Identification of regulatory B cells in vivo and elucidation of its suppressive mechanism

• Project/Area Number: 24689023
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Yoshihiro Baba 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)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥26,520,000 (Direct Cost: ¥20,400,000、Indirect Cost: ¥6,120,000); Fiscal Year 2014: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2013: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2012: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: 制御性B細胞 / 炎症 / 自己免疫疾患 / IL-10 / プラズマブラスト / 多発性硬化症 / B細胞 / EAE / 自己免疫性炎症

Outline of Final Research Achievements

B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL- 10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factor Blimp1 in B lineage cells developed an exacerbated EAE. Hence, plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation. As with mice, we established that human plasmablasts derived from naive B cells selectively secreted IL-10, reinforcing the importance of plasmablasts as IL-10-producing regulatory cells.

Research Products

• [Journal Article] Sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis. (2016)
  • Author(s): Ohmi Y, Ise W, Harazono A, Takakura D, Fukuyama H, Baba Y, Narazaki M, Shoda H, Takahashi N, Ohkawa Y, Ji S, Sugiyama F, Fujio K, Kumanogoh A, Yamamoto K, Kawasaki N, Kurosaki T, Takahashi Y, Furukawa K.
  • Journal Title: Nature Communications Volume: in press Issue: 1 Pages: 11205-11205
  • DOI: 10.1038/ncomms11205
  • NAID: 120007135549
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of Calcium Signaling in B Cell Activation and Biology. (2015)
  • Author(s): Baba Y & Kurosaki T
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 393 Pages: 143-174
  • Acknowledgement Compliant
• [Journal Article] Signals controlling the development and activity of regulatory B-lineage cells. (2015)
  • Author(s): Baba, Y., Matsumoto, M., Kurosaki, T.
  • Journal Title: Int Immunol. Volume: 27 Issue: 10 Pages: 487-93
  • DOI: 10.1093/intimm/dxv027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. (2015)
  • Author(s): Shanmughapriya S, Rajan S, Hoffman NE, Zhang X, Guo S, Kolesar JE, Hines KJ, Ragheb J, Jog NR, Caricchio R, Baba Y, Zhou Y, Kaufman BA, Cheung JY, Kurosaki T, Gill DL, Madesh M.
  • Journal Title: Sci Signal. Volume: 8 Issue: 366
  • DOI: 10.1126/scisignal.2005673
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. (2014)
  • Author(s): Mastumoto, M., Baba, A., Yokota, T., Nishikawa, H., Ohkawa, Y., Kayama, H., Kallies, A., Nut, S. L., Sakaguchi, S., Takeda, K., Kurosaki, T., and Baba, Y.
  • Journal Title: Immunity Volume: 41 Issue: 6 Pages: 1040-1051
  • DOI: 10.1016/j.immuni.2014.10.016
  • Peer Reviewed / Open Access
• [Journal Article] Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. (2014)
  • Author(s): Hendron E, Wang X, Zhou Y, Cai X, Goto J, Mikoshiba K, Baba Y, Kurosaki T, Wang Y, Gill DL.
  • Journal Title: Cell Calcium. Volume: 56 Pages: 482-492
  • Peer Reviewed / Open Access
• [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 Issue: 3 Pages: 635-44
  • DOI: 10.1016/j.neuron.2014.03.027
  • Peer Reviewed / Open Access
• [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 Issue: 1 Pages: 3704-3704
  • DOI: 10.1038/ncomms4704
  • Peer Reviewed / Open Access
• [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 Issue: 10 Pages: 2082-97
  • DOI: 10.1016/j.jmb.2014.03.006
  • Peer Reviewed / Open Access
• [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 Issue: 14 Pages: 2238-49
  • DOI: 10.1182/blood-2012-08-450403
  • Peer Reviewed / Open Access
• [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 RA, Liu F, Hu Y, Baba Y, Theodore P, Kurosaki T, Lowell CA.
  • Journal Title: Blood Volume: in press
  • 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 Volume: 39 Issue: 2 Pages: 136-147
  • DOI: 10.1016/j.molimm.2013.10.006
  • Peer Reviewed / Open Access
• [Journal Article] Surf4 modulates STIMl-dependent calcium entry. (2012)
  • Author(s): Fujii y Baba Y
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 422 Pages: 615-620
  • Peer Reviewed
• [Presentation] Regulatory function of B cells in autoimmune inflammation. (2016)
  • Author(s): 馬場義裕
  • Organizer: 生医研セミナー
  • Place of Presentation: 九州大学
  • Year and Date: 2016-02-18
  • Invited
• [Presentation] Regulatory function of B cells in autoimmune inflammation (2016)
  • Author(s): 馬場義裕
  • Organizer: The 7th IFReC International Symposium "Immunology at the Forefront"
  • Place of Presentation: Grand Front Osaka
  • Year and Date: 2016-01-22
  • Int'l Joint Research / Invited
• [Presentation] 炎症を制御するIL-10産生B細胞の誘導機序 (2015)
  • Author(s): 馬場義裕
  • Organizer: 第43回日本臨床免疫学総会
  • Place of Presentation: 神戸国際会議場、神戸
  • Year and Date: 2015-10-22
  • Invited
• [Presentation] B細胞ストア作動性カルシウム流入による自己免疫性炎症反応の制御機構 (2015)
  • Author(s): 馬場義裕
  • Organizer: 日本薬学会第135回年会
  • Place of Presentation: 神戸学院大学（兵庫県、神戸）
  • Year and Date: 2015-03-27
  • Invited
• [Presentation] B細胞におけるSOCEの生理的役割 (2013)
  • Author(s): 馬場義裕
  • Organizer: 第90回日本生理学会大会シンポジウム
  • Place of Presentation: タワーホール船堀, 東京(招待講演)
  • Year and Date: 2013-03-28
• [Presentation] The mechanism of calcium influx induced by ER calcium sensor STIM and its physiological function (2012)
  • Author(s): 馬場義裕
  • Organizer: 第85回日本生化学学会大会シンポジウム
  • Place of Presentation: 福岡国際会議場, 福岡(招待講演)
  • Year and Date: 2012-12-14
• [Presentation] Physiological significance for Calcium Influx in B cell (2012)
  • Author(s): 馬場義裕
  • Organizer: 第40回日本臨床免疫学会シンポジウム
  • Place of Presentation: 京王プラザホテル, 東京(招待講演)
  • Year and Date: 2012-09-27
• [Book] B細胞ストア作動性カルシウム流入による自己免疫性炎症反応の制御機構 (2016)
  • Author(s): 馬場義裕
  • Total Pages: 5
  • Publisher: 薬学雑誌
• [Book] The Frontiers in Life Sciences B細胞による腫瘍制御 (2015)
  • Author(s): 馬場義裕
  • Total Pages: 10
  • Publisher: 南山堂
• [Book] 実験医学増刊号 自己免疫疾患: IL-10産生B細胞による自己免疫疾患の制御 (2015)
  • Author(s): 馬場義裕
  • Total Pages: 5
  • Publisher: 羊土社
• [Book] First Author's (2014)
  • Author(s): 松本真典、黒崎知博、馬場義裕
  • Total Pages: 1
  • Publisher: ライフサイエンス新着論文レビュー
• [Book] 臨床免疫・アレルギー科 (2013)
  • Author(s): 馬場義裕
  • Total Pages: 5
  • Publisher: 科学評論社
• [Book] YAKUGAKU ZASSHI (2013)
  • Author(s): 松本真典、馬場義裕
  • Total Pages: 7
  • Publisher: 日本薬学会