Regulation of B-cell memory formation by metabolic programs

• Project/Area Number: 16K15295
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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)
• Co-Investigator(Renkei-kenkyūsha): HANIUDA Kei 東京理科大学, 研究推進機構生命医科学研究所, 助教 (40734918)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 胚中心 / メモリーB細胞 / ミトコンドリア代謝 / 解糖系 / BCL6 / プラズマ細胞 / B細胞 / 免疫記憶

Outline of Final Research Achievements

During immune responses, antigen-responding B cells are activated and form germinal centers (GC) in the lymphoid organs. The GC B cells undergo somatic hypermutation in their immunoglobulin genes encoding B-cell receptors (BCR), and diversify the BCR affinity to antigen. High affinity B cells are then selected in the GC through T-cell help and finally differentiate into memory B cells. Memory B cells have abilities to survive for a long time and to rapidly respond to antigen to proliferate and differentiate into plasma cells. In this study, we elucidated mechanisms for how GC B cells maintain proliferation and how memory B cells live long and respond rapidly in terms of mitochondrial and glycolysis metabolisms, utilizing our original methodology, the induced GC B (iGB) cell culture system.

Research Products

• [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] 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] The quantity of CD40 signaling in pre-GC phase determine the differentiation into functionally distinct memory B cell subsets via Mef2b expression. (2016)
  • Author(s): Takuya Koike, Shu Horiuchi, Kei Haniuda, 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: 2016-12-07
• [Presentation] B細胞補助受容体CD19による胚中心形成メカニズムの解析 (2016)
  • Author(s): 長谷川仁士、羽生田圭、北村大介
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [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