Mechanisms for induction and regulation of memory B cell subsets exhibiting distinct recall responses

• Project/Area Number: 20K21533
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• 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)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
• Keywords: 記憶B細胞 / 免疫応答 / リコール応答 / 形質細胞 / 自己免疫疾患 / 胚中心B細胞 / 免疫記憶 / 分化誘導

Outline of Research at the Start

ウィルス等の抗原が体内に侵入すると、B細胞はそれに対する抗体を産生するとともに、記憶B細胞に分化し永く生存する。再び侵入した同じ抗原に出会うと、記憶B細胞は形質細胞に分化して抗体を産生するか、胚中心B細胞に分化し記憶B細胞を再生する。この2種類のリコール応答は2つの異なる記憶B細胞サブセットに担われているが、初回の免疫応答においてこれらのサブセットへの分化運命はB細胞が受けるCD40シグナルの量により決定される。本研究では、このCD40刺激の量的違いが生む異なる細胞内分子経路を見出し、任意の記憶B細胞サブセットを優位に誘導できるワクチン方法の開発をめざす。

Outline of Final Research Achievements

In the immune response to external antigens, responding B cells differentiate into memory B (Bmem ) cells, mostly through germinal centers (GCs), and are maintained in the body for a long period. Upon reencounter with the same antigens, Bmem cells mostly differentiate to plasma cells and produce antibodies, while some Bmem cells differentiate to GC B cells and regenerate Bmem cells, as shown in mice. The two ways of the ‘recall’ responses are mainly caused by CD80-high and CD80-low Bmem cell subsets, respectively. We recently found that differentiation toward these two subsets is determined by the strength of CD40 signaling in B cells during the primary immune response. In this study, we sought to elucidate the mechanisms for the induction, maintenance, and recall-response regulation of these Bmem cell subsets as well as of Bmem cells that generate plasma cells to produce autoantibodies in autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究により、初回接種時に2つのBmem細胞サブセットの産生を調節することで、二次免疫あるいは感染時に抗体産生とBmem細胞再産生のバランスが予測できる新たなワクチンの開発が可能となる。また、自己免疫疾患において、自己反応性Bmem細胞の形質細胞への分化あるいはBmem細胞維持を阻害する治療に応用が可能となる。具体的には、自己免疫モデルマウスにおいて、自己反応性Bmem細胞が交差反応性の口腔内共生細菌に反応して形質細胞へ分化することが明らかになった。自己抗体が交差反応するこの細菌と自己抗原との共通エピトープを同定すれば、自己反応性Bmem細胞の選択的制御が可能となる。

Research Products

• [Journal Article] Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nep (2023)
  • Author(s): Nihei, Y., Haniuda, K., Higashiyama, M., Asami, S., Iwasaki, H., Fukao, Y., Nakayama, M., Suzuki, H., Kikkawa, M., Kazuno, S., Miura, Y., Suzuki, Y., Kitamura, D.
  • Journal Title: Science Advances Volume: 9 Issue: 12
  • DOI: 10.1126/sciadv.add6734
  • Peer Reviewed / Open Access
• [Journal Article] Commensal bacteria and the lung environment are responsible for Th2-mediated memory yielding natural IgE in MyD88-deficient mice. (2023)
  • Author(s): Amano, S., Haniuda, K., Fukao, S., Aoki, H., Ueha, S., Kitamura, D.
  • Journal Title: Journal of Immunology Volume: 210 Issue: 7 Pages: 959-972
  • DOI: 10.4049/jimmunol.2200888
  • Peer Reviewed
• [Journal Article] cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells (2022)
  • Author(s): Fukushima Yuji、Sakamoto Keiko、Matsuda Michiyuki、Yoshikai Yasunobu、Yagita Hideo、Kitamura Daisuke、Chihara Misaki、Minato Nagahiro、Hattori Masakazu
  • Journal Title: Cell Reports Volume: 40 Issue: 12 Pages: 111373-111373
  • DOI: 10.1016/j.celrep.2022.111373
  • Peer Reviewed / Open Access
• [Journal Article] RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling. (2022)
  • Author(s): Kuhn LB, Valentin S, Stojanovic K, Strobl DC, Babushku T, Wang Y, Rambold U, Scheffler L, Grath S, John-Robbert D, Blum H, Feuchtinger A, Blutke A, Weih F, Kitamura D, Rad R, Strobl LJ, Zimber-Strobl U.
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 913275-913275
  • DOI: 10.3389/fimmu.2022.913275
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment. (2022)
  • Author(s): Fu, Y., Wang, J., Zhou, B., Pajulas, A., Gao, H., Ramdas, B., Koh, B., Ulrich, B.J., Yang, S., Kapur, R., Renauld, J.-C., Paczesny, S., Liu, Y., Tighe, R.M., Licona-Limon, P., Flavell, R.A., Takatsuka, S., Kitamura, D., Tepper, R.S., Sun, J., and Kaplan, M.H.
  • Journal Title: Science Immunology Volume: 7 Issue: 68
  • DOI: 10.1126/sciimmunol.abi9768
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Integrin CD11b provides a new marker of pre-germinal center IgA+ B cells in murine Peyer's patches. (2022)
  • Author(s): Gao P, Adachi T, Okai S, Morita N, Kitamura D, Shinkura R.
  • Journal Title: International Immunology Volume: 34 Issue: 5 Pages: 249-262
  • DOI: 10.1093/intimm/dxab113
  • Peer Reviewed / Open Access
• [Journal Article] Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria. (2021)
  • Author(s): Fukao, S., Haniuda, K., Tamaki, H. and Kitamura, D.
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.72116
  • Peer Reviewed / Open Access
• [Journal Article] C/EBPβ induces B‐cell acute lymphoblastic leukemia and cooperates with <i>BLNK</i> mutations (2021)
  • Author(s): Kurata Morito、Onishi Iichiro、Takahara Tomoko、Yamazaki Yukari、Ishibashi Sachiko、Goitsuka Ryo、Kitamura Daisuke、Takita Junko、Hayashi Yasuhide、Largaesapda David A、Kitagawa Masanobu、Nakamura Takuro
  • Journal Title: Cancer Science Volume: 112 Issue: 12 Pages: 4920-4930
  • DOI: 10.1111/cas.15164
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-directed pathway discovery elucidates an miR-221/222-mediated regulatory circuit in class switch recombination. (2021)
  • Author(s): Wigton, E.J., Mikami, Y., McMonigle, R.J., Castellanos, C.A., Wade-Vallance, A.K., Zhou, S.K., Kageyama, R., Litterman, A., Roy, S., Kitamura, D., Dykhuizen, E.C., Allen, C.D.C., Hu, H., O'Shea, J.J., Ansel, K.M.
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 11
  • DOI: 10.1084/jem.20201422
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanisms for the regulation of memory B-cell recall responses in mice. (2021)
  • Author(s): Kitamura, D.
  • Journal Title: International Immunology Volume: 33 Issue: 12 Pages: 791-796
  • DOI: 10.1093/intimm/dxab042
  • Peer Reviewed / Open Access
• [Journal Article] Multi-faceted regulation of IgE production and humoral memory formation (2021)
  • Author(s): Haniuda, K. and Kitamura, D.
  • Journal Title: Allergology International Volume: 70 Issue: 2 Pages: 163-168
  • DOI: 10.1016/j.alit.2020.11.002
  • NAID: 130008024333
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] A novel cancer immunotherapy using tumor-infiltrating B cells in the APCmin/+ mouse model. (2021)
  • Author(s): Wang X., Asami, S. and Kitamura D.
  • Journal Title: PLoS ONE Volume: 16 Issue: 1 Pages: e0245608-e0245608
  • DOI: 10.1371/journal.pone.0245608
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic reprogramming induces germinal center B cell differentiation through Bcl6 locus remodeling. (2020)
  • Author(s): Haniuda, K., Fukao, S. and Kitamura, D.
  • Journal Title: Cell Reports Volume: 33 Issue: 5 Pages: 108333-108333
  • DOI: 10.1016/j.celrep.2020.108333
  • Peer Reviewed / Open Access
• [Journal Article] Tracing self-reactive B cells in normal mice. (2020)
  • Author(s): Nojima, T., Reynolds, A.E., Kitamura, D., Kelsoe, G. and Kuraoka, M.
  • Journal Title: The Journal of Immunology Volume: 205 Issue: 1 Pages: 90-101
  • DOI: 10.4049/jimmunol.1901015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation (2020)
  • Author(s): Kodama Tadahiro、Hasegawa Mika、Sakamoto Yui、Haniuda Kei、Kitamura Daisuke
  • Journal Title: International Immunology Volume: - Issue: 6 Pages: 385-395
  • DOI: 10.1093/intimm/dxaa009
  • Peer Reviewed
• [Presentation] Identification of IgA autoantibodies against glomerular mesangial cells and the target autoantigen using an IgA nephropathy mouse model (2022)
  • Author(s): Yoshihito Nihei, Kei Haniuda, Mizuki Higashiyama, Hiroyuki Iwasaki, Shohei Asami, Yusuke Suzuki, Daisuke Kitamura
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] A mechanism for anti-mesangium IgA production in an IgA nephropathy mouse model (2022)
  • Author(s): Mizuki Higashiyama, Kei Haniuda, Yoshihito Nihei, Riku Hisato, Daisuke Kitamura
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Pathogenic antibody production by microbiota in an IgA nephropathy mouse model. (2021)
  • Author(s): 北村大介
  • Organizer: 5th Symposium of the International Immunological Memory and Vaccine Forum
  • Int'l Joint Research / Invited
• [Presentation] IgA腎症におけるIgA自己抗体産生 (2021)
  • Author(s): 北村大介、二瓶義人、東山瑞希、岩崎裕幸、久斗陸、羽生田圭、鈴木祐介
  • Organizer: 第85回日本インターフェロン・サイトカイン学会学術集会
  • Invited
• [Presentation] B細胞におけるIgE産生制御 (2021)
  • Author(s): 北村大介
  • Organizer: 第7回総合アレルギー講習会
  • Invited
• [Patent(Industrial Property Rights)] IgA腎症に関連する自己抗体 (2021)
  • Inventor(s): 北村大介，鈴木祐 介，二瓶義人
  • Industrial Property Rights Holder: 北村大介，鈴木祐 介，二瓶義人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas