T細胞に依存しない新たな補助シグナル分子機能の解明

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021016
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 東 みゆき 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (90255654)
• Co-Investigator(Kenkyū-buntansha): 橋口 昌章 獨協医科大学, 医学部, 助教 (20372443) ; 大野 建州 東京医科歯科大学, 大学院・医歯学総合研究科, 助教 (80435635) ; 神村 洋介 東京医科歯科大学, 大学院・医歯学総合研究科, 助教 (40549929) ; 長谷 英徳 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (70332997)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥7,700,000 (Direct Cost: ¥7,700,000); Fiscal Year 2011: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2010: ¥3,600,000 (Direct Cost: ¥3,600,000)
• Keywords: 免疫 / 補助シグナル分子 / T細胞 / 免疫制御

Research Abstract

T細胞補助シグナル分子研究は、T細胞上に発現される補助シグナル分子受容体と抗原提示細胞上に発現されるリガンド分子による抗原特異的適応免疫応答に焦点が当たってきたが、本研究では、免疫細胞ではなく組織細胞上に発現される補助シグナル分子リガンドとランゲルハンス細胞あるいはミエロイド系細胞に発現誘導される補助シグナル分子受容体との結合によるT細胞非依存性の免疫応答への関与に注目し検討することで、補助シグナル分子の新たな機能的役割を明らかにすることを目的とした。
プロジェクト1:角化上皮細胞に発現誘導される免疫抑制補助シグナル分子B7-H1(CD274)の機能を明確にする目的で、B7-H1トランスジェニックマウス(Tg)を作成した。化学発癌物質メチルコラントレンにより誘導される早期皮膚炎症と発癌を検討したところ、皮膚炎症はB7-H1:PD-1経路依存性に抑制されたが、上皮発癌率は有意に増加した。B7-H1過剰発現上皮細胞では、上皮間葉移行に関連する接着分子カドヘリンや転写因子発現に変化がおきており、B7-H1による内因性のシグナルが上皮細胞に悪性転化に至る変化を与えた可能性が示された。
プロジェクト2:我々が報告したB7-H3の新規受容体Tlt-2は、T細胞におけるTlt2の発現と機能的関与は少なく、マクロファージなどのミエロイド細胞上に恒常的な発現が認められることから、Tlt2の機能を明確にする目的で、Tlt-2欠損マウスの作出に取り組んだ。Tlt-2欠損マウスにいて、胸腺、脾臓、リンパ節、骨髄、腹腔内細胞における免疫細胞構成比に明らかな違いは認められなかった。ヒトにおいては、Tlt-2とB7-H3は結合しないという論文が発表されたが、我々はヒトにおいてもTlt-2とB7-H3は結合し、この結合はマウスと同様T細胞機能増強に働くことを新たに示した。

Research Products

• [Journal Article] Antibodies against B7-DC with differential binding properties exert opposite effects (2012)
  • Author(s): Ritprajak P, Hashiguchi M, Akiba H, Yagita H, Okumura K, Azuma M
  • Journal Title: Hybridoma Volume: 31 Issue: 1 Pages: 40-47
  • DOI: 10.1089/hyb.2011.0087
  • Peer Reviewed
• [Journal Article] Human B7-H3 binds to Triggering receptor expressed on myeloid cell-like transcript 2(TLT-2) and enhances T cell responses. Open J (2012)
  • Author(s): M. Hashiguchi, Y. Inamochi, S. Nagai, S., N. Otsuki, P. Jinhua, H. Kobori, Y. Kanno, T. Kobata, M. Azuma
  • Journal Title: Immunol. Peer-reviewed Volume: 2 Issue: 01 Pages: 9-16
  • DOI: 10.4236/oji.2012.21002
  • Peer Reviewed
• [Journal Article] B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin (2011)
  • Author(s): Cao Y, Zhang L, Kamimura Y, Ritprajak P, Hashiguchi M, Hirose S, Azuma M
  • Journal Title: Cancer Res Volume: 71 Issue: 4 Pages: 1235-43
  • DOI: 10.1158/0008-5472.can-10-2217
  • Peer Reviewed
• [Journal Article] Immunoregulatory molecules B7-H1 (CD274) contributes to skin carcinogenesis (2011)
  • Author(s): Cao Y, Zhang L, Ritprajak P, Tsushima F, Youngnak-Piboonratanakit P, Kamimura Y, Hashiguchi M, Azuma M
  • Journal Title: Cancer Res Volume: 71 Issue: 14 Pages: 4737-4741
  • DOI: 10.1158/0008-5472.can-11-0527
  • Peer Reviewed
• [Journal Article] Essential role of B7-H1 in double-stranded RNA-induced augmentation of an asthma phenotype in mice (2011)
  • Author(s): Matsumoto K.
  • Journal Title: Am J Respir Cell Mol Biol Volume: (in press)
  • Peer Reviewed
• [Journal Article] B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin (2011)
  • Author(s): Cao Y.
  • Journal Title: Cancer Res Volume: 71(4) Pages: 1235-43
  • Peer Reviewed
• [Journal Article] Immunoregulatory molecules B7-H1 (CD274) contributes to skin carcinogenesis. (2011)
  • Author(s): Cao Y.
  • Journal Title: Cancer Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymphnode dendritic cells in the generation of antigen-specific CD4^+Foxp3^+ regulatory T cells in the establishment of oral tolerance (2010)
  • Author(s): T Fukaya.
  • Journal Title: Blood Volume: 116(13) Pages: 2266-2276
  • Peer Reviewed
• [Journal Article] GITR ligand-mediated local expansion of regulatory T cells contributes to immune privilege of corneal allografts (2010)
  • Author(s): J Hori.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 51(21) Pages: 6556-65
  • Peer Reviewed
• [Journal Article] Programmed death-1 (PD-1) signaling and regulatory T cells (Tregs) collaborate to resist the function of adoptive transferred cytotoxic T lymphocytes (CTLs) in advanced acute myeloid leukemia (AML) (2010)
  • Author(s): Zhou Q.
  • Journal Title: Blood Volume: 116(14) Pages: 2484-93
  • Peer Reviewed
• [Journal Article] Role of the glucocorticoid-induced TNFR-related protein (GITR)-GITR ligand pathway in innate and adaptive immunity (2010)
  • Author(s): Azuma M
  • Journal Title: Cri Rev Immunol Volume: 30(6) Pages: 457-57
  • Peer Reviewed
• [Journal Article] In vivo function of immune inhibiotory molecule B7-H4 in a murine vascularized model of cardiac transplantation (2010)
  • Author(s): Yamaura K.
  • Journal Title: American J Transplant Volume: 10(10) Pages: 2355-62
  • Peer Reviewed
• [Presentation] Immunoregulatory molecule CD274 (B7-H1/PD-L1) contributes to skin carcinogenesis (2011)
  • Author(s): 張晨陽、曹寓佳、大野建州、津島文彦、東みゆき
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Overexpression of B7-H1 on epidermal keratinocytes promotes squamous cell carcinoma (2010)
  • Author(s): Cao Y.
  • Organizer: American Association of Immunologists, Immunology 2010
  • Place of Presentation: Baltimore, USA
• [Presentation] B7-H1 on epidermal keratinocytes downregulates skin inflammation, but promotes squamous cell carcinoma formation (2010)
  • Author(s): Cao Y.
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] Triggering receptor expressed on myeloid cells-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses in mice and humans (2010)
  • Author(s): Hashiguchi M.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8^+ T cell responses (2010)
  • Author(s): Ritprajak P.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] Antibodies against B7-DC with differential binding properties exert opposite effects : Implication of dual functions in PD-1 and B7-DC interactions (2010)
  • Author(s): Azuma M.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] Overexpression of B7-H1 on epidermal keratinocytes promotes squamous cell carcinoma formation (2010)
  • Author(s): Cao Y.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] Enhancement of effector CD8^+ T cell function by tumor-associated B7-H3 and modulation of its counter receptor triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) at tumor sites. (2010)
  • Author(s): Kobori H.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] The GITR-GITR ligand pathway acts as a mediator of cutaneous DC migration and promotes T cell-mediated immunity (2010)
  • Author(s): Kamimura Y.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] The GITR-GITR ligand pathway acts as a mediator of cutaneous DC migration and promotes T cell-mediated immunity. (2010)
  • Author(s): Azuma M.
  • Organizer: DC2010 : Forum on Vaccine Science
  • Place of Presentation: Lugano, Switzerland