Mechanisms of Generation, Maintenance, and Activation of Humoral Memory

2013 Fiscal Year Final Research Report

• Project/Area Number: 21229007
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: KUROSAKI Tomohiro 大阪大学, 免疫学フロンティア研究センター, 特任教授 (50178125)
• Co-Investigator(Kenkyū-buntansha): BABA Yoshihiro 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (20415269)
• Co-Investigator(Renkei-kenkyūsha): TAKAHASHI Yoshimasa 国立感染症研究所, 免疫部, 室長 (60311403)
• Project Period (FY): 2009-05-11 – 2014-03-31
• Keywords: 液性免疫記憶 / 免疫記憶 / 存在部位 / メモリーTfh / 細胞増殖 / メモリー亜集団

Research Abstract

Once the pathogen invades into our body, the immune system operates and remembers this pathogen even after the pathogen is eliminated from the body. Then, when the same pathogen is invaded again, our immune system is able to respond to it quickly, thereby eliminating the pathogen very efficiently. Here, we have been addressing the mechanism underlying such quick responses. First, we have shown that memory B cells residue in the place, where these B cells easily access to the invaded pathogen. Second, memory B cells acquire the rapid differentiation activity through down-regulation of the transcription factor Bach2. This down-regulation took place during primary infection. Finally, memory B cells activate memory T cells quickly, which, in turn, facilitate differentiation of memory B cells. The above three mechanisms are operating in a cooperative manner.

Research Products

• [Journal Article] Intrinsic disorder mediates cooperative signal transduction in STIM1 (2014)
  • Author(s): Furukawa, Y., Teraguchi, S., Ikegami, T., Dagliyan, O., Jin, L., Hall, D., Dokholyan, N.V., Namba, K., Akira, S., Kurosaki, T., Baba, Y., Standley, D.M.
  • Journal Title: J Mol Biol Volume: 426 Pages: 2082-97
  • DOI: 10.1016/j.jmb.2014.03.006
  • Peer Reviewed
• [Journal Article] Positive Feedback Within a Kinase Signaling Complex Functions as a Switch Mechanism for NF-κB Activation (2014)
  • Author(s): Shinohara, H., Behar, M., Inoue, K., Hiroshima, M., Yasuda, T., Nagashima, T., Kimura, S., Sanjo, H., Maeda, S., Yumoto, N., Ki, Sewon, Akira, S., Sako, Y., Hoffmann, A., Kurosaki, T., Okada-Hatakeyama, M.
  • Journal Title: Science Volume: 344 Pages: 760-764
  • DOI: 10.1126/science
  • Peer Reviewed
• [Journal Article] STIM1 Controls Neuronal Ca^<2+> Signaling, mGluR1-Dependent Synaptic Transmission, and Cerebellar Motor Behavior (2014)
  • Author(s): Hartmann. J., Karl, R.M., Alexander, R.P., Adelsberger, H., Brill, M.S., Ruhlmann, C., Ansel, A., Sakimura, K., Baba. Y., Kurosaki, T., Misgeld, T., Konnerth, A
  • Journal Title: Neuron Volume: 82 Pages: 635-44
  • DOI: 10.1016/j.neuron.2014.03.027
  • Peer Reviewed
• [Journal Article] An ITAM-Syk-CARD9 signaling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells (2014)
  • Author(s): Yasukawa. S., Miyazaki, Y., Yoshii, C., Nakaya, M., Ozaki, N., Toda, S., Kuroda, E., Ishibashi, K., Yasuda, T., Natsuaki, Y., Mi-ichi, F., Iizasa, E., Nakahara, T., Yamazaki, M., Kabashima, K., Iwakura, Y., Takai, T., Saito, T., Kurosaki, T., Malissen, B., Ohno, N., Furue, M., Yoshida, H., and Hara, H
  • Journal Title: Nature Comm Volume: 5 Pages: 3755
  • DOI: 10.1038/ncomms4755
  • Peer Reviewed
• [Journal Article] Generation of colonic IgA-secreting cells in the cecal patch (2014)
  • Author(s): Masahata, K., Umemoto, E., Kayama, H., Kotani, M., Nakamura, S., Kurakawa, T., Kikuta, J., Gotoh, K., Motooka, D., Sato, S., Higuchi, T., Baba, Y., Kurosaki, T., Kinoshita, M., Shimada, Y., Kimura, T., Okumura, R., Takeda, A., Tajima, M., Yoshie, O., Fukuzawa, M., Kiyono, H., Fagarasan, S., Iida, T., Ishii, M., Takeda, K
  • Journal Title: Nature Comm Volume: 5 Pages: 3704
  • DOI: 10.1038/ncomms4704
  • Peer Reviewed
• [Journal Article] The Menin-Bach2 axis is critical for regulating CD4 T cell senescence and cytokine homeostasis (2014)
  • Author(s): Kuwahara, M., Suzuki, J., Tofukuji, S., Yamada, T., Kanoh, M., Matsumoto, A., Maruyama, S., Kometani, K., Kurosaki, T., Ohara, O., Nakayama, T., Yamashita, M
  • Journal Title: Nature Comm Volume: 5 Pages: 3555
  • DOI: 10.1038/ncomms4555
  • Peer Reviewed
• [Journal Article] The STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense (2014)
  • Author(s): Zhang, H., Clemens, R.A., Liu, F., Hu, Y., Baba, Y., Theodore, P., Kurosaki, T., and Lowell, C.A.
  • Journal Title: Blood Volume: 123 Pages: 2238-49
  • DOI: 10.1182/blood-2012-08-450403
  • Peer Reviewed
• [Journal Article] Calcium signaling in B cells : Regulation of cytosolic Ca^<2+> increase and its sensor molecules, STIM1 and STIM2 (2013)
  • Author(s): Baba, Y., Matsumoto, M., Kurosaki, T
  • Journal Title: Mol. Immunol
  • DOI: 10.1016/j.molimm.2013.10.006
• [Journal Article] Downregulation of PLCγ2/β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer (2013)
  • Author(s): Capietto, A.H., Kim, S., Sanford, D.E., Liehan, D.C., Hikida, M., Kurosaki, T., Novack, D.V. and Faccio, R
  • Journal Title: J. Exp. Med Volume: 210 Pages: 2257-2271
  • DOI: 10.1084/jem.20130281
  • Peer Reviewed
• [Journal Article] Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells (2013)
  • Author(s): Sasaki, Y., Sano, S., Nakahara, M., Murata, S., Kometani, K., Aiba, Y., Sakamoto, S., Watanabe, Y., Tanaka, K., Kurosaki, T., and Iwai, K
  • Journal Title: EMBO J Volume: 32 Pages: 2463-76
  • DOI: 10.1038/emboj.2013.184
  • Peer Reviewed
• [Journal Article] PDK1 controls upstream PI3K expression and PIP3 generation (2013)
  • Author(s): Dieterle, A.M., Bohler, P., Keppeler, H., Alers, S., Berleth, N., Drieβen, S., Hieke, N., Pietkiewicz, S., Loffler, A.S., Peter, C., Gray, A., Leslie, N.R., Shinohara, H., Kurosaki, T., Engelke, M., Wienands, J., Bonin, M., Wesselborg, S., and Stork, B
  • Journal Title: Oncogene
  • DOI: 10.1038/onc.2013.266
  • Peer Reviewed
• [Journal Article] Repression of the Transcription Factor Bach2 Contributes to Predisposition of IgG1 Memory B Cells toward Plasma Cell Differentiation (2013)
  • Author(s): Kometani, K., Nakagawa, R., Shinnakasu, R., Kaji, T., Rybouchkin, A., Moriyama, S., Furukawa, K., Koseki, H., Takemori, T. and Kurosaki, T
  • Journal Title: Immunity Volume: 39 Pages: 136-147
  • DOI: 10.1016/j.molimm.2013.10.006
  • Peer Reviewed
• [Journal Article] Bach2 maintains T cells in a naive state by suppressing effector memory-related genes (2013)
  • Author(s): Tsukumo, S., Unno, M., Muto, A., Takeuchi, A., Kometani, K., Kurosaki, T., Igarashi, K., Saito, T
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 110 Pages: 10735-40
  • DOI: 10.1073/pnas.1306691110
  • Peer Reviewed
• [Journal Article] B-Cell Responses to Pulmonary Virus Infection (2012)
  • Author(s): Takahashi, Y., Onodera, T., Kobayashi, K., and Kurosaki, T
  • Journal Title: Infec. Disord. Drug. Targets Volume: 12 Pages: 232-40
  • DOI: 10.2174187152612800564400
• [Journal Article] Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection (2012)
  • Author(s): Onodera, T., Takahashi, Y., Yokoi, Y., Ato, M., Kodama, Y., Hachimura, S., Kurosaki, T., and Kobayashi, K
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 109 Pages: 2485-90
  • DOI: 10.1073/pnas.1115369109
  • Peer Reviewed
• [Journal Article] CIN85 drives B cell responses by linking BCR signals to the canonical NF-κB pathway (2011)
  • Author(s): Kometani, K., Yamada, T., Sasaki, Y., Yokosuka, T., Saito, T., Rajewsky, K., Ishiai, M., Hikida, M. and Kurosaki, T
  • Journal Title: J. Exp. Med Volume: 208 Pages: 1447-1457
  • DOI: 10.1084/jem.20102665
  • Peer Reviewed
• [Journal Article] Regulation of BCR Signaling (2011)
  • Author(s): Kurosaki, T
  • Journal Title: Mol. Immunol Volume: 48 Pages: 1287-1291
  • DOI: 10.1016/j.molimm.2010.12.007
• [Journal Article] Stim1, PKCδ and RasGRP set a threshold for pro-apoptotic Erk signaling during B cell development (2011)
  • Author(s): Limnander, A., Depeille, P., Freedman, T.S., Liou, J., Leitges, M., Kurosaki, T., Roose, J.P. and Weiss, A
  • Journal Title: Nat. Immunol Volume: 12 Pages: 425-433
  • DOI: 10.1038/ni.2016
  • Peer Reviewed
• [Journal Article] The calcium sensors STIM1 and STIM2 control B cell regulatory function through IL-10 production (2011)
  • Author(s): Matsumoto, M., Fujii, Y., Baba, A., Hikida, M., Kurosaki, T. and Baba, Y.
  • Journal Title: Immunity Volume: 34 Pages: 703-714
  • DOI: 10.1016/j.immuni.2011.03.016
  • Peer Reviewed
• [Journal Article] ERKs induce expression of the transcriptional repressor Blimp-1 and subsequent plasma cell differentiation (2011)
  • Author(s): Yasuda T., Kometani, K., Takahashi, N., Imai, Y., Aiba, Y. and Kurosaki, T
  • Journal Title: Sci. Signal Volume: 4, (169) Pages: ra25
  • DOI: 10.1126/scisignal.2001592
  • Peer Reviewed
• [Journal Article] Unique properties of memory B cells of different isotypes (2010)
  • Author(s): Kurosaki, T., Aiba, Y., Kometani, K., Moriyama, S., and Takahashi, Y
  • Journal Title: Immunol. Rev Volume: 237 Pages: 104-16
  • DOI: 10.1126/scisignal.2001592
  • Peer Reviewed
• [Journal Article] Preferential localization of IgG memory B cells adjacent to contracted germinal centers (2010)
  • Author(s): Aiba, Y., Kometani, K., Hamadate, M., Moriyama, S., Sakaue-Sawano, A., Tomura, M., Luche, H., Fehling, H.J., Casella, R., Kanagawa, O., Miyawaki, A., and Kurosaki, T
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. Volume: 107 Pages: 12192-7
  • DOI: 10.1073/pnas.1005443107
  • Peer Reviewed
• [Journal Article] Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells (2010)
  • Author(s): Numaga, T., Nishida, M., Kiyonaka, S., Kato, K., Katano, M., Mori, E., Kurosaki, T., Inoue, R., Hikida, M., Putney, J.W.Jr. and Mori, Y
  • Journal Title: J. Cell. Sci Volume: 123 Pages: 927-938
  • DOI: 10.1242/jcs.061051
  • Peer Reviewed
• [Journal Article] MAGUK-controlled ubiquitination of CARMA1 modulates Lymphocyte NF-κB activity (2010)
  • Author(s): Moreno-Garcia, M.E., Sommer, K., Shinohara, H., Bandaranayake, A.D., Kurosaki, T., and Rawlings, D.J.
  • Journal Title: Mol. Cell. Biol Volume: 30 Pages: 922-934
  • DOI: 10.1128/MCB.01129-09
• [Journal Article] Immobile BCRs : The safety on the signal trigger (2010)
  • Author(s): Sasaki, Y. and Kurosaki, T
  • Journal Title: Immunity Volume: 32 Pages: 143-144
  • DOI: 10.1016/j.immuni.2010.02.007
• [Journal Article] Comprehending the complex connection between PKCβ, TAK1, and IKK in BCR signaling (2009)
  • Author(s): Shinohara, H. and Kurosaki, T
  • Journal Title: Immunol. Rev Volume: 232 Pages: 300-318
  • DOI: 10.1111/j.1600-065X.2009.00836.x
• [Journal Article] FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B-Cell receptor-mediated signaling (2009)
  • Author(s): Kochi, Y., Kyouzen, K., Yamada, R., Suzuki, A., Kurosaki, T., Nakamura, Y., and Yamamoto, K
  • Journal Title: J. Immunol Volume: 183 Pages: 5502-5510
  • DOI: 10.4049/jimmunol.0901982
  • Peer Reviewed
• [Journal Article] Physiological function and molecular basis of STIM1-mediated calcium entry in immune cells (2009)
  • Author(s): Baba, Y. and Kurosaki, T
  • Journal Title: Immunol. Rev Volume: 231 Pages: 174-88
  • DOI: 10.1111/j.1600-065X.2009.00813.x
• [Journal Article] Memory B cells contribute to rapid Bcl6 expression by memory T_<FH> cells
  • Author(s): Ise, W., Inoue, T., McLachlan, JB, Kometani, K., Kubo, M., Okada, T., Kurosaki T
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A Volume: (in press)
  • Peer Reviewed
• [Presentation] Calcium Signaling in B Lymphocytes. (2014)
  • Author(s): Kurosaki, T
  • Organizer: Keystone Symposia : Biolgy of B Cell Reponses
  • Place of Presentation: Keystone, USA
  • Year and Date: 2014-02-11
• [Presentation] 免疫レセプター抑制(ITIM)モチーフの発見 (2013)
  • Author(s): 黒崎知博
  • Organizer: 文部科学省卓越プログラムシンポジューム免疫科学のフロンティアー牟田達史博士メモリアルシンポジューム
  • Place of Presentation: 仙台
  • Year and Date: 2013-12-21
• [Presentation] B cell intrinsic and extrinsic mechanisms for rapid responsiveness of IgG1 type memory B cells (2013)
  • Author(s): Kurosaki, T., Kometani, K., Ise, W. , Shinnakasu, R
  • Organizer: 第36回分子日本分子生物学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-05
• [Presentation] B cell intrinsic and extrinsic mechanisms for rapid responsiveness of IgG1 type memory B cells (2013)
  • Author(s): Kurosaki, T
  • Organizer: 2013 Oversea Scholar Seminar, Tsinghua University
  • Place of Presentation: Beijing, China
  • Year and Date: 2013-11-14
• [Presentation] Calcium Signaling in B Lymphocytes (2013)
  • Author(s): Kurosaki, T
  • Organizer: Immune-related Pathologies : Understanding Leukocyte Signaling and Emerging therapies - IMPULSE 2013
  • Place of Presentation: Matrahaza, Hungary
  • Year and Date: 2013-09-02
• [Presentation] Cellular and molecular mechanisms for rapid responsiveness of humoral memory responses (2013)
  • Author(s): Kurosaki, T
  • Organizer: Seminar, Okinawa Institute of Science and Technology Graduate University
  • Place of Presentation: Okinawa
  • Year and Date: 2013-05-04
• [Presentation] B Cell Intrinsic and Extrinsic Mechanisms for Rapid Responsiveness of IgG1 Type Memory B Cells (2013)
  • Author(s): Kurosaki, T
  • Organizer: Keystone Symposia : B Cell Development and Function
  • Place of Presentation: Keystone Resort, USA
  • Year and Date: 2013-02-13
• [Presentation] Regulation of memory antibody response by antigen-specific memory CD4 T cells. (2012)
  • Author(s): Ise, W., Kurosaki, T
  • Organizer: The 41st Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2012-12-06
• [Presentation] Signaling to Control Developmental Transitions (2012)
  • Author(s): Kurosaki, T
  • Organizer: Keystone Symposia "Regulation of Lymphocyte Signaling."
  • Place of Presentation: Keystone, USA
  • Year and Date: 2012-03-14
• [Presentation] Contribution of transcription factors to rapid responsiveness of IgG type memory B cells (2011)
  • Author(s): Kurosaki, T
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-28
• [Presentation] Protective memory B cell responses to influenza virus infection (2011)
  • Author(s): Takahashi, Y
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-28
• [Presentation] Function of Calcium Signaling in B Lymphocytes (2011)
  • Author(s): Kurosaki, T
  • Organizer: The 1st International Meeting on Ion Channel Signaling Mechanisums : from Basic Science to Clinical Application
  • Place of Presentation: Marrakesh, Morocco
  • Year and Date: 2011-11-01
• [Presentation] Calcium Signaling in immune cells (2011)
  • Author(s): Kurosaki, T
  • Organizer: FASEB Summer Research Conferences - Signal Transduction in the Immune System
  • Place of Presentation: Snowmass, USA
  • Year and Date: 2011-06-21
• [Presentation] Function of Calcium in Lymphocytes (2011)
  • Author(s): Kurosaki, T
  • Organizer: Advances in Immunology and Cancer Biology
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2011-04-17
• [Presentation] Function of Store-Operated Calcium Entry in B Lymphocytes (2011)
  • Author(s): Kurosaki, T
  • Organizer: Keystone Symposia, B Cells : New Insights into Normal versus Dysregulated Function
  • Place of Presentation: Whistler, Canada
  • Year and Date: 2011-04-13
• [Presentation] Store-operated Calcium Entry in B cells (2010)
  • Author(s): Kurosaki, T
  • Organizer: Symposia Track 4-1 : Lymphocyte Signaling. The 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-23
• [Presentation] Preferential localization of IgG memory B cells adjacent to contracted germinal centers (2010)
  • Author(s): Kurosaki, T
  • Organizer: The 4th International Symposium on B cells and Autoimmunity
  • Place of Presentation: Nara, Japan
  • Year and Date: 2010-08-20
• [Presentation] Unique properties of memory B lymphocytes (2010)
  • Author(s): Kurosaki, T
  • Organizer: Freiburg Institute for Advanced Studies Monday Seminar Series
  • Place of Presentation: Freiburg, Germany
  • Year and Date: 2010-06-21
• [Presentation] ストア作動性カルシウム流入活性化機構とその生理的役割 (2010)
  • Author(s): Baba, Y
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
  • Year and Date: 2010-05-19
• [Presentation] Regulation of B Cell Development (2010)
  • Author(s): Kurosaki, T
  • Organizer: Renal Transplantation Forum 2010
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2010-05-15
• [Presentation] Store-operated calcium entry in B cells (2009)
  • Author(s): Baba, Y., Matsumoto, M., Kurosaki, T
  • Organizer: 第39回日本免疫学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-03
• [Presentation] Role of PLCγ2 in humoral memory (2009)
  • Author(s): Kurosaki, T
  • Organizer: EMBO Conference Signaling in the Immune System : Lymphocyte signaling from development to effector function
  • Place of Presentation: Siena, Italy
  • Year and Date: 2009-09-15
• [Remarks] 日経産業新聞(10面)「免疫細胞の記憶解明」2013年7月12日化学工業日報(9面)「転写因子発現量に依存」2013年7月12日 ■新聞報道
• [Remarks] 日経産業新聞(10面)「多発性硬化症悪化防ぐ仕組み解明」2011年7月15日 ■新聞報道
• [Remarks] 化学工業日報(朝刊9面)「B細胞活性化の仕組み解明アダプター分子『CIN85』シグナル伝達に必須」2011年6月28日 ■新聞報道
• [Remarks] 日刊工業新聞(朝刊27面)「肺炎球菌へのB細胞抗体必須分子を特定」2011年6月28日 ■新聞報道
• [Remarks] 日刊工業新聞(朝刊27面)「肺炎球菌へのB細胞抗体必須分子を特定」2011年6月28日 ■新聞報道
• [Remarks] 化学工業日報(朝刊9面)「免疫応答の可視化成功」2011年6月3日 ■新聞報道
• [Remarks] 科学新聞(4面)「Bリンパ球の抗体産生細胞への分化」2011年4月29日 ■新聞報道
• [Remarks] 黒崎知博「超初心者向け『先生, 免疫って何ですか』」ラボカフェ, 10月25日,2013,大阪 ■アウトリーチ活動
• [Remarks] 黒崎知博「免疫記憶の謎に挑む」WPI6拠点合同シンポジウム世界トップレベルの科学を愉しむ. 11月24日, 2012, つくば ■アウトリーチ活動
• [Remarks] 黒崎知博「いちばん新しい免疫の話」サイエ ンスカフェ・オンザエッジ, 11月10日, 2012, 福岡 ■アウトリーチ活動
• [Remarks] 審良静男, 黒崎知博「第3回免疫の不思議」サイエンスカフェ・オンザエッジ, 1月18日, 2011, 大阪 ■アウトリーチ活動
• [Remarks] ホームページ
  • URL: http://lymph.ifrec.osaka-u.ac.jp/research_j.htm1