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Colitogenic memory T cells are maintained by IL-7-producing cells in bone marrow.

Research Project

Project/Area Number 20590736
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

NEMOTO Yasuhiro  Tokyo Medical and Dental University, 大学院・医歯学総合研究科, GCOE拠点形成特任教員 (20456213)

Co-Investigator(Kenkyū-buntansha) 渡辺 守  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)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords炎症性腸疾患 / IL-7 / メモリーT細胞 / 骨髄 / 腸内細菌 / 無菌マウス / 間葉系幹細胞 / CD4^+ T細胞 / CD4^+T細胞 / CD4+T細胞
Research Abstract

The aim of this study is to clarify the maintenance system of colitogenic memory CD4^+ T cells, which posses the "pathogenic memory" of inflammatory bowel disease, and to develop the epoch-making treatment for this disease.
We have proved following things. 1) Although intestinal bacteria is essential for the development of colitis and cytokine production from effector T cells, it is not essential for the maintenance of colitogenic memory CD4^+ T cells. 2) IL-7^<-/-> x RAG-1^<-/-> mice were transplanted with BM cells of RAG-1^<-/-> (IL-7^<+/+>→IL-7^<-/->) or IL-7^<-/-> x RAG-1^<-/-> mice (IL-7^<-/->→IL-7^<-/->). IL-7 mRNA and protein were detected in BM, but not in colon, of in IL-7^<+/+>→IL-7^<-/-> mice, but not from IL-7^<-/->→IL-7^<-/-> mice. IL-7^<+/+>→IL-7^<-/->, but not IL-7^<-/->→IL-7^<-/-> recipients, transferred with CD4^+CD45RB^<high> T cells 4 weeks after transplantation, developed colitis. 3) Bone marrow mesenchymal stem cells (MSC), even over the 40^<th> passage, expressed ^<high>er levels of IL-7 mRNA and protein than those of freshly isolated IL-7^+ BM cells. 4) Co-culture with IL-7 producing MSC induced extensive proliferation of CFSE-labeled colitogenic CD4^+ T cells in vitro. 5) CD4^+CD45RB^<high> T cell-transferred IL-7^<-/-> x RAG-1^<-/-> mice previously transplanted with IL-7 producing MSC developed Th1/Th17-meidated colitis.
Collectively, IL-7 producing bone marrow MSC play the important role in the maintenance system of colitogenic memory CD4^+ T cells. These findings are the progress in the investigation of IBD pathogenesis, suggesting the possibility of novel effective treatment, which targets this system.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (51 results)

All 2011 2010 2009 2008

All Journal Article (24 results) (of which Peer Reviewed: 22 results) Presentation (26 results) Book (1 results)

  • [Journal Article] Upregulated IL-7 receptor (alpha) expression on colitogenic memory CD4+ T cells may participate in the development and persistence of chronic colitis.2011

    • Author(s)
      Shinohara T, Nemoto Y Watanabe M, et al.
    • Journal Title

      J Immunol. 186

      Pages: 2623-2632

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Upregulated IL-7 receptor(alpha)expression on colitogenic memory CD4^+ T cells may participate in the development and persistence of chronic colitis.2011

    • Author(s)
      Shinohara T, Nemoto Y, et al.
    • Journal Title

      The Journal of Immunology

      Volume: 186 Pages: 2623-2632

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IL-2 is positively involved in the development of colitogenic CD4+ IL-7R alpha high memory T cells in chronic colitis.2010

    • Author(s)
      Kameyama K, Nemoto Y, Watanabe M, et al.
    • Journal Title

      Eur J Immunol. 40

      Pages: 2423-2436

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] IL-2 is positively involved in the development of colitogenic CD4^+ IL-7Ralpha high memory T cells in chronic colitis.2010

    • Author(s)
      Kameyama K, Nemoto Y, et al
    • Journal Title

      European Journal of Immunology

      Volume: 40 Pages: 2423-2436

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Persistent retention of colitogenic CD4+ memory T cells causes inflammatory bowel diseases to become intractable.2009

    • Author(s)
      Kanai T, Nemoto Y, Watanabe M, et al.
    • Journal Title

      Inflamm Bowel Dis. 15(Review)

      Pages: 926-934

    • Related Report
      2010 Final Research Report
  • [Journal Article] Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis.2009

    • Author(s)
      Nemoto Y, Kanai T, Watanabe M, et al.
    • Journal Title

      J Immunol. 183

      Pages: 5059-5068

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitis.2009

    • Author(s)
      Tomita T, Nemoto Y, Watanabe M, et al.
    • Journal Title

      Eur J Immunol. 39

      Pages: 2737-2747

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Long-lived colitogenic CD4^+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis.2009

    • Author(s)
      Nemoto Y, Kanai T, et al.
    • Journal Title

      J Immunol. 183

      Pages: 5059-68

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4^+ memory T cells in chronic colitis.2009

    • Author(s)
      Tomita T, Nemoto Y, et al.
    • Journal Title

      Eur J Immunol. 39

      Pages: 2737-47

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Homeostatic(IL-7)and effector(IL-17)cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory bowel disease.2009

    • Author(s)
      Kanai T, Nemoto Y, et al.
    • Journal Title

      Curr Opin Gastroenterol 25

      Pages: 306-13

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Persistent retention of colitogenic CD4^+ memory T cells causes inflammatory bowel diseases to become intractable.2009

    • Author(s)
      Kanai T, Nemoto Y, et al.
    • Journal Title

      Inflamm Bowel Dis 15

      Pages: 926-34

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow.2008

    • Author(s)
      Fujii T, Nemoto Y, Watanabe M, et al.
    • Journal Title

      Eur J Immunol 38

      Pages: 3290-3303

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice.2008

    • Author(s)
      Tomita T, Nemoto Y, Watanabe M, et al.
    • Journal Title

      Inflamm Bowel Dis. 14

      Pages: 1630-1640

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis.2008

    • Author(s)
      Nemoto Y, Kanai T, Watanabe M, et al.
    • Journal Title

      Inflamm Bowel Dis. 14

      Pages: 1491-1503

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis.2008

    • Author(s)
      Totsuka T, Watanabe M, et al.
    • Journal Title

      Eur J Immunol. 38

      Pages: 1275-1286

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Continuous generation of colitogenic CD4+ T cells in persistent colitis.2008

    • Author(s)
      Tomita T, Nemoto Y, Watanabe M, et al.
    • Journal Title

      Eur J Immunol. 38

      Pages: 1264-1274

    • Related Report
      2010 Final 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, Nemoto Y, Watanabe M, et al.
    • Journal Title

      J Immunol. 180

      Pages: 5291-5299

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Persistent retention of colitogenic CD4^+ memory T cells causes inflammatorybowel diseases to become intractable.2008

    • Author(s)
      Kanai T, Nemoto Y, et al.
    • Journal Title

      Inflamm Bowel Dis. (In press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FTY720 suppresses the development of colitis in lymphoid-null mice bymodulating the trafficking of colitogenic CD4^+ T cells in bone marrow.2008

    • Author(s)
      Fujii T, Nemoto Y, et al
    • Journal Title

      Eur J Immunol. 38

      Pages: 3290-303

    • 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, Nemoto Y, et al.
    • Journal Title

      Inflamm Bowel Dis. 14

      Pages: 1630-40

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Negative feedback regulation of colitogenic CD4^+T cells by increasedgranulopoiesis.2008

    • Author(s)
      Nemoto Y, Kanai T, et al
    • Journal Title

      Inflamm Bowel Dis. 2008 14

      Pages: 1491-503

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

    • Author(s)
      Totsuka T, Nemoto Y, et al
    • Journal Title

      Eur J Immunol 38

      Pages: 1275-86

    • 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, Nemoto Y, et al
    • Journal Title

      Eur J Immunol. 38

      Pages: 1264-74

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

    • Author(s)
      Tomita T, Nemoto Y, et al
    • Journal Title

      J Immunol 180

      Pages: 5291-9

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] 腸炎惹起性メモリーCD4+ T細胞再循環経路をターゲットとした炎症性腸疾患の治療戦略2010

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      JDDW2011
    • Place of Presentation
      横浜
    • Year and Date
      2010-10-14
    • Related Report
      2010 Final Research Report
  • [Presentation] 腸炎惹起性メモリーCD4^+ T細胞再循環経路をターゲットとした炎症性腸疾患の治療戦略2010

    • Author(s)
      根本泰宏
    • Organizer
      JDDW 2011(日本消化器病関連週間)
    • Place of Presentation
      横浜
    • Year and Date
      2010-10-14
    • Related Report
      2010 Annual Research Report
  • [Presentation] IL-7-producing mesenchymal stromal cells sustaincolito genic memory CD4+ T cells for thepersistence of inflammatory bowel disease2010

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      第14回国際免疫学会総会
    • Place of Presentation
      神戸
    • Year and Date
      2010-08-25
    • Related Report
      2010 Final Research Report
  • [Presentation] IL-7-producing mesenchymal stromal cells sustain colitogenic memory CD4^+T cells for the persistence of inflammatory bowel disease2010

    • Author(s)
      Nemoto T
    • Organizer
      国際免疫学会総会
    • Place of Presentation
      神戸
    • Year and Date
      2010-08-25
    • Related Report
      2010 Annual Research Report
  • [Presentation] 炎症性腸疾患メモリーCD4+ T細胞は腸内細菌非依存的/IL-7 依存的に維持される2010

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      第47回日本消化器免疫学会総会
    • Place of Presentation
      滋賀
    • Year and Date
      2010-07-09
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症性腸疾患メモリーCD4^+ T細胞は腸内細菌非依存的/IL-7依存的に維持される2010

    • Author(s)
      根本泰宏
    • Organizer
      日本消化器免疫学会総会
    • Place of Presentation
      滋賀
    • Year and Date
      2010-07-09
    • Related Report
      2010 Annual Research Report
  • [Presentation] IL-7-producing mesenchymal stemcells sustain colitogenic memory CD4+ T cells for the persistence of chcolitis2010

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      DDWronic2010
    • Place of Presentation
      ニューオリンズ
    • Year and Date
      2010-05-02
    • Related Report
      2010 Final Research Report
  • [Presentation] IL-7-producing mesenchymal stem cells sustain colitogenic memory CD4^+ T cells for the persistence of chronic colitis2010

    • Author(s)
      Nemoto T
    • Organizer
      DDW 2010(米国消化器病関連週間)
    • Place of Presentation
      米国(ニューオリンズ)
    • Year and Date
      2010-05-02
    • Related Report
      2010 Annual Research Report
  • [Presentation] Long-lived Colitogenic CD4+ Memory T Cells can be Maintained Outside the Intestine in theAbsence of Commesal Bacteria2009

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      The 3rd Japan & US Collaboration Conferencein Gastroenterology
    • Place of Presentation
      東京
    • Year and Date
      2009-11-20
    • Related Report
      2010 Final Research Report
  • [Presentation] Long-lived Colitogenic CD4^+ Memory T Cells can be Maintained Outside the Intestine in the Absence of Commesal Bacteria.2009

    • Author(s)
      根本泰宏、渡辺守, 他
    • Organizer
      The 3rd Japan & US Collaboration Conference in Gastroenterology
    • Place of Presentation
      東京
    • Year and Date
      2009-11-20
    • Related Report
      2009 Annual Research Report
  • [Presentation] 腸内細菌から直接的自然免疫と抗原刺激を受ける炎症性腸疾患メモリーCD4+T細胞の維持機構2009

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      JDDW2009
    • Place of Presentation
      京都
    • Year and Date
      2009-10-15
    • Related Report
      2010 Final Research Report
  • [Presentation] 腸内細菌から直接的自然免疫と抗原刺激を受ける炎症性腸疾患メモリーCD4^+T細胞の維持機構2009

    • Author(s)
      根本泰宏、渡辺守, 他
    • Organizer
      JDDW 2009(日本消化器関連学会週間)
    • Place of Presentation
      京都
    • Year and Date
      2009-10-15
    • Related Report
      2009 Annual Research Report
  • [Presentation] 炎症性腸疾患治療標的としてのIL-7 高産生細胞の同定2009

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      第46回消化器免疫学会
    • Place of Presentation
      松山
    • Year and Date
      2009-07-24
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症性腸疾患治療標的としてのIL-7高産生細胞の同定2009

    • Author(s)
      根本泰宏、渡辺守, 他
    • Organizer
      第46回消化器免疫学会
    • Place of Presentation
      松山
    • Year and Date
      2009-07-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] Long-lived Colitogenic CD4+ Memory T Cells can be Maintained Outside the Intestine in the Absence of Commesal Bacteria2009

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      14thICMI
    • Place of Presentation
      ボストン
    • Year and Date
      2009-07-07
    • Related Report
      2010 Final Research Report
  • [Presentation] Long-lived Colitogenic CD4^+ Memory T Cells can be Maintained Outside the Intestine in the Absence of Commesal Bacteria2009

    • Author(s)
      根本泰宏、渡辺守, 他
    • Organizer
      14^<th>ICMI(国際粘膜免疫学会)
    • Place of Presentation
      ボストン
    • Year and Date
      2009-07-07
    • Related Report
      2009 Annual Research Report
  • [Presentation] Long-lived Colitogenic CD4+ Memory TCells Residing Outside the Intestine Participate in the Perpetuation of ChronicColitis2009

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      DDW2009
    • Place of Presentation
      シカゴ
    • Year and Date
      2009-05-31
    • Related Report
      2010 Final Research Report
  • [Presentation] Long-lived Colitogenic CD4^+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis2009

    • Author(s)
      根本泰宏、渡辺守, 他
    • Organizer
      DDW 2009(米国消化器病関連週間)
    • Place of Presentation
      シカゴ
    • Year and Date
      2009-05-31
    • Related Report
      2009 Annual Research Report
  • [Presentation] IL-7 を標的とした腸炎惹起性メモリーT細胞の制御2008

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      JDDW2008
    • Place of Presentation
      東京
    • Year and Date
      2008-10-03
    • Related Report
      2010 Final Research Report
  • [Presentation] IL-7を標的とした腸炎惹起性メモリーT細胞の制御2008

    • Author(s)
      TDDW
    • Organizer
      ワークショップ
    • Place of Presentation
      東京
    • Year and Date
      2008-10-03
    • Related Report
      2008 Annual Research Report
  • [Presentation] 骨髄における腸炎惹起性メモリーT細胞と顆粒球造血系のクロストーク, ミニシンポジウム2008

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      日本本泰宏第45回消化器免疫学会
    • Place of Presentation
      京都
    • Year and Date
      2008-07-04
    • Related Report
      2010 Final Research Report
  • [Presentation] 骨髄における腸炎惹起性メモリーT細胞と穎粒球造血系のクロストーク2008

    • Author(s)
      日本消化器免疫学会
    • Organizer
      ミニシンポジウム
    • Place of Presentation
      京都
    • Year and Date
      2008-07-04
    • Related Report
      2008 Annual Research Report
  • [Presentation] Negative Feedback Regulation of Pathogenic CD4+ T Cells by Increased Granulopoiesis.2008

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      DDW2008
    • Place of Presentation
      San Diego.
    • Year and Date
      2008-05-20
    • Related Report
      2010 Final Research Report
  • [Presentation] Negative Feedback Regulation of Pathogenic CD4^<+>T Cells by Increased Granulopoiesis2008

    • Author(s)
      Nemoto
    • Organizer
      DDW
    • Place of Presentation
      San Diego
    • Year and Date
      2008-05-20
    • Related Report
      2008 Annual Research Report
  • [Presentation] 腸炎骨髄に存在する腸炎惹起性CD4+メモリー細胞による自然免疫系へのフィードバック機構2008

    • Author(s)
      根本泰宏, 金井隆典, 渡辺守, 他
    • Organizer
      第94回消化器病学会総会
    • Place of Presentation
      福岡
    • Year and Date
      2008-05-08
    • Related Report
      2010 Final Research Report
  • [Presentation] 腸炎骨髄に存在する腸炎惹起性CD4^+メモリー細胞による自然免疫系へのフィードバック機構2008

    • Author(s)
      根本泰宏
    • Organizer
      消化器病学会総会
    • Place of Presentation
      福岡
    • Year and Date
      2008-05-08
    • Related Report
      2008 Annual Research Report
  • [Book] 消化器と免疫2009

    • Author(s)
      根本泰宏、渡辺守, 他
    • Publisher
      マイライフ社
    • Related Report
      2010 Final Research Report 2009 Annual Research Report

URL: 

Published: 2008-04-01   Modified: 2016-04-21  

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