Role of memory T helper cells in vivo

• Project/Area Number: 22689014
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: TOKOYODA Koji 千葉大学, 大学院・医学研究院, 講師 (20362402)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥21,840,000 (Direct Cost: ¥16,800,000、Indirect Cost: ¥5,040,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2010: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: 免疫記憶 / ヘルパーT細胞 / 骨髄 / 二次免疫反応 / 抗原提示細胞 / 自己免疫 / CD69 / プラズマ細胞

Research Abstract

We focused on CD69 which is known as an activation marker, because resting memory T helper cells expressed it in the bone marrow and clarified the essential role of CD69 in relocation of splenic effector T helper cells to the bone marrow by using CD69-deficient mice which our laboratory generated. Moreover, we also found the sufficient role of CD49b, also called as integrin alpha2, in their relocation by using CD49b-deficient mice (in revision). These data suggest that effector T helper cells expressing both CD69 and CD49b from the secondary lymphoid organs relocate to the bone marrow by a two-step process.
To examine roles of bone marrow memory T helper cells, we evaluated humoral immune response of CD69-deficient mice which lacks them. CD69-deficient mice have a marked reduction of production of high-affinity antibodies and generation of long-lived plasma cells in the bone marrow, although they normally produced antibodies and generate splenic plasmablasts in the early phase of an immune response. The reduction was due to a defective help of bone marrow memory T helper cells for homing of plasmablasts to the bone marrow. Since this helper function is antigen-dependent, the data suggests a fact of T-B interaction via T-cell receptor/MHC class II. Since CD69-deficient mice can normally generate follicular helper T cells and germinal center B cells, this help for B lineages is a novel role of bone marrow memory T helper cells after germinal center reaction. We are identifying the essential candidates for this T-cell help and the studies will contribute the understanding of T helper cell memory.

Research Products

• [Journal Article] Type II membrane protein CD69 regulates the formation of resting T-helper memory (2012)
  • Author(s): Shinoda, K., Tokoyoda, K., Hanazawa, A., Hayashizaki, K., Zehentmeier, S., Hosokawa, H., Iwamura, C, Koseki, H., Tumes, D.J., Radbruch, A., Nakayama T.
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: (in press) Issue: 19 Pages: 7409-7414
  • DOI: 10.1073/pnas.1118539109
  • Peer Reviewed
• [Journal Article] Signals controlling rest and reactivation of T helper memory lymphocytes in bone marrow. (2012)
  • Author(s): Tokoyoda, K., Radbruch, A.
  • Journal Title: Cell. Mol. Life Sci. Volume: 69 Issue: 10 Pages: 1609-1613
  • DOI: 10.1007/s00018-012-0969-6
  • Peer Reviewed
• [Journal Article] Eomesodermin controls interleukin-5 production in memory T helper 2 cells through inhibition of activity of the transcription factor GATA3 (2011)
  • Author(s): Endo, Y., Iwamura, C., Kuwahara, M., Suzuki, A., Sugaya, K., Tumes, J. D., Tokoyoda, K. Hosokawa, H., Yamashita, M. Nakayama, T
  • Journal Title: Immunity Volume: 35 Issue: 5 Pages: 733-745
  • DOI: 10.1016/j.immuni.2011.08.017
  • Peer Reviewed
• [Journal Article] IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation (2011)
  • Author(s): Takahashi, K., Hirose, K., Kawashima, S., Niwa, Y., Wakashin, H., Iwata, A., Tokoyoda, K., Renauld, J.-C., Iwamoto, I. and Nakayama, T., Nakajima, H.
  • Journal Title: J. Allergy Ciln. Immunol Volume: 128 Pages: 1067-1076
  • Peer Reviewed
• [Journal Article] IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation (2011)
  • Author(s): Takahashi, K., Hirose, K., Kawashima, S., Niwa, Y., Wakashin, H., Iwata, A., Tokoyoda, K., Renauland Nakad, J.-C., Iwamoto, I., Nakayama, T. Nakajima, H
  • Journal Title: J. Allergy Ciln. Immunol Volume: 128 Issue: 5 Pages: 1067-1076
  • DOI: 10.1016/j.jaci.2011.06.018
  • Peer Reviewed
• [Journal Article] Persistence of effector memory Th1 cells is regulated by the homeobox protein Hopx (2010)
  • Author(s): Albrecht, I., Niesner, U., Janke, M., Menning, A., Loddenkemper, C., Kuhl, A.A., Lepenies, I., Lexberg, M.H., Westendorf, K., Hradilkova, K., Grun, J., Hamann, A., Epstein, J.A., Chang, H.D., Tokoyoda, K. and Radbruch, A.
  • Journal Title: Eur. J. Immunol Volume: 40 Issue: 11 Pages: 2993-3006
  • DOI: 10.1002/eji.201040936
  • Peer Reviewed
• [Journal Article] Persistence of effector memory Th1 cells is regulated by Hopx. (2010)
  • Author(s): Albrecht, I
  • Journal Title: European Journal of Immunology Volume: 40 Pages: 2993-3006
  • Peer Reviewed
• [Presentation] CD69 regulates the formation of resting T-helper memory. (2012)
  • Author(s): Shinoda, K., Tokoyoda, K., Hanazawa, A., Hayashizaki, K., Hosokawa, H., Iwamura, C., Koseki, H., Tumes, D., Radbruch, A., Nakayama, T.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2012-12-06
• [Presentation] CD69 regulates the formation of resting T-helper memory. (2012)
  • Author(s): Shinoda, K., Tokoyoda, K., Hanazawa, A., Hayashizaki, K., Nakayama, T.
  • Organizer: 34^<th> NAITO CONFERENCE on Infection, Immunity, and their control for Health.
  • Place of Presentation: 札幌
  • Year and Date: 2012-10-18
• [Presentation] Generation and maintenance of memory CD4 T cells. (2012)
  • Author(s): Nakayama, T., Endo, Y., Kuwahara, M., Yamashita, M., Iwamura, C., Shinoda, K., Tokoyoda, K.
  • Organizer: 34^<th> NAITO CONFERENCE on Infection, Immunity, and their control for Health.
  • Place of Presentation: 札幌
  • Year and Date: 2012-10-18
• [Presentation] CD69 and CD49b regulate the establishment and maintenance of T helper cell memory (2012)
  • Author(s): Tokoyoda, K., Hanazawa, A., Shinoda, K., Radbruch, A., Nakayama, T.
  • Organizer: 3rd European Congress of Immunology
  • Place of Presentation: Glasgow, Scotland.
  • Year and Date: 2012-09-06
• [Presentation] CD69 and CD49b regulate the establishment and maintenance of T helper cell memory. (2012)
  • Author(s): Tokoyoda, K., Hanazawa, A., Shinoda, K., Radbruch, A., Nakayama, T.
  • Organizer: 3^<rd> European Congress of Immunology
  • Place of Presentation: Glasgow, Scotland
  • Year and Date: 2012-09-06
• [Presentation] helper cell memory in bone marrow (2012)
  • Author(s): Tokoyoda, K. Resting T
  • Organizer: Joint Henry Kunkel Society and IMPAM meeting (招待講演)
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-06-05
• [Presentation] Resting T helper cell memory in bone marrow. (2012)
  • Author(s): Tokoyoda, K.
  • Organizer: Joint Henry Kunkel Society and IMPAM meeting
  • Place of Presentation: Berlin, Germany(招待講演)
  • Year and Date: 2012-06-05
• [Presentation] Resting T helper cell memory in bone marrow. (2012)
  • Author(s): Tokoyoda, K.
  • Organizer: 3rd International Synthetic Immunology Workshop (招待講演)
  • Place of Presentation: 京都
  • Year and Date: 2012-05-18
• [Presentation] Resting T helper cell memory in bone marrow. (2012)
  • Author(s): Tokoyoda, K.
  • Organizer: 3^<rd> International Synthetic Immunology Workshop
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2012-05-18
• [Presentation] CD69 regulates the formation of resting T-helper memory (2012)
  • Author(s): Shinoda, K., Tokoyoda, K., Hanazawa, A., Hayashizaki, K., Hosokawa, H., Iwamura, C., Koseki, H., Tumes, D., Radbruch, A., and Nakayama, T.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸
• [Presentation] CD69 regulates the formation of resting T-helper memory (2012)
  • Author(s): Shinoda, K., Tokoyoda, K., Hanazawa, A., Hayashizaki, K., and Nakayama, T.
  • Organizer: THE 34th NAITO CONFERENCE ON Infection, Immunity, and their control for Health
  • Place of Presentation: Sapporo
• [Presentation] Generation and maintenance of memory CD4 T cells (2012)
  • Author(s): Nakayama, T., Endo, Y., Kuwahara, M., Yamashita, M., Iwamura, C., Shinoda, K., and Tokoyoda, K.
  • Organizer: THE 34th NAITO CONFERENCE ON Infection, Immunity, and their control for Health.(招待講演)
  • Place of Presentation: Sapporo
• [Presentation] 骨髄におけるTヘルパ.記憶の成立 (2011)
  • Author(s): 常世田好司、篠田健太、花澤麻美、林崎浩史、Andreas Radbruch、中山俊憲
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-28
• [Presentation] 骨髄におけるTヘルパー記憶の成立/Establishment of T helper memory in bone marrow (2011)
  • Author(s): Tokoyoda, K., Shinoda, K., Hanazawa, A., Hayashizaki, K., Radbruch, A., Nakayama, T.
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張
  • Year and Date: 2011-11-28
• [Presentation] 多発性筋炎マウスモデルにおける肥満細胞の役割の解析 (2011)
  • Author(s): 横田雅也、鈴木浩太郎、中込大樹、岩田有史、常世田好司、中山俊憲、上阪等、中島裕史
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-27
• [Presentation] 多発性筋炎マウスモデルにおける肥満細胞の役割の解析/Crucial roles of mast cells in a murine model of polymyositis (2011)
  • Author(s): 横田雅也、鈴木浩太郎、中込大樹、岩田有史、常世田好司、中山俊憲、上阪等、中島裕史
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張
  • Year and Date: 2011-11-27
• [Presentation] IL-22は気道上皮細胞によるIL-25産生を抑制し、アレルギ.性気道炎症を制御する (2011)
  • Author(s): 高橋健太郎、廣瀬晃一、川島沙紀、丹羽祐輔、若新英史、岩田有史、小林芳久、常世田好司、中山俊憲、谷口正実、秋山一男
  • Organizer: 第61回日本アレルギ. 学会秋季学術大会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-11
• [Presentation] IL-22は気道上皮細胞によるIL-25産生を抑制し、アレルギー性気道炎症を制御する (2011)
  • Author(s): 高橋健太郎、廣瀬晃一、川島沙紀、丹羽祐輔、若新英史、岩田有史、小林芳久、常世田好司、中山俊憲、谷口正実、秋山一男
  • Organizer: 第61回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-11
• [Presentation] 骨髄と免疫記憶 (2011)
  • Author(s): 常世田好司
  • Organizer: 第20回日本バイオイメージング学会学術集会(招待講演)
  • Place of Presentation: 北海道(千歳市)
  • Year and Date: 2011-09-01
• [Presentation] 骨髄と免疫記憶 (2011)
  • Author(s): 常世田好司
  • Organizer: 第20回日本バイオイメージング学会学術集会
  • Place of Presentation: 北海道(招待講演)
  • Year and Date: 2011-09-01
• [Presentation] Memory CD4 T cells reside and rest in the bone marrow (2010)
  • Author(s): 常世田好司
  • Organizer: 第40回日本免疫学会(第5回日本免疫学会研究奨励賞受賞発表)
  • Place of Presentation: 東京
  • Year and Date: 2010-12-03
• [Presentation] Memory CD4 T cells reside and rest in the bone marrow. (2010)
  • Author(s): 常世田好司
  • Organizer: 第40回日本免疫学会(第5回日本免疫学会研究奨励賞受賞発表)
  • Place of Presentation: 東京
  • Year and Date: 2010-12-03