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2010 Fiscal Year Final Research Report

Molecular mechanisms that regulate the formation of the thymic microenvironments

Research Project

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Project/Area Number 20390144
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionThe University of Tokushima

Principal Investigator

TAKAHAMA Yousuke  The University of Tokushima, 疾患ゲノム研究センター, 教授 (20183858)

Co-Investigator(Kenkyū-buntansha) NITTA Takeshi  徳島大学, 疾患ゲノム研究センター, 講師 (30373343)
UENO Tomoo  徳島大学, 疾患ゲノム研究センター, 講師 (30360506)
Project Period (FY) 2008 – 2010
Keywords免疫学 / 獲得免疫 / 胸腺分化 / 胸腺微小環境 / 胸腺上皮細胞 / 胸腺髄質上皮細胞 / 胸腺皮質上皮細胞 / ケモカイン / 胸腺プロテアソーム / ・5t / RANKL / Aire / CCR7 / XCL1
Research Abstract

The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. We have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL and lymphotoxin, produced by positively selected thymocytes promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance. Our results also demonstrate that the XCL1-mediated medullary accumulation of thymic dendritic cells contributes to regulatory T cell development and is regulated by Aire and that thymoproteasome-dependent self-peptide production is required for the development of an immunocompetent repertoire of CD8+ T cells.

  • Research Products

    (18 results)

All 2011 2010 2009 2008 Other

All Journal Article (8 results) (of which Peer Reviewed: 8 results) Presentation (6 results) Book (1 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development.2011

    • Author(s)
      Lei Y, Mat Ripen A, Ishimaru N, Ohigashi I, Nagasawa T, Jeker L, Bosl M, Hollander GA, Hayashi Y, de Waal Malefyt R, Nitta T, Takahama Y.
    • Journal Title

      J Exp Med. 208

      Pages: 383-394

    • Peer Reviewed
  • [Journal Article] Cytokine crosstalk for thymic medulla formation.2011

    • Author(s)
      Nitta T, Ohigashi I, Nakagawa Y, Takahama Y.
    • Journal Title

      Curr Op Immunol. 23

      Pages: 190-197

    • Peer Reviewed
  • [Journal Article] Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells.2010

    • Author(s)
      Nitta T, Murata S, Sasaki K, Fujii H, Mat Ripen A, Ishimaru N, Koyasu S, Tanaka K, Takahama Y.
    • Journal Title

      Immunity. 32

      Pages: 29-40

    • Peer Reviewed
  • [Journal Article] Role of thymic cortex-specific self-peptides in positive selection of T cells.2010

    • Author(s)
      Takahama Y, Nitta T, Mat Ripen A, Nitta S, Murata S, Tanaka K.
    • Journal Title

      Sem Immunol. 22

      Pages: 287-293

    • Peer Reviewed
  • [Journal Article] CCR7-mediated medulla migration of developing thymocytes is essential for negative selection to tissue-restricted antigens.2009

    • Author(s)
      Nitta T, Nitta S, Lei Y, Lipp M, Takahama Y.
    • Journal Title

      Proc Natl Acad Sci USA. 106

      Pages: 17129-17133

    • Peer Reviewed
  • [Journal Article] Gene expression profile of third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development.2009

    • Author(s)
      Sultana DA, Tomita S, Hamada M, Iwanaga Y, Kitahama Y, Khang NV, Hirai S, Ohigashi I, Nitta S, Amagai T, Takahashi S, Takahama Y.
    • Journal Title

      Blood. 113

      Pages: 2976-2987

    • Peer Reviewed
  • [Journal Article] Thymic microenvironments for T-cell repertoire formation.2008

    • Author(s)
      Nitta T, Murata S, Ueno T, Tanaka K, Takahama Y.
    • Journal Title

      Adv Immunol. 99

      Pages: 59-94

    • Peer Reviewed
  • [Journal Article] The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator.2008

    • Author(s)
      Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y, Matsumoto M, Matsuo K, Penninger JM, Takayanagi H, Yokota Y, Yamada H, Yoshikai Y, Inoue J, Akiyama T, Takahama Y.
    • Journal Title

      Immunity. 29

      Pages: 438-450

    • Peer Reviewed
  • [Presentation] T-cell repertoire formation in the thymus.2010

    • Author(s)
      Takahama Y.
    • Organizer
      Cold Spring Harbor Asia Conferences -Frontiers of Immunology in Health and Diseases-
    • Place of Presentation
      中国蘇州
    • Year and Date
      2010-11-09
  • [Presentation] Thymic microenvironments that shape T cell repertoire.2010

    • Author(s)
      Takahama Y.
    • Organizer
      14th International Congress of Immunology.
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-08-23
  • [Presentation] XCL1 regulates medullary accumulation of thymic dendritic cells and thymic development of regulatory T cells.2010

    • Author(s)
      Takahama Y.
    • Organizer
      Gordon Research Conferences on Chemotacitc cytokines.
    • Place of Presentation
      イタリアルッカ
    • Year and Date
      2010-06-01
  • [Presentation] Aire regulates XCL1-mediated medullary accumulation of thymic dendritic cells and thymic development of regulatory T cells.2010

    • Author(s)
      Takahama Y.
    • Organizer
      ThymOz VI International Conference on T Cell Biology.
    • Place of Presentation
      オーストラリア グラッドストーン
    • Year and Date
      2010-03-21
  • [Presentation] Positive selection by thymo proteasome-expressing thymic epithelial cells shapes immunocompetent repertoire of CD8 T cells.2009

    • Author(s)
      Takahama Y.
    • Organizer
      2nd European Congress of Immunology
    • Place of Presentation
      ドイツベルリン
    • Year and Date
      2009-09-14
  • [Presentation] Thymoproteasome governs positive selection of CD8 T cells.2008

    • Author(s)
      Takahama Y.
    • Organizer
      ThymUS International Conference.
    • Place of Presentation
      プエルトリコサンホアン
    • Year and Date
      2008-11-12
  • [Book] Systems Biology : The Challenge of Complexity. (Toward understanding how the immune system establishes a diverse yet self-tolerant T-cell repertoire: stepwise roles of thymic microenvironments.) (eds. Nakanishi S, Kageyama R, Watanabe D).2009

    • Author(s)
      Nitta T, Takahama Y.
    • Total Pages
      71-82
    • Publisher
      Springer Tokyo
  • [Remarks] ホームページ等

    • URL

      http://www.genome.tokushima-u.ac.jp/dei/index.html

  • [Patent(Industrial Property Rights)] Method of acquiring immunological tolerance2010

    • Inventor(s)
      高浜洋介
    • Industrial Property Rights Holder
      Takahama Y, JST.
    • Industrial Property Number
      U.S.Patent, 7671250 B2
    • Acquisition Date
      2010-03-02
    • Overseas
  • [Patent(Industrial Property Rights)] 蛍光集団の評価装置、コンピュータ実行可能な蛍光集団の評価プログラム、及び蛍光集団の評価システム2008

    • Inventor(s)
      高浜洋介、新田剛、中野義太郎
    • Industrial Property Rights Holder
      (株)ニコン、徳島大学
    • Industrial Property Number
      特許出願,2008-179765
    • Filing Date
      2008-07-10

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Published: 2012-01-26   Modified: 2016-04-21  

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