Regulation of B lymphocyte activation by molecular interactions in glycocalyx

• Project/Area Number: 18H02610
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Tsubata Takeshi 東京医科歯科大学, 難治疾患研究所, 教授 (80197756)
• Co-Investigator(Kenkyū-buntansha): 赤津 ちづる 東京医科歯科大学, 難治疾患研究所, 助教 (60735984) ; 王 継揚 東京医科歯科大学, 難治疾患研究所, 特任講師 (80231041)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: Glycocalyx / レクチン / シスリガンド / Bリンパ球 / 免疫不全 / シグナル伝達 / シアル酸 / Siglec / CD22 / BCR / 糖鎖シスリガンド / チロシンホスファターゼ / Proximity labeling / 分化過程での制御 / CD72 / proximity labeling / CEACAM-1

Outline of Final Research Achievements

Glycans in glycoproteins and glycolipids on the cell surface form a layer rich in glycans called glycocalyx. In glycocalyx, lectins, proteins recognize specific glycans, interact with corresponding glycan ligands. In this study, we demonstrate that CD22, an inhibitory receptor and a sialic acid-binding lectin expressed in B lymphocytes, positively and negatively regulate BCR signaling by interacting with different sialic acid-containing ligands, thereby contributing to the quality control of B lymphocytes. This result suggests a crucial role of molecular interaction in glycocalyx in the regulation of cellular functions.

Academic Significance and Societal Importance of the Research Achievements

レクチンは種々の異なる糖タンパク質や糖脂質に結合し、その結合はタンパク質同士の結合に比べて弱い場合が多いため、レクチンの役割には不明な点が多い。本研究では、種々の新規ツールを駆使することで、レクチンの１つであるCD22とその糖鎖リガンドとの相互作用がどのようにCD22の機能を制御し、細胞機能を制御するかを明らかにした。このことで、レクチンと糖鎖の相互作用の重要性を明らかにするとともに、その解析法を進歩させた。また、CD22が免疫不全B細胞の機能を回復させることを明らかにしたことは、免疫不全症の新たな治療法の開発に結びつくと期待される。

Research Products

• [Int'l Joint Research] Stanford University/Duke University/UCSF(米国)
• [Int'l Joint Research] University of Erlangen(ドイツ)
• [Int'l Joint Research] University of Alberta(カナダ)
• [Journal Article] The inhibitory coreceptor CD22 restores B cell signaling by developmentally regulating <i> Cd45 ^?/? </i> immunodeficient B cells (2022)
  • Author(s): Akatsu Chizuru、Alborzian Deh Sheikh Amin、Matsubara Naoko、Takematsu Hiromu、Schweizer Astrid、Abdu-Allah Hajjaj H. M.、Tedder Thomas F.、Nitschke Lars、Ishida Hideharu、Tsubata Takeshi
  • Journal Title: Science Signaling Volume: 15 Issue: 723 Pages: 723-723
  • DOI: 10.1126/scisignal.abf9570
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of inhibitory B cell co‐receptors in B cell self‐tolerance to non‐protein antigens* (2022)
  • Author(s): Tsubata Takeshi
  • Journal Title: Immunological Reviews Volume: 307 Issue: 1 Pages: 53-65
  • DOI: 10.1111/imr.13059
  • Peer Reviewed
• [Journal Article] The Protein Tyrosine Phosphatase SHP-1 (PTPN6) but Not CD45 (PTPRC) Is Essential for the Ligand-Mediated Regulation of CD22 in BCR-Ligated B Cells (2021)
  • Author(s): Alborzian Deh Sheikh Amin、Akatsu Chizuru、Abdu-Allah Hajjaj H. M.、Suganuma Yuki、Imamura Akihiro、Ando Hiromune、Takematsu Hiromu、Ishida Hideharu、Tsubata Takeshi
  • Journal Title: The Journal of Immunology Volume: 206 Issue: 11 Pages: 2544-2551
  • DOI: 10.4049/jimmunol.2100109
  • Peer Reviewed / Open Access
• [Journal Article] A CD22?Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity (2021)
  • Author(s): Ballet Romain、Brennan Martin、Brandl Carolin、Feng Ningguo、Berri Jeremy、Cheng Julian、Oc?n Borja、Alborzian Deh Sheikh Amin、Marki Alex、Bi Yuhan、Abram Clare L.、Lowell Clifford A.、Tsubata Takeshi、Greenberg Harry B.、Macauley Matthew S.、Ley Klaus、Nitschke Lars、Butcher Eugene C.
  • Journal Title: Nature Immunology Volume: 22 Issue: 3 Pages: 381-390
  • DOI: 10.1038/s41590-021-00862-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of Siglec Cis-Ligands by Proximity Labeling (2020)
  • Author(s): Alborzian Deh Sheikh Amin、Akatsu Chizuru、Tsubata Takeshi
  • Journal Title: Methods in Molecular Biology Volume: 2132 Pages: 75-83
  • DOI: 10.1007/978-1-0716-0430-4_8
  • ISBN: 9781071604298, 9781071604304
• [Journal Article] Inhibitory B cell co-receptors and autoimmune diseases. (2019)
  • Author(s): Tsubata, T
  • Journal Title: Immunol. Med. Volume: 42 Pages: 108-116
  • Peer Reviewed / Open Access
• [Journal Article] Essential role of NADPH oxidase-dependent production of reactive oxygen species in maintenance of sustained B cell receptor signaling and B cell proliferation. (2019)
  • Author(s): Feng, Y.-y., Tang, M., Suzuki, M., Gunasekara, C., Anbe, Y., Hiraoka, Y., Liu. J., Grasberger, H., Ohkita, M., Matsumura, Y., Wang, J.-y. and Tsubata, T.
  • Journal Title: J. Immunol. Volume: 202 Pages: 2546-2557
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD22-binding synthetic sialosides regulate B lymphocyte proliferation through CD22 ligand-dependent and independent pathways, and enhance antibody production in mice. (2018)
  • Author(s): Matsubara, N., Imamura, A., Yonemizu, T., Akatsu, C., Yang, H., Ueki, A., Watanabe, N., Abdu-Allah, H., Numoto, N., Takematsu, H., Kitazume, S., Tedder, T. F., Marth, J. D., Ito, N., Ando, H., Ishida, H., Kiso, M. and Tsubata, T.
  • Journal Title: Front. Immunol. Volume: 9 Pages: 820-820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ligand recognition determines the role of inhibitory B cell co-receptors in the regulation of B cell homeostasis and autoimmunity. (2018)
  • Author(s): Tsubata, T.
  • Journal Title: Front Immunol. Volume: 9 Pages: 2276-2276
  • Peer Reviewed / Open Access
• [Presentation] 抑制性B細胞共受容体 CD22(Siglec-2) による糖鎖依 存的な免疫不全B細胞の機能回復 (2021)
  • Author(s): 赤津ちづる、Alborzian-Deh-Sheikh Amin、鍔田武志.
  • Organizer: 第 94 回日本生化学会大会
• [Presentation] The SHP-1-activating inhibitory co-receptor CD22 paradoxically augments BCR signaling in immunodeficient B cells. (2020)
  • Author(s): Chizuru Akatsu, Amin Alborzian Deh Sheikh and Takeshi Tsubata.
  • Organizer: The 14th International Conference on Protein Phosphatase
  • Int'l Joint Research
• [Presentation] Development of anti-CD22 antibody that inhibits ligand binding of CD22. (2019)
  • Author(s): Long Wang、Endo Ayaka、Takematsu Hiromu、Fedder Thomas、Tsubata Takeshi.
  • Organizer: The Regular Meeting of the Japanese Biochemical Society Kanto Branch
• [Presentation] 抑制性 B 細胞共受容体 CD72 による SLE 関連自己抗原への自己免疫応答の抑制 (2019)
  • Author(s): 赤津ちづる、遠藤萌恵、沼本修孝、Quan-Zhen Li、関根英治、藤田禎三、伊藤暢聡、鍔田武志 .
  • Organizer: 第 34 回自己免疫研究会
• [Presentation] 内因性糖鎖リガンドによる CD22/Siglec-2 の機能制御. (2019)
  • Author(s): Amin Alborzian Deh Sheikh, 赤津ちづる、鍔田武志.
  • Organizer: 第 5 回糖鎖免疫研究会
• [Presentation] The Inhibitory B Cell Co-Receptor CD72 Regulates Tolerance to Self Nucleic Acids Crucial for Development of Systemic Lupus Erythematosus. (2018)
  • Author(s): Takeshi Tsubata
  • Organizer: Keystone Symposia, B cells: Mechanisms in Immunity and Autoimmunity
  • Int'l Joint Research / Invited
• [Presentation] The role of CD22 glycan cis-ligands in the regulation of B cell tonic signaling. (2018)
  • Author(s): Amin Alborzian Deh Sheikh, Chizuru Akatsu, Hideharu Ishida and Takeshi Tsubata.
  • Organizer: The Regular Meeting of the Japanese Biochemical Society Kanto Branch
• [Presentation] The role of ligand recognition of SHP-1 activating receptor CD22 in the regulation of B cell tonic signaling. (2018)
  • Author(s): Amin Alborzian Deh Sheikh, Chizuru Akatsu, Hideharu Ishida and Takeshi Tsubata.
  • Organizer: Workshop on Frontiers in Phosphatase Research and Drug Discovery (ICPP13)
  • Int'l Joint Research
• [Presentation] Ligand recognition determines functional properties of inhibitory B cell co-receptors. (2018)
  • Author(s): Takeshi Tsuabta.
  • Organizer: International Symposium on B cells
  • Int'l Joint Research
• [Presentation] Roles of CD72 in the regulation of autoantibody production and type 1 interferon production in autoimmune disease. (2018)
  • Author(s): Chizuru Akatsu, Quan-Zhen Li, and Takeshi Tsubata
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology
• [Presentation] CD22 の糖鎖リガンドは B 細胞抗原受容体 （BCR）の機能変化依存的に CD22 の BCR 抑制機能を制御する. (2018)
  • Author(s): 赤津ちづる、Alborzian-Deh-Sheikh Amin、石田秀治、鍔田武志
  • Organizer: 第 91 回日本生化学会大会
• [Book] Identification of Siglec Cis-ligands by Proximity Labeling. In “Lectin Purification and Analysis: Methods and Protocols” ed. by Jun Hirabayashi (2020)
  • Author(s): Alborzian Deh Sheikh, A., Akatsu, C. and Tsubata, T.
  • Total Pages: 693
  • Publisher: Springer
  • ISBN: 9781071604298
• [Book] Development of Siglec Regulators. In “Glycoscience: Basic Science to Applications” ed. by Naoyuki Taniguchi, Tamao Endo, Jun Hirabayashi, Shoko Nishihara, Kenji Kadomatsu, Kazunari Akiyoshi and Kiyoko F. Aoki-Kinoshita (2019)
  • Author(s): Tsubata, T
  • Total Pages: 405
  • Publisher: Springer
  • ISBN: 9789811358562