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

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590718
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo 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
• 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

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。

Research Products

• [Journal Article] Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and 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
  • Peer Reviewed
• [Journal Article] Colitogenic CD4+ effector-memory T cells actively recirculate in chronic coliti0c 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
  • 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
  • Peer Reviewed
• [Journal Article] Continuous generation of colitogenic CD4(+) Tcells 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
  • 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
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis (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
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-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) Pages: G199-207
  • 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, 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
  • Peer Reviewed
• [Journal Article] IL-7 Is essential for the development and the persistence of chronic colitis (2007)
  • 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
  • Peer Reviewed
• [Journal Article] Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis (2007)
  • Author(s): Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Takeda K, Watanabe M
  • Journal Title: Gastroenterology 132(1) Pages: 176-189
  • Peer Reviewed
• [Journal Article] Extracorporeal elimination of TNF-alpha-producing CD14(dull)CD16(+) monocytes in leukocytapheresis therapy for ulcerative colitis (2007)
  • 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
  • Peer Reviewed
• [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
• [Presentation] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis (2007)
  • 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
• [Presentation] IL-7 is essential for the development and the persistence of chronic colitis (2007)
  • 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
• [Presentation] Uniqueness of colitogenic lamina propria CD4+ T cells for the perpetuation of colitis (2007)
  • 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
• [Presentation] Bone marrow is a reservoir for persistent colitogenic CD + TEM cells in IL-7 dependent manner (2007)
  • 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
• [Presentation] IL-7 is essential for the development and persistence of chronic colitis (2007)
  • 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
• [Presentation] Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis (2007)
  • 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
• [Presentation] Ameliorating effect of anti-NKG2D in CD4+ cell-mediated murine model of chronic colitis (2007)
  • 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
• [Presentation] Continuous recirculation of colitogenic CD4+ T cells may be required for perpetuation of chronic colitis (2007)
  • 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
• [Presentation] Blockade of TNF-α inhibits tumor progression in colitis-associated cancer (2007)
  • 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