Molecular mechanisms of memory B cell differentiation in germinal centers

• Project/Area Number: 23390121
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: TOKUHISA Takeshi 千葉大学, 医学(系)研究科(研究院), 教授 (20134364)
• Co-Investigator(Kenkyū-buntansha): ARIMA Masafumi 千葉大学, 大学院・医学研究院, 講師 (00202763) ; SAKAMOTO Akemi 千葉大学, 大学院・医学研究院, 助教 (90359597)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,890,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥4,590,000); Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2011: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 免疫記憶 / Ｂリンパ球 / 胚中心 / サイトカイン / 抗体産生細胞 / IgE抗体 / Bリンパ球

Research Abstract

To elucidate a role of IL-21 or Bcl6 in differentiation of high affinity IgG producing memory B cells and long-lived plasma cells in germinal centers, we used IL-21-deficient or Bcl6-deficient mice. Using these mice, we demonstrated that IL-21 is essential to differentiation of high affinity IgG producing long-lived plasma cells, and that IL-21 or Bcl6 represses the Ig class switch recombination to IgE and augments the differentiation of high affinity IgG producing memory B cells and long-lived plasma cells.

Research Products

• [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] Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis (2013)
  • Author(s): Takahashi W, Watanabe E, Fujimura L, Watanabe-Takano H, Yoshidome H, Swanson PE, Tokuhisa T, Oda S, and Hatano M
  • Journal Title: Crit. Care Volume: 17
  • Peer Reviewed
• [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] Leukotriene C4 aggravates bleomycin-induced pulmonary fibrosis in mice (2013)
  • Author(s): Hirata H, Arima M, Fukushima Y, Sugiyama K, Tokuhisa T, and Fukuda T
  • Journal Title: Respirology Volume: 18 Issue: 4 Pages: 674-681
  • DOI: 10.1111/resp.12072
  • Peer Reviewed
• [Journal Article] ADAR1 induces adenosine-targeted DNA mutations in senescent Bcl6-deficient cells (2013)
  • Author(s): Tsuruoka, N., Arima, M., Yoshida, N., Okada, S., Sakamoto, A., Hatano, M., Satake, H., Arguni, E., Wang, J.-Y., Yang, J.-H., Nishikura, K., Sekiya, S., Shozu, M. and Tokuhisa, T.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 2 Pages: 826-836
  • DOI: 10.1074/jbc.m112.365718
  • Peer Reviewed
• [Journal Article] Generation of tissue-specific H-2K(d) transgenic mice for the study of K(d)-restricted malaria epitope-specific CD8(+) T-cell responses in vivo (2013)
  • Author(s): Huang J, Li X, Kohno K, Hatano M, Tokuhisa T, Murray PJ, Brocker T, and Tsuji M
  • Journal Title: J. Immunol. Methods Volume: 387 Issue: 1-2 Pages: 254-261
  • DOI: 10.1016/j.jim.2012.10.019
  • Peer Reviewed
• [Journal Article] Critical role of the IgM Fc receptor in IgM homeostasis, B cell survival and humoral immune responses (2012)
  • Author(s): Ouchida, R., Mori, H., Hase, K., Takatsu, H., Kurosaki, T., Tokuhisa, T., Ohno, H., Wang. J. -Y.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 109 Issue: 40 Pages: 2699-2706
  • DOI: 10.1073/pnas.1210706109
  • Peer Reviewed
• [Journal Article] CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema (2012)
  • Author(s): Shigeta, A., Tada, Y., Wang, J.-Y., Ishizaki, S., Tuyusaki, J., Yamauchi, K., Kasahara, Y., Iesato, K., Tanabe, N., Takiguchi, Y., Sakamoto, A., Tokuhisa, T., Shibuya, K., Hiroshima, K., West, J. and Tatsumi, K.
  • Journal Title: American Journal of Physiology Volume: 303 Issue: 2 Pages: 141-151
  • DOI: 10.1152/ajplung.00337.2011
  • Peer Reviewed
• [Journal Article] BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signalling in angiogenesis (2012)
  • Author(s): Ohnuki H, Inoue H, Takemori N, Nakayama H, Sakaue T, Fukuda S, Miwa D, Nishiwaki E, Hatano M, Tokuhisa T, Endo Y, Nose M, and Higashiyama S
  • Journal Title: Blood Volume: 119 Issue: 11 Pages: 2688-2698
  • DOI: 10.1182/blood-2011-03-345306
  • Peer Reviewed
• [Journal Article] Critical role of the IgM Fc receptor in IgM homeostasis, B cell survival, and humoral immune responses. (2012)
  • Author(s): Ouchida, R.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 109 Pages: 2699-2706
  • Peer Reviewed
• [Journal Article] BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signalling in angiogenesis. (2012)
  • Author(s): Ohnuki, H.
  • Journal Title: Blood Volume: 119 Pages: 2688-2698
  • Peer Reviewed
• [Journal Article] Bcl6 in pulmonary epithelium coordinately controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation (2011)
  • Author(s): Seto T, et al
  • Journal Title: Clin Exp Allergy Volume: 41 Issue: 11 Pages: 1568-78
  • DOI: 10.1111/j.1365-2222.2011.03836.x
  • Peer Reviewed
• [Journal Article] Over-expression of the LTC(4) synthase gene in mice reproduces human aspirin-induced asthma (2011)
  • Author(s): Hirata H, Arima M, Fukushima Y, Honda K, Sugiyama K, Tokuhisa T, and Fukuda T
  • Journal Title: Clin. Exp. Allergy Volume: 41 Issue: 8 Pages: 1133-1142
  • DOI: 10.1111/j.1365-2222.2011.03720.x
  • Peer Reviewed
• [Journal Article] Outcome prediction in sepsis combined use of genetic polymorphisms - A study in Japanese population (2011)
  • Author(s): Shimada T, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Watanabe E, Abe R, Nakada TA, Tateishi Y, Otani S, Hirasawa H, Tokuhisa T, and Uno H
  • Journal Title: Cytokine Volume: 54 Issue: 1 Pages: 79-84
  • DOI: 10.1016/j.cyto.2010.12.001
  • Peer Reviewed
• [Journal Article] CXCR4 expression on activated B cells is down-regulated by CD63 and IL-21 (2011)
  • Author(s): Yoshida N, Kitayama D, Arima M, Sakamoto A, Inamine A, Takano H, Hatano M, Koike T, and Tokuhisa T
  • Journal Title: J. Immunol Volume: 186 Issue: 5 Pages: 2800-2808
  • DOI: 10.4049/jimmunol.1003401
  • Peer Reviewed
• [Journal Article] Bcl6 is required for the development of mouse CD4^+ and CD8α^+ dendritic cells (2011)
  • Author(s): Ohtsuka H, Sakamoto A, Pan J, Inage S, Horigome S, Ichii H, Arima M, Hatano M, Okada S, and Tokuhisa T
  • Journal Title: J. Immunol Volume: 186 Issue: 1 Pages: 255-263
  • DOI: 10.4049/jimmunol.0903714
  • Peer Reviewed
• [Journal Article] Bcl6 is required for the development of mouse CD4^+ and CD 8α^+ dendritic cells (2011)
  • Author(s): Ohtsuka, et al.
  • Journal Title: J.Immunol. Volume: 186 Pages: 255-263
  • Peer Reviewed
• [Journal Article] CXCR4 expression on activated B cells is down-regulated by CD63 and IL-21 (2011)
  • Author(s): Yoshida, et al.
  • Journal Title: J.Immunol. Volume: 186 Pages: 2800-2808
  • Peer Reviewed
• [Journal Article] Bcl6 in pulmonary epithelium coordinately controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation (2011)
  • Author(s): Seto, et al.
  • Journal Title: Clin.Exp.Allergy Volume: 41 Pages: 1568-1578
  • Peer Reviewed
• [Presentation] 免疫記憶細胞の形成と維持 (2014)
  • Author(s): 徳久剛史
  • Organizer: 東京免疫フォーラム
  • Place of Presentation: 東京
  • Year and Date: 2014-02-24
• [Presentation] 免疫記憶細胞の形成と維持 (2014)
  • Author(s): 徳久剛史
  • Organizer: 東京免疫フォーラム
  • Place of Presentation: 東京大学医科学研究所（東京都）
  • Invited
• [Presentation] IgE 抗体産生機構と制御法の開発 (2013)
  • Author(s): 徳久剛史, 有馬雅史
  • Organizer: 第25回日本アレルギー学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-05-12
• [Presentation] Development of High Affinity IgE B Cells (2013)
  • Author(s): Tokuhisa T
  • Organizer: Chiba and Auckland University Immunology Forum
  • Place of Presentation: New Zealand
  • Year and Date: 2013-02-23
• [Presentation] 免疫記憶細胞の形成と維持 (2012)
  • Author(s): 徳久剛史
  • Organizer: 第40回日本臨床免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2012-09-29
• [Presentation] 若き臨床研究者たちへ (2012)
  • Author(s): 徳久剛史
  • Organizer: 第51回日本鼻科学会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2012-09-28
• [Presentation] 免疫記憶と慢性アレルギー (2012)
  • Author(s): 徳久剛史
  • Organizer: 第6回日本アミノ酸学会
  • Place of Presentation: 松戸市
  • Year and Date: 2012-09-28
• [Presentation] B cell activation and memory (2011)
  • Author(s): Tokuhisa, T.
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張メッセ(千葉市)(招待講演)
  • Year and Date: 2011-11-27
• [Presentation] 老化すると免疫記憶にもボケがでるか (2011)
  • Author(s): 徳久剛史
  • Organizer: 第11回日本抗加齢医学会「加齢と免疫」シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2011-05-28
• [Presentation] 免疫記憶細胞の形成と維持
  • Author(s): 徳久剛史
  • Organizer: 日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Invited
• [Remarks] 分化制御学教室のホームページ
  • 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
  • URL: http://www.m.chiba-u.ac.jp/class/devgen/
• [Remarks] 分化制御学
  • URL: http://www.m.chiba-u.ac.jp/class/devgen/
• [Remarks]
  • URL: http://www.m.chiba-u.ac.jp/class/devgen/