Molecular mechanisum of memory CD8 T cell differentiation

• Project/Area Number: 24590573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: SAKAMOTO Akemi 千葉大学, 医学(系)研究科(研究院), 助教 (90359597)
• Co-Investigator(Kenkyū-buntansha): TOKUHISA Takeshi 千葉大学, 学長 (20134364)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: メモリーＴ細胞 / ＣＤ８Ｔ細胞 / Ｂｃｌ６ / 転写因子 / サイトカイン / メモリー Ｔ 細胞 / ＣＤ８ Ｔ 細胞 / CD8T細胞 / Bcl6 / 免疫記憶 / mTOR / CD4T細胞

Outline of Final Research Achievements

Bcl6, a sequence specific transcriptional repressor, is important for generation and maintenance of central memory CD8+ T cells. However, the molecular mechanism involved in the generation is largely unknown. We demonstrated that Bcl6 negatively regulates the in vivo differentiation of both activated CD25+ CD8+ T cells and KLRG1hi effector CD8+ T cells. Since the induction of CD25 expression was more rapid and the amount of phosphorylated STAT5 was higher in the in vitro activated Bcl6-deficient CD8+ T cells than in the activated wild type CD8+ T cells, the IL-2 signaling was negatively regulated in activated CD8+ T cells by Bcl6. We also confirmed the Bcl6 binding to the various regions in the CD25 and IL-2 genes. These results indicate that Bcl6 is responsible for the differentiation of memory precursor CD8+ T cells by regulating the IL-2 signaling in activated CD8+ T cells.

Research Products

• [Journal Article] DA-Raf-dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation. (2014)
  • Author(s): Watanabe-Takano H, Takano K, Sakamoto A, Matsumoto K, Tokuhisa T, Endo T, Hatano M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 22
  • DOI: 10.1073/pnas.1321574111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells. (2014)
  • Author(s): Ikari J, Inamine A, Yamamoto T, Watanabe-Takano H, Yoshid a N, Fujimura L, Taniguchi T, Sakamoto A, Hatano M, Tatsumi K, Tokuhisa T, Arima M.
  • Journal Title: Allergy. Volume: 69 Issue: 2 Pages: 223-230
  • DOI: 10.1111/all.12328
  • Peer Reviewed / Open Access
• [Journal Article] Lack of both α2-antiplasmin and plasminogen activator inhibitor type-1 induces high IgE production (2013)
  • Author(s): Okada K, Ueshima S, Kawao N, Yano M, Tamura Y, Tanaka M, Sakamoto A, Hatano M, Arima M, Miyata S, Nagai N, Tokuhisa T, and Matsuo O
  • Journal Title: Life Sci Volume: 93 Issue: 2-3 Pages: 89-95
  • DOI: 10.1016/j.lfs.2013.05.023
  • Peer Reviewed
• [Journal Article] CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema. (2012)
  • Author(s): Shigeta A. et al
  • Journal Title: Am. J. Physiol. Lung Cell Mol. Physiol. Volume: 303 Pages: 141-51
  • Peer Reviewed
• [Journal Article] Crystal structure of human REV7 in complex with a human REV3 fragment and structural implication of the interaction between DNA polymerase zeta and REV1 (2010)
  • Author(s): Hara K, Hashimoto H, Murakumo Y, Kobayashi S, Kogame T, Unzai S, Akashi S, Takeda S, Shimizu T, Sato M
  • Journal Title: J Biol Chem Volume: 285 Issue: 40 Pages: 12299-12307
  • DOI: 10.1074/jbc.
  • Peer Reviewed / Open Access
• [Presentation] 肝臓における薬物代謝の性差を制御する新規分子の探索 (2015)
  • Author(s): 紙谷 聡英、近田裕美、井田絹代、坂本明美、徳久剛史.
  • Organizer: 第8回日本性差医学・医療学会学術集会
  • Place of Presentation: ホテルクレメント徳島（徳島県・徳島市）
  • Year and Date: 2015-01-31 – 2015-02-01
• [Presentation] Role of enteric neurons in regulation of intestinal epithelial homeostasis. (2014)
  • Author(s): Fujimura L, Ohara Y, Arima M, Sakamoto A, Tokuhisa T, Hatano M.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 肝臓における薬物代謝の性差を制御する分子メカニズム (2014)
  • Author(s): 近田裕美 ら
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 京都
• [Presentation] Possible role of enteric neurons in regulation of intestinal microbiota. (2013)
  • Author(s): Fujimura L. et al.
  • Organizer: 第４２回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Bcl6 regulate production of SLAM-Associated protein in follicular helper T cells. (2013)
  • Author(s): Taniguchi T. et al.
  • Organizer: 第４２回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Naive CD4 T cells are instructed to differentiate into effector or memory CD4 T cells (2012)
  • Author(s): KOHNO Mani et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Presentation] A role of Bcl6 in differentiation of memory precursor CD8 T cells (2012)
  • Author(s): PAN Jing et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際展示場（神戸）
• [Presentation] Bcl6 is required for ICOSL expression on activated B cells (2012)
  • Author(s): IIJIMA Yuta et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Presentation] Regulation of SLAM-associated protein in follicular helper T cells by Bcl6. (2012)
  • Author(s): Taniguchi, T. et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Presentation] Roles of ADAR1 in somatic hypermutation and class switch recombination on germinal center B cells. (2012)
  • Author(s): Turuoka, N. et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Presentation] Nitric oxide derived from enteric neurons regulates intestinal barrier function. (2012)
  • Author(s): Fujimura, L. et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: ポートピアホテル（神戸）
• [Presentation] Role of IL-33 in a suppressive function of Bcl6 for IL-4 production by memory Th2 cells. (2012)
  • Author(s): Arima, M. et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際展示場（神戸）
• [Presentation] Heterogeneity of Naive CD4 T cells
  • Author(s): Akemi Sakamoto et al
  • Organizer: The 1st Symposium of International Immunological Memory and Vaccine Forum
  • Place of Presentation: 東京ステーションカンファレンス（東京）
• [Presentation] Phf11 promotes IgE class switch recombination in activated B cells.
  • Author(s): Yamamoto T. et al
  • Organizer: 第４１回日本免疫学会
  • Place of Presentation: 神戸国際展示場（神戸）
• [Book] Recent Res. Devel. Immunology, Roles of Bcl6 in dendritic cell homeostasis (2012)
  • Author(s): Akemi Sakamoto, Hiroyuki Matsuyama, Yuki Hayashi, Shun Hasegawa, Yuta Iijima、Mani Kohno, Jin Pan, Sumina Inage and Takeshi Tokuhisa
  • Publisher: Research Signpost
• [Remarks] 千葉大学大学院医学研究院・粘膜免疫学
  • URL: http://www.m.chiba-u.ac.jp/class/mucosa/
• [Remarks] 千葉大学大学院医学研究院 分化制御学
  • URL: http://www.m.chiba-u.ac.jp/class/devgen/
• [Remarks] 千葉大学 大学院医学研究院 分化制御学