Thymic microenvironments for shaping T cell repertoire

2011 Fiscal Year Final Research Report

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 19059010
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokushima
• Principal Investigator: TAKAHAMA Yousuke 徳島大学, 疾患ゲノム研究センター, 教授 (20183858)
• Co-Investigator(Kenkyū-buntansha): MATSUMOTO Mitsuru 徳島大学, 疾患酵素学研究センター, 教授 (60221595)
• Project Period (FY): 2007 – 2011
• Keywords: 免疫学 / 自己識別 / 自己寛容 / 胸腺 / 胸腺微少環境 / 胸腺上皮細胞 / 胸腺プロテアソーム / β5t / Aire / RANKL / CCL21 / XCL1

Research Abstract

Ｔ lymphocytes are the cells that play an essential role in distinguishing non-self from self. T lymphocytes acquirｅ this ability through shaping a ｒｅｐｅｒtｏirｅ of recognition specificity ｄｕring the development in the thymus. However, how T lymphocytes are generated and selected in the thymus is still not well understood. This study identified (1) chemokines that are produced by thymic medullary epithelial cells and are essential for establishment of sｅlf-tolerance, (2) cytokines that are essential for the growth and development of thymic medullary epithelial cells, (3) proteasomes that are ｅxpressed in thymic cortical epithelial cells and are essential for positive selection of immunocompetent CD8 T lymphocytes. In addition, (4) we revealed that Airｅ regulates the development of thymic medullary epithelial cells, and (5) we begun the analysis how medullary and cortical　thymic epithelial cells are generated from common epithelial progenitor cells.

Research Products

• [Journal Article] Rank signaling links the development of invariant γδ T cell progenitors and Aire+ medullary epithelium (2012)
  • Author(s): Roberts NM, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR, McConnell FM, Desanti GE, Benezech C, Parnell SM, Cunningham AF, Paolino M, Penninger J, Simon K, Nitta T, Ohigashi I, Takahama Y, Caamano JH, Hayday AC, Lane PJ, Jenkinson EJ, Anderson G
  • Journal Title: Immunity Volume: 36 Pages: 427-437
  • DOI: DOT:10.1016/j.immuni.2012.01.016
  • Peer Reviewed
• [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 T, Nagasawa T, Jeker L, Bosl M, Hollander GA, Hayashi Y, de Waal Malefyt R, Nitta T, Takahama Y
  • Journal Title: J Exp Med. Volume: 208 Pages: 383-394
  • DOI: DOI:10.1084/jem.20102327
  • 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 Volume: 32 Pages: 29-40
  • DOI: DOI:10.1016/j.immuni.2009.10.009
  • Peer Reviewed
• [Journal Article] Biphasic Aire ｅxpression in early embryos and in medullary thymic epithelial cells prior to end-stage terminal differentiation. (2010)
  • Author(s): Nishikawa Y, Hirota F, Yano M, Kitajima H, Miyazaki J, Kawamoto H, Mouri Y, Matsumoto M
  • Journal Title: J Exp Med. Volume: 207 Pages: 963-971
  • DOI: DOI:10.1084/jem.20092144
  • 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. Volume: 106 Pages: 17129-17133
  • DOI: DOI:10.1073/pnas.0906956106
  • 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 Volume: 29 Pages: 438-450
  • DOI: DOI:10.1016/j.immuni.2008.06.018
  • Peer Reviewed
• [Journal Article] The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. (2008)
  • Author(s): Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima, D, Maruyama Y, Asaumi Y, Kitazawa J, Takayanagi H, Penninger JM, Inoue J
  • Journal Title: Immunity Volume: 29 Pages: 423-437
  • DOI: DOI:10.1016/j.immuni.2008.06.015
  • Peer Reviewed
• [Journal Article] Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. (2008)
  • Author(s): Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y, Williams IR, Hubert FX, Scott HS, Takahama Y, Hollander GA, Reith W
  • Journal Title: Immunity Volume: 29 Pages: 451-463
  • DOI: DOI:10.1016/j.immuni.2008.08.007
  • Peer Reviewed
• [Journal Article] Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. (2008)
  • Author(s): Yano M, Kuroda N, Han H, Meguro-Horike M, Nishikawa Y, Kiyonari H, Maemura K, Yanagawa Y, Obata K, Takahashi S, Ikawa T, Satoh R, Kawamoto H, Mouri Y, Matsumoto M.
  • Journal Title: J Exp Med. Volume: 205 Pages: 2827-2838
  • DOI: DOI:10.1084/jem.20080046
  • Peer Reviewed
• [Journal Article] Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology. (2008)
  • Author(s): Matsumoto M, Zhou Y, Matsuo S, Nakanishi H, Hirose K, Oura H, Arase S, Ishida-Yamamoto A, Bando Y, Izumi K, Kiyonari H, Oshima N, Nakayama R, Matsushima A, Hirota F, Mouri Y, Kuroda N, Sano S, Chaplin DD.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 105 Pages: 6720-6724
  • DOI: DOI:10.1073/pnas.0709345105
  • Peer Reviewed
• [Journal Article] Regulation of CD8+ T cell development by thymus-specific proteasomes (2007)
  • Author(s): Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K.
  • Journal Title: Science Volume: 316 Pages: 1349-1353
  • DOI: DOI:10.1126/science.1141915
  • Peer Reviewed
• [Presentation] T lymphocyte repertoire formation in thymic microenvironments. (2012)
  • Author(s): Takahama Y.
  • Organizer: 5th Congress of the Federation of Immunological Societies of Asia Oceania.
  • Place of Presentation: インド, ニューデリー[招待講演]
  • Year and Date: 2012-03-15
• [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[招待講演]
  • 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[招待講演]
  • 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 Conference on Chemotactic Cytokines
  • Place of Presentation: イタリア, ルッカ[招待講演]
  • Year and Date: 2010-06-01
• [Presentation] Thymus-specific self-peptide repertoirｅ shapes immunocompetent repertoire of T cells (2009)
  • Author(s): Takahama Y.
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪[招待講演]
  • Year and Date: 2009-12-02
• [Presentation] Positive selection by thymoproteasome-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[招待講演]
  • Year and Date: 2009-09-14
• [Presentation] RANK ligand produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. (2008)
  • Author(s): Takahama Y.
  • Organizer: 4th Congress of the Federation of Immunology Societies of Asia-Oceania
  • Place of Presentation: 台湾台北[招待講演]
  • Year and Date: 2008-10-18
• [Presentation] The chemokine system in the construction and function of the thymus (2008)
  • Author(s): Takahama Y.
  • Organizer: Keystone Symposium on Chemokines and Chemokine Receptors
  • Place of Presentation: 米国, デンバー[招待講演]
  • Year and Date: 2008-01-14
• [Presentation] Thymic microenvironments for shaping T-cell repertoire (2007)
  • Author(s): Takahama Y.
  • Organizer: 第37回日本免疫学会
  • Place of Presentation: 東京[招待講演]
  • Year and Date: 2007-11-21
• [Presentation] Thymic microenvironments and central tolerance (2007)
  • Author(s): Takahama Y.
  • Organizer: 13th International Congress of Immunology
  • Place of Presentation: ブラジル, リオデジャネイロ[招待講演]
  • Year and Date: 2007-08-22
• [Book] Systems Biology: The Challenge of Complexity. eds. Nakanishi S, Kageyama R, Watanabe D., Toward understanding how the immune system establishes a diverse yet self-tolerant T-cell repertoire: stepwise roles of thymic microenvironments. (2009)
  • Author(s): Nitta T, Takahama Y.
  • Total Pages: 71-82
  • Publisher: Springer
• [Book] Effector CD4+ T Cells in Health and Disease., Development of helper and regulatory CD4+ T cells in the thymus. (2008)
  • Author(s): Liu C, Takahama Y.
  • Total Pages: 192-196
  • Publisher: Transworld
• [Remarks] 徳島新聞 免疫システム制御細胞生成メカニズム解明 20110507
• [Remarks] 日本経済新聞 キラーＴ細胞生成の酵素解明 20100530
• [Remarks] 朝日新聞 がん攻撃キラーＴ細胞生成のカギは胸腺内の酵素 20100126
• [Remarks] 読売新聞 自己免疫疾患抑制たんぱく質を発見 20081208
• [Remarks] 朝日新聞 自己免疫病のカギ握るたんぱく質確認 20080929
• [Remarks] 日本免疫学会主催の科学コミュニケーション活動「免疫ふしぎ未来」 参加(東京) 20110821
• [Remarks] 日本免疫学会主催の科学コミュニケーション活動「免疫ふしぎ未来」 参加(東京) 20090502-03
• [Remarks] 日本免疫学会主催の科学コミュニケーション活動「免疫ふしぎ未来」 主催(東京) 20080503-4
• [Remarks] 日本免疫学会主催の科学コミュニケーション活動「免疫ふしぎ未来」 創設と主催(東京, 徳島) 20070503-04
• [Remarks] 第14回国際免疫学会議組織委員会主催の科学コミュニケーション活動 Immunology in Japan(神戸) 20100822-27
• [Remarks]
  • URL: http://immself.umin.jp
• [Remarks]
  • URL: http://www.genome.tokushima-u.ac.jp/dei
• [Remarks]
  • URL: http://www.tokushima-u.ac.jp/ier/autoimmunity/
• [Patent(Industrial Property Rights)] Evaluation device for fluorescent group, computer-executable evaluation program for fluorescent group, and evaluation system for fluorescent group. (2010)
  • Inventor(s): Takahama Y, Nitta T, Nakano Y.
  • Industrial Property Rights Holder: 国立大学法人徳島大学, 株式会社二コン
  • Industrial Property Number: 米国特許PF11001,12/979, 858
  • Filing Date: 2010-12-28
  • Overseas
• [Patent(Industrial Property Rights)] Method of acquiring immunological tolerance (2010)
  • Inventor(s): Takahama Y.
  • 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)二コン, 徳島大学
  • Industrial Property Number: 特許出願,2008-179765
  • Filing Date: 2008-07-10