)
  • Author(s): TATEISHI Ryosuke, AKIYAMA Nobuko, YOSHINAGA Riko, MIYAUCHI Maki, INOUE Jun-ichiro, and AKIYAMA Taishin
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: コンベンションセンター（札幌）
  • Year and Date: 2015-11-19
• [Presentation] RANKシグナルによる制御性T細胞の胸腺内分化誘導 (2015)
  • Author(s): 秋山 伸子、立石 涼介、良永 理子、井上 純一郎、秋山 泰身
  • Organizer: 京都T細胞会議
  • Place of Presentation: 芝蘭会館（京都）
  • Year and Date: 2015-05-15
• [Presentation] Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN (2014)
  • Author(s): Taishin Akiyama
  • Organizer: 第43回 日本免疫学会学術集会
  • Place of Presentation: 京都、京都国際会議
  • Year and Date: 2014-12-11
• [Presentation] T cell-specific CNOT3 depletion alters thymic T cell development and provokes autoimmunity (2014)
  • Author(s): ITOH-KUREHA Taku
  • Organizer: 第43回 日本免疫学会学術集会
  • Place of Presentation: 京都、京都国際会議
  • Year and Date: 2014-12-10
• [Presentation] 非古典的NF-kB経路の振動による転写制御メカニズムの解析 (2014)
  • Author(s): 関 崇生
  • Organizer: 第37回 日本分子生物学会年会
  • Place of Presentation: 神戸、神戸国際会議場
  • Year and Date: 2014-11-27
• [Presentation] T細胞特異的CNOT3欠損マウスにおけるT細胞分化・機能異常と自己免疫疾患発症 (2014)
  • Author(s): 呉羽 拓
  • Organizer: 第37回 日本分子生物学会年会
  • Place of Presentation: 神戸、神戸国際会議場
  • Year and Date: 2014-11-26
• [Presentation] ETS ファミリー転写因子Spi-B は髄質上皮細胞の遺伝子発現を制御する (2014)
  • Author(s): 秋山 泰身
  • Organizer: 第24回京都T細胞会議
  • Place of Presentation: 京都、芝蘭会館
  • Year and Date: 2014-05-16