Functional analysis of memory B cells as the effector cells

• Project/Area Number: 16H05206
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Tokyo University of Science
• Principal Investigator: Kitamura Daisuke 東京理科大学, 研究推進機構生命医科学研究所, 教授 (70204914)
• Research Collaborator: HANIUDA kei
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 免疫記憶 / 胚中心 / 免疫応答 / エフェクター細胞 / アレルギー

Outline of Final Research Achievements

Memory B (Bm) cells are generated during the T-cell-dependent primary response and crucial in the antibody recall response in which they expand and produce a large amount of high-affinity antibody against re-invaded antigens. We have found that a fraction of Bm cells produce a cytokine IL-9 and facilitate the antibody recall response of Bm cells that express IL-9-receptor, and also suppress ICOS-ligand expression on Bm cells and thus regulate germinal-center formation by Bm cells. Our data suggested that IL-9 production by Bm cells is augmented at the recall response by stimulation through CD40. From these data, we propose a new role of Bm cells as the effector cells that regulate immune responses.

Academic Significance and Societal Importance of the Research Achievements

ワクチンによって免疫記憶が形成され維持されることの実態は記憶B細胞が産生され維持されることである。記憶B細胞は元の病原体に出合うと増殖し、大量に抗体を産生することで病原体を排除する。記憶B細胞はそれだけでなく、サイトカインを介して記憶B細胞の免疫応答を制御するエフェクター細胞としての役割を果たすことを我々は見出した。長期間生存する抗原特異的な記憶B細胞はエフェクター細胞として、想起応答のみならず自己免疫やアレルギーといった慢性免疫疾患の発症や病態をも制御している可能性がある。

Research Products

• [Int'l Joint Research] Ludwig Institute for Cancer Research/Catholic University of Leuven(ベルギー)
• [Journal Article] PRMT5 is essential for B cell development and germinal center dynamics. (2019)
  • Author(s): Litzler, L.C., Zahn, A., Meli, A.P., Hebert, S., Patenaude, A., Methot, S.P., Sprumont, A., Bois, T., Kitamura, D., Costantino, S., King, I.L., Kleinman, C.L., Richard, S., Di Noia, J.M.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 22-22
  • DOI: 10.1038/s41467-018-07884-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription Factor STAT3 Serves as a negative regulator controlling IgE class switching in mice. (2018)
  • Author(s): Dascani, P., Ding, C., Kong, K., Tieri, D., Hu, X., Zhang, H., Kitamura, D., Bolli, R., Rouchka, E.C., Yan, J.
  • Journal Title: ImmunoHorizens Volume: 2 Issue: 11 Pages: 349-362
  • DOI: 10.4049/immunohorizons.1800069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-9 receptor signaling in memory B cells regulates humoral recall responses. (2018)
  • Author(s): Takatsuka, S., Yamada, H., Haniuda, K., Saruwatari, H., Ichihashi, M., Renauld, J.-C. and Kitamura, D.
  • Journal Title: Nature Immunology Volume: 19 Issue: 9 Pages: 1025-1034
  • DOI: 10.1038/s41590-018-0177-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A splenic IgM memory subset with antibacterial specificities is sustained from persistent mucosal responses. (2018)
  • Author(s): Le Gallou, S., Zhou, Z., Thai, L.H., Fritzen, R., de Los Aires, A.V., Megret, J., Yu, P., Kitamura, D., Bille, E., Tros, F., Nassif, X., Charbit, A., Weller, S., Weill, J.C. and Reynaud, C.A.
  • Journal Title: Journal of Experimental Medicine Volume: 215 Issue: 8 Pages: 2035-2053
  • DOI: 10.1084/jem.20180977
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cbl ubiquitin ligases control B cell exit from the germinal-center reaction. (2018)
  • Author(s): Li, X., Gadzinsky, A., Gong, L., Tong, H., Calderon, V., Li, Y., Kitamura, D., Klein, U., Langdon, W.Y., Hou, F., Zou, Y.R. and Gu, H.
  • Journal Title: Immunity Volume: 48 Issue: 3 Pages: 530-541
  • DOI: 10.1016/j.immuni.2018.03.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Host DNases prevent vascular occlusion by neutrophil extracellular traps (2017)
  • Author(s): Jimenez-Alcazar Miguel、Rangaswamy Chandini、Panda Rachita、Bitterling Josephine、Simsek Yashin J.、Long Andy T.、Bilyy Rostyslav、Krenn Veit、Renn? Christoph、Renn? Thomas、Kluge Stefan、Panzer Ulf、Mizuta Ryushin、Mannherz Hans Georg、Kitamura Daisuke、Herrmann Martin、Napirei Markus、Fuchs Tobias A.
  • Journal Title: Science Volume: 358 Issue: 6367 Pages: 1202-1206
  • DOI: 10.1126/science.aam8897
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The AID-Cre-ERT2 model: A tool for monitoring B cell immune responses and generating selective hybridomas. (2017)
  • Author(s): Le Gallou, S., Nojima, T., Kitamura, D., Weill, J.C. and Reynaud, C.A.
  • Journal Title: Methods Mol. Biol. Volume: 1623 Pages: 243-251
  • DOI: 10.1007/978-1-4939-7095-7_19
  • ISBN: 9781493970940, 9781493970957
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Vitro-Induced Germinal Center B Cell Culture System (2017)
  • Author(s): Haniuda Kei, Nojima Takuya and Kitamura Daisuke
  • Journal Title: Methods in Molecular Biology Volume: 1623 Pages: 125-133
  • DOI: 10.1007/978-1-4939-7095-7_11
  • ISBN: 9781493970940, 9781493970957
  • Peer Reviewed
• [Journal Article] BCR and endosomal TLR signals synergize to increase AID expression and establish central B cell tolerance. (2017)
  • Author(s): Kuraoka, M., Snowden, P.B., Nojima, T., Verkoczy, L., Haynes, B.F., Kitamura, D., Kelsoe, G.
  • Journal Title: Cell Reports Volume: 18 Issue: 7 Pages: 1627-1635
  • DOI: 10.1016/j.celrep.2017.01.050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differing requirements for MALT1 function in peripheral B cell survival and differentiation. (2017)
  • Author(s): Lee, P., Zhu, Z., Hachmann, J., Nojima, T., Kitamura, D., Salvesen, G., Rickert, R.C.
  • Journal Title: The Journal of Immunology Volume: 198 Issue: 3 Pages: 1066-1080
  • DOI: 10.4049/jimmunol.1502518
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DNase γ, DNase I and caspase-activated DNase cooperate to degrade dead cells. (2016)
  • Author(s): Koyama, R., Arai, T., Kijima, M., Sato, S., Miura, S., Yuasa, M., Kitamura, D., Mizuta, R.
  • Journal Title: Genes to Cells Volume: 21 Issue: 11 Pages: 1150-1163
  • DOI: 10.1111/gtc.12433
  • Peer Reviewed
• [Journal Article] Autonomous membrane IgE signaling prevents IgE-memory formation. (2016)
  • Author(s): Haniuda, K., Fukao, S., Kodama, T., Hasegawa, H., Kitamura, D.
  • Journal Title: Nature Immunology Volume: 17 Issue: 9 Pages: 1109-1117
  • DOI: 10.1038/ni.3508
  • Peer Reviewed
• [Journal Article] IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. (2016)
  • Author(s): Domeier, P.P., Chodisetti, S.B., Soni, C., Schell, S.L., Elias, M.J., Wong, E.B., Cooper, T.K., Kitamura, D., Rahman, Z.S.
  • Journal Title: Journal of Experimental Medicine Volume: 213 Issue: 5 Pages: 715-732
  • DOI: 10.1084/jem.20151722
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Mechanisms for Memory B-Cell Formation and Function: Possible Implications for Vaccination. (2019)
  • Author(s): Daisuke Kitamura
  • Organizer: The 3rd Annual Chiba University-UCSD Symposium on Mucosal Immunology, Allergy and Vaccines
  • Int'l Joint Research
• [Presentation] Regulatory Mechanisms for Memory B Cell Development and Function. (2018)
  • Author(s): Daisuke Kitamura
  • Organizer: KEYSTONE SYMPOSIA, B Cells: Mechanisms in Immunity and Autoimmunity
  • Int'l Joint Research / Invited
• [Presentation] IL-9 receptor signaling in memory B cells regulates humoral recall responses. (2018)
  • Author(s): Daisuke Kitamura
  • Organizer: 2nd International Innovation Dialogue on Genome Engineering Animal Models and Biomedical Research Symposium
  • Int'l Joint Research / Invited
• [Presentation] B細胞による獲得免疫応答とその制御メカニズム (2018)
  • Author(s): 北村大介
  • Organizer: 第4回川島カンファレンス
  • Invited
• [Presentation] IgE/B細胞メモリー (2017)
  • Author(s): 北村大介
  • Organizer: 第４回総合アレルギー講習会 ~Total Allergistをめざして～
  • Invited
• [Presentation] Germinal center B cell development by glycolysis and mitochondrial metabolism. (2017)
  • Author(s): Kei Haniuda, Saori Fukao, Daisuke Kitamura
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Regulation of IL-9 receptor expression on B cells during immune response. (2016)
  • Author(s): Hiroyuki Yamada, Shogo Takatsuka, Daisuke Kitamura
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-06
• [Presentation] How do different classes of B cell receptors signal differently? (2016)
  • Author(s): Daisuke Kitamura
  • Organizer: Symposium hosted by Klaus Rajewsky: Mechanisms of Molecular and Cellular Immunity 1964-2016.
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2016-11-04
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] Ｂ細胞集団の製造方法、及びそれを用いたモノクローナル抗体の製造方法 (2017)
  • Inventor(s): 北村大介，馬渡達也，中石智之，北寛士，北野光昭
  • Industrial Property Rights Holder: 北村大介，馬渡達也，中石智之，北寛士，北野光昭
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-004860
  • Filing Date: 2017-01-16