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Immunosenescent colitogenic CD4^+ T cells convert to regulatory cells and suppress colitis

Research Project

Project/Area Number 19590718
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

TOTUKA Teruji  Tokyo Medical and Dental University, 医学部附属病院, 助教 (70447465)

Co-Investigator(Kenkyū-buntansha) WATANABE Mamoru  東京医科歯科大学, 大学院・医歯学総合研究科・消化器病態学, 教授 (10175127)
KANAI Takanori  慶應義塾大学, 内科, 准教授 (40245478)
ARAKI Akihiro  東京医科歯科大学, 医学部附属病院, 助教 (80361690)
Co-Investigator(Renkei-kenkyūsha) WATANABE Mamoru  東京医科歯科大学, 大学院・医歯学総合研究科, 消化器病態学 (10175127)
KANAI Takanori  慶應義塾大学, 内科, 准教授 (40245478)
ARAKI Akihiro  東京医科歯科大学, 医学部附属病院, 助教 (80361690)
Project Period (FY) 2007 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Keywords加齢化免疫記憶CD4^+T細胞 / 炎症性腸疾患 / マウスモデル / 新規治療法 / 老化CD4+T細胞 / 制御性T細胞 / 腸炎惹起生免疫記憶T細胞 / マウス大腸炎モデル / 加齢化免疫記憶T細胞 / 抑制性T細胞
Research Abstract

炎症性腸疾患の病因として炎症惹起性CD4^+T細胞が広く知られているが、長期生存した腸炎惹起性CD4^+T細胞がどのような形質を獲得するかは未だ不明である。そこで我々は、CD4^+CD45RB^(high)移入大腸炎を作製し、大腸炎を発症したマウスの大腸より取り出したlaminapropria(LP)CD4^+T細胞を再度免疫不全マウスの腹腔内に移入、LPCD4^+T細胞移入を繰り返す事により長期生存炎症惹起性CD4^+T細胞を作製、この細胞の機能について検討した。
大腸炎を発症したマウスの大腸より取り出したLPCD4^+T細胞を再度免疫不全マウスの腹腔内に移入、LPCD4^+T細胞移入を繰り返し、大腸炎の発症を経時的に検討した。また、同時にIFN-γ、TNF-α、IL-17などのTh1、Th17サイトカインの産生能を検討した。次にLPCD4^+T細胞移入を繰り返し7世代で腸炎未発症マウスのLPCD4^+T細胞、1世代で腸炎を発症したマウスのLPCD4^+T細胞をnaive CD4^+CD45RB^(high)T細胞と共移入し、腸炎抑制能を検討した。
LPCD4^+T細胞移入を繰り返すことで、腸炎発症までの期間が延長し、6世代までは全例腸炎を発症したが7世代以降は腸炎未発症マウスが出現し大腸炎発症率も減少した。また、7世代マウスは、Th1、Th17サイトカイン産生が低下した。1世代LPCD4^+T細胞を共移入した群は腸炎を発症したが、腸炎未発症7世代LPCD4^+T細胞を共移入した群は腸炎を発症しなかった。
これは、病的CD4^+T細胞が、その病的CD4^+T細胞を抑制する制御性CD4^+T細胞に変化したことを示した画期的な業績である。

Report

(3 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • Research Products

    (34 results)

All 2008 2007

All Journal Article (23 results) (of which Peer Reviewed: 23 results) Presentation (11 results)

  • [Journal Article] Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis2008

    • Author(s)
      Totsuka T, Kanai T, Nemoto Y, Tomita T, Tsuchiya K, Sakamoto N, Okamoto R,Watanabe M
    • Journal Title

      Eur J Immunol 38(5)

      Pages: 1275-1286

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Colitogenic CD4+ effector-memory T cells actively recirculate in chronic coliti0c mice2008

    • Author(s)
      Tomita T, Kanai T, Nemoto Y, Fujii T, Nozaki K, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Totsuka T, Watanabe M
    • Journal Title

      Inflamm Bowel Dis 14(12)

      Pages: 1630-1640

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Negative feedback regulation of colitogenic CD4(+) T cells by increased granulopoiesis2008

    • Author(s)
      Nemoto Y, Kanai T, Tohda S, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M
    • Journal Title

      Inflamm Bowel Dis 14(11)

      Pages: 1491-1503

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Continuous generation of colitogenic CD4(+) Tcells in persistent colitis2008

    • Author(s)
      Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Watanabe M
    • Journal Title

      Eur J Immunol 38(5)

      Pages: 1264-1274

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis2008

    • Author(s)
      Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M
    • Journal Title

      J Immunol 180(8)

      Pages: 5291-5299

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis2008

    • Author(s)
      Tomita T, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Sakamoto N, Watanabe M
    • Journal Title

      J Immunol 180(1)

      Pages: 383-390

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis2008

    • Author(s)
      Ito Y, Kanai T, Totsuka T, Okamoto R, Tsuchiya K, Nemoto Y, Yoshioka A, Tomita T, Nagaishi T, Sakamoto N, Sakanishi T, Okumura K, Yagita H, Watanabe M
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol 294(1)

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Immunosenescent colitogenic CD4(+)T cells convert to regulatory cell sand suppress colitis.2008

    • Author(s)
      Totsuka T, Kanai T, Nemoto Y, Tomita T, Tsuchiya K, Sakamoto N, Okamoto R, Watanabe M
    • Journal Title

      Eur J Immunol. 38(5)

      Pages: 1275-1286

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Colitogenic CD4+effector-memory T cells actively recirculate in chroniccolitic mice.2008

    • Author(s)
      Tomita T, Kanai T, Nemoto Y, Fujii T, Nozaki K, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Totsuka T, Watanabe M
    • Journal Title

      Inflamm Bowel Dis 14(12)

      Pages: 1630-1640

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Negative feedback regulation of colitogenic CD4(+)T cells by increased granulopoiesis.2008

    • Author(s)
      Nemoto Y, Kanai T, Tohda S, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M
    • Journal Title

      Inflamm Bowel Dis 14(11)

      Pages: 1491-1503

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Continuous generation of colitogenic CD4(+)T cells in persistent colitis.2008

    • Author(s)
      Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Watanabe M
    • Journal Title

      Eur J Immunol. 38(5)

      Pages: 1264-1274

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+T cells in chronic colitis.2008

    • Author(s)
      Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M
    • Journal Title

      J Immunol. 180(8)

      Pages: 5291-5299

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Systemic, but not intestinal. IL-7 is essential for the persistence of chroniccolitis.2008

    • Author(s)
      Tomita T, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Sakamoto N, Watanabe M
    • Journal Title

      J Immunol. 180(1)

      Pages: 383-390

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+Tcell-mediated colitis.2008

    • Author(s)
      Ito Y, Kanai T, Totsuka T, Okamoto R, Tsuchiya K, Nemoto Y, Yoshioka A, Tomita T, Nagaishi T, Sakamoto N, Sakanishi T, Okumura K, Yagita H, Watanabe M
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol. 294(1)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Immunosenescent colitogenic CD4^+ T cells convert to regulatory cells and suppress colitis.2008

    • Author(s)
      Teruji T
    • Journal Title

      European journal of immunology (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis.2008

    • Author(s)
      Tomita T, Totsuka T
    • Journal Title

      Journal of immunology 180(1)

      Pages: 383-390

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis.2008

    • Author(s)
      Ito Y, Totsuka T
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol. 294(1)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation2007

    • Author(s)
      Makita S, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Yamamoto M, Kiyono H, Watanabe M
    • Journal Title

      J Immunol 178(8)

      Pages: 4937-4946

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] IL-7 Is essential for the development and the persistence of chronic colitis2007

    • Author(s)
      Totsuka T, Kanai T, Nemoto Y, Makita S, Okamoto R, Tsuchiya K, Watanabe M
    • Journal Title

      J Immunol 178(8)

      Pages: 4737-4748

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis2007

    • Author(s)
      Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Takeda K, Watanabe M
    • Journal Title

      Gastroenterology 132(1)

      Pages: 176-189

    • NAID

      40015644486

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Extracorporeal elimination of TNF-alpha-producing CD14(dull)CD16(+) monocytes in leukocytapheresis therapy for ulcerative colitis2007

    • Author(s)
      Kanai T, Makita S, Kawamura T, Nemoto Y, Kubota D, Nagayama K, Totsuka T, Watanabe M
    • Journal Title

      Inflamm Bowel Dis 13(3)

      Pages: 284-290

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation.2007

    • Author(s)
      Makita S, Totsuka T
    • Journal Title

      Journal of immunology 178(8)

      Pages: 4937-4946

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IL-7 Is essential for the development and the persistence of chronic colitis.2007

    • Author(s)
      Totsuka T
    • Journal Title

      Journal of immunology 178(8)

      Pages: 4737-4748

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] Colitogenic CD4+ T Cells convert to regulatory cells to suppress colitis in the process of the immunosenescence2008

    • Author(s)
      Totsuka T, Kanai T Nemoto Y, Tomita T, Watanabe M
    • Organizer
      DDW 2008
    • Place of Presentation
      San Diego
    • Year and Date
      2008-05-20
    • Related Report
      2008 Final Research Report
  • [Presentation] Colitogenic CD4+ T Cells convert to regulatory cells to suppress colitis in the process of the immunosenescence.2008

    • Author(s)
      Totsuka T, Kanai T Nemoto Y, Tomita T, Watanabe M
    • Organizer
      DDW 2008
    • Place of Presentation
      San Diego
    • Year and Date
      2008-05-20
    • Related Report
      2008 Annual Research Report
  • [Presentation] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis2007

    • Author(s)
      Tomita T, Kanai T, Nemoto Y, Fujii T,Shinohara T, Kameyama K, Totsuka T, Watanabe M
    • Organizer
      日本免疫学会総会・学術集会
    • Place of Presentation
      東京
    • Year and Date
      2007-11-22
    • Related Report
      2008 Final Research Report
  • [Presentation] IL-7 is essential for the development and the persistence of chronic colitis2007

    • Author(s)
      Totsuka T, Kanai T, Nemoto Y, Tomita T, Makita S, Watanabe M
    • Organizer
      ICMI2007
    • Place of Presentation
      東京
    • Year and Date
      2007-07-11
    • Related Report
      2008 Final Research Report
  • [Presentation] Uniqueness of colitogenic lamina propria CD4+ T cells for the perpetuation of colitis2007

    • Author(s)
      Kanai T, Nemoto Y, Shinohara T, Fujii T, Ito Y, Tomita T, Okamoto R, Tsuchiya K, Totsuka T, Watanabe M
    • Organizer
      ICMI2007
    • Place of Presentation
      東京
    • Year and Date
      2007-07-11
    • Related Report
      2008 Final Research Report
  • [Presentation] Bone marrow is a reservoir for persistent colitogenic CD + TEM cells in IL-7 dependent manner2007

    • Author(s)
      Nemoto Y, Kanai T, Makita S, Totsuka T, Watanabe M
    • Organizer
      ICMI2007
    • Place of Presentation
      東京
    • Year and Date
      2007-07-11
    • Related Report
      2008 Final Research Report
  • [Presentation] IL-7 is essential for the development and persistence of chronic colitis2007

    • Author(s)
      Totsuka T, Kanai T, Nemoto Y, Tomita T, Makita S, Totsuka T, Watanabe M
    • Organizer
      DDW 2007
    • Place of Presentation
      Washington.D.C
    • Year and Date
      2007-05-22
    • Related Report
      2008 Final Research Report
  • [Presentation] Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis2007

    • Author(s)
      Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Watanabe M
    • Organizer
      DDW 2007
    • Place of Presentation
      Washington.D.C
    • Year and Date
      2007-05-22
    • Related Report
      2008 Final Research Report
  • [Presentation] Ameliorating effect of anti-NKG2D in CD4+ cell-mediated murine model of chronic colitis2007

    • Author(s)
      Ito Y, Kanai T, Fujii Y, Nemoto Y, Makita S, Totsuka T, Tsuchiya K, Yagita H, Watanabe M
    • Organizer
      DDW 2007
    • Place of Presentation
      Washington.D.C
    • Year and Date
      2007-05-21
    • Related Report
      2008 Final Research Report
  • [Presentation] Continuous recirculation of colitogenic CD4+ T cells may be required for perpetuation of chronic colitis2007

    • Author(s)
      Tomita T, Kanai T, Fujii Y, Nemoto Y, Makita S, Totsuka T, Watanabe M
    • Organizer
      DDW 2007
    • Place of Presentation
      Washington.D.C
    • Year and Date
      2007-05-21
    • Related Report
      2008 Final Research Report
  • [Presentation] Blockade of TNF-α inhibits tumor progression in colitis-associated cancer2007

    • Author(s)
      Onizawa M, Kanai T, Nemoto Y, Oshima S, Makita S, Okamoto R, Totsuka T, Yagita H, Watanabe M
    • Organizer
      DDW 2007
    • Place of Presentation
      Washington.D.C
    • Year and Date
      2007-05-20
    • Related Report
      2008 Final Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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