1994 Fiscal Year Annual Research Report

T細胞活性化のシグナル伝達

Research Project

Project/Area Number	06282102
Research Institution	Chiba University
Principal Investigator	斉藤隆千葉大学, 医学部, 教授 (50205655)
Co-Investigator(Kenkyū-buntansha)	南康博大坂大学, 細胞生体工学センター, 助手 (70229772) 岸原健二九州大学, 生体防御医学研究所, 助手 (80214774) 高橋秀実日本医科大学, 医学部, 助教授 (40221361) 藤原大美大阪大学, 医学部, 助教授 (70116094) 上出利光北海道大学, 免疫科学研究所, 教授 (00160185)
Keywords	T細胞活性化 / TCR構造異常 / HS1 / CD45 / CD28 / Syk / Jak / Co-stimulator
Research Abstract	T細胞の活性化に重要な3つのシグナル;TCR複合体を介する認識シグナル、CD28を介するCo-stimulationシグナル、IL-2Rを介する増殖シグナルの解析を進めた。 (1)TCRシグナル: ζ鎖欠損マウスを用い、in vivoでもCD3を介する2つのシグナルモジュールが存在し、ζ特異的シグナルの存在を明らかにした。担癌状態でTCR複合体の構造異常が誘導されたが、特殊なマクロファージとT細胞の相互作用によることが明らかになった。また、ペプチド抗原は細胞外でも最小ペプチドにプロセスされ、これによって特異的T細胞の活性化が抑制されることを発見した。抗原受容体により活性化されるチロシンキナーゼの基質としてHS1とCb1をクローニングした。HS1のリン酸化にはSrc型キナーゼとSyk型キナーゼの協調(Lyn+SykまたはFyn+ZAP70)が重要であり、Cb1の活性化にはFynが重要なことが判明した。一方、フォスファターゼCD45は、欠損マウスの解析より、T細胞の選択、TCRα鎖のallelic exclusionおよび移植片の拒絶などに重要な役割を果たしていることがわかった。 (2)Co-stimulationシグナル: Co-stimulatorとしてのB7のオルタナティブスプライシング産物MB7-2をクローニングした。B7やMB7-2をメラノーマに発現させることにより、転移の阻害に成功した。一方、CD28を介するシグナルが、従来のIL-2産生に重要であるのみならず、IL-2R発現に不可欠であることを正常T細胞のシステムで証明した。更に、CD28、CTLA-4の高発現に成功し、両者がヘテロダイマーは形成しないことを明らかにした。 (3)増殖シグナル: IL2レセプター各鎖とJakおよびSykファミリーキナーゼの機能的会合を調べ、β鎖にはSyk、Jak1が、γ鎖にはJak3が会合していることを明らかにした。Sykは、IL-2によるc-mycの誘導に重要なことや、bc12がIL-2シグナルの標的であることも明らかにした。

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] Ohno,H.: "Preferential usage of the FcRγ in the T cell antigen receptor complex by γδ T cells localized in epithelia.21GC01:Journal of Experimental Medicine" 179. 365-369 (1994)
[Publications] Nakano,H.: "Activation of phospholipase C-γ1 through transfected platelet-derived growth factor receptor enhances interleukin 2 production upon antigen stimulation in a T-cell line." Molecular and Cellular Biology. 14. 1213-1219 (1994)
[Publications] Kuwabara,I.: "Transition from TCRβ dimer- to TCRαβ-expressing cells by introduction of an α chain in an immature thymocyte cell line." The Journal of Immunology. 152. 2148-2156 (1994)
[Publications] Ohno,H.: "Targeted disruption of the CD3η locus causes high lethality in mice: Modulation of Oct-1 transcription on the opposite strand." The EMBO Journal. 13. 1157-1165 (1994)
[Publications] Kojima,H.: "Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes." Immunity. 1. 357-364 (1994)
[Publications] Aoe,T.: "Different cytoplasmic structure of the CD3ζ family dimer modulates the activation signal and function of T cells." International Immunology. 6. 1671-1679 (1994)
[Publications] Gunji,Y.: "High frequency of cancer patients bearing abnormal assembly of the T cell receptor-CD3 complex in peripheral blood T lymphocytes." Japanese Journal of Cancer Research. 85. 1189-1192 (1994)
[Publications] Arase,H.: "Fas-mediated cytotoxicity by freshly isolated natural killer cells." Journal of Experimental Medicine. (in press).
[Publications] Aoe,T.: "Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex." Journal of Experimental Medicine. (in press).
[Publications] Kurosaki,T.: "Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling." Journal of Experimental Medicine. 179. 1725-1729 (1994)
[Publications] Lin,T.: "Characteristics of fetal thymus-derived T cell receptor γδ intestinal intraepithelial lymphocytes. Eur." Journal of Immunology. 24. 1792-1798 (1994)
[Publications] Kawai,K.: "Impaired development of Vγ3 dendritic epidermal T cells in p.561ck protein tyrosin kinase-deficient and CD45 protein tyrosine phoshpatase-deficient mice." Journal of Experimental Medicine. 181. 345-349 (1995)
[Publications] Takahashi,H.: "An immunodominant determinant of HIV-1 envelope recognized by both class-I-restricted CD8^+ CTL and class-II-restricted CD4^+ helper T cells shares similar MHC-hinding sites" In Vaccine. 94. 181-188 (1994)
[Publications] Takeshita,T.: "Molecular analysis of the same HIV peptide functionally binding both a class I and class II MHC molecule." J.Immunol.(in press).
[Publications] Inobe,M.: "Identification of an alternatively spliced from of the murine homologue of B7." Biochem Biophys. Res. Commun.200. 443-449 (1994)
[Publications] Hirasawa,M.: "Integrin expression and ability to adhere to extracellular matrix proteins and endothelial cells in human lung cancer lines." Br. J. Cancer. 70. 466-473 (1994)
[Publications] Kijimoto-Ochiai,S.: "Demonstration of the interaction between the CD23 molecule and the galactose residue of glycoproteins." Immunology Letters. 40. 49-53 (1994)
[Publications] Zou,J-P.: "Recovery of anti-tumor CD4^+ T cell responsiveness suppressed in the tumorbearing state by release from tumor burden." J.Canser Res. Clin. Oncol.120. 279-285 (1994)
[Publications] Narumiya,S.: "Pre-B cells adhere to fibronectin via interactions of VLA-5/vitronectin receptor with RGDS as well as of VLA-4 with V region sequences at its different binding sites." Int.Immunol.6. 139-147 (1994)
[Publications] Mizuhara,H.: "T cell activation associated hepatic injury: Mediation by tumor necrosis factor and protection by interleukin-6." J.Exp. Med.179. 1529-1537 (1994)
[Publications] Yamamoto,N.: "Regulatory mechanisms for production of interferon-γ and tumor necrosis factor by anti-tumor T cells or macrophages in the tumor-bearing state" J.Immunol.(in press).
[Publications] Ninami,Y.: "Signal transduction mediated by the reconstituted IL-2 receptor: Evidence for cell type-specific function of IL-2 receptor β-chain." J.Immunol.152. 5680-5690 (1994)
[Publications] Kawahara,A.: "Evidence for a critical role for the cytoplasmic region of the interleukin 2(IL-2) receptor γ chain in IL-2, IL-4 and IL-7 signalling." Mol. Cell. Biol.14. 5433-5440 (1994)
[Publications] Miyazaki,T.: "Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits." Science. 266. 1045-1047 (1994)
[Publications] Minami,Y.: "Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: Possible link with the c-mycinduction pathway." Immunity. 2. 89-100 (1995)
[Publications] Minami,Y.: "The IL-2 signaling rccruitment and activation of multiple protein tyrosine kinases by the IL-2 receptor components" Curr. Opin. Cell. Biol.(in press).

1994 Fiscal Year Annual Research Report

T細胞活性化のシグナル伝達

Principal Investigator

斉藤 隆 千葉大学, 医学部, 教授 (50205655)

Research Products

[Publications] Ohno,H.: "Preferential usage of the FcRγ in the T cell antigen receptor complex by γδ T cells localized in epithelia.21GC01:Journal of Experimental Medicine" 179. 365-369 (1994)

[Publications] Nakano,H.: "Activation of phospholipase C-γ1 through transfected platelet-derived growth factor receptor enhances interleukin 2 production upon antigen stimulation in a T-cell line." Molecular and Cellular Biology. 14. 1213-1219 (1994)

[Publications] Kuwabara,I.: "Transition from TCRβ dimer- to TCRαβ-expressing cells by introduction of an α chain in an immature thymocyte cell line." The Journal of Immunology. 152. 2148-2156 (1994)

[Publications] Ohno,H.: "Targeted disruption of the CD3η locus causes high lethality in mice: Modulation of Oct-1 transcription on the opposite strand." The EMBO Journal. 13. 1157-1165 (1994)

[Publications] Kojima,H.: "Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes." Immunity. 1. 357-364 (1994)

[Publications] Aoe,T.: "Different cytoplasmic structure of the CD3ζ family dimer modulates the activation signal and function of T cells." International Immunology. 6. 1671-1679 (1994)

[Publications] Gunji,Y.: "High frequency of cancer patients bearing abnormal assembly of the T cell receptor-CD3 complex in peripheral blood T lymphocytes." Japanese Journal of Cancer Research. 85. 1189-1192 (1994)

[Publications] Arase,H.: "Fas-mediated cytotoxicity by freshly isolated natural killer cells." Journal of Experimental Medicine. (in press).

[Publications] Aoe,T.: "Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex." Journal of Experimental Medicine. (in press).

[Publications] Kurosaki,T.: "Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling." Journal of Experimental Medicine. 179. 1725-1729 (1994)

[Publications] Lin,T.: "Characteristics of fetal thymus-derived T cell receptor γδ intestinal intraepithelial lymphocytes. Eur." Journal of Immunology. 24. 1792-1798 (1994)

[Publications] Kawai,K.: "Impaired development of Vγ3 dendritic epidermal T cells in p.561ck protein tyrosin kinase-deficient and CD45 protein tyrosine phoshpatase-deficient mice." Journal of Experimental Medicine. 181. 345-349 (1995)

[Publications] Takahashi,H.: "An immunodominant determinant of HIV-1 envelope recognized by both class-I-restricted CD8^+ CTL and class-II-restricted CD4^+ helper T cells shares similar MHC-hinding sites" In Vaccine. 94. 181-188 (1994)

[Publications] Takeshita,T.: "Molecular analysis of the same HIV peptide functionally binding both a class I and class II MHC molecule." J.Immunol.(in press).

[Publications] Inobe,M.: "Identification of an alternatively spliced from of the murine homologue of B7." Biochem Biophys. Res. Commun.200. 443-449 (1994)

[Publications] Hirasawa,M.: "Integrin expression and ability to adhere to extracellular matrix proteins and endothelial cells in human lung cancer lines." Br. J. Cancer. 70. 466-473 (1994)

[Publications] Kijimoto-Ochiai,S.: "Demonstration of the interaction between the CD23 molecule and the galactose residue of glycoproteins." Immunology Letters. 40. 49-53 (1994)

[Publications] Zou,J-P.: "Recovery of anti-tumor CD4^+ T cell responsiveness suppressed in the tumorbearing state by release from tumor burden." J.Canser Res. Clin. Oncol.120. 279-285 (1994)

[Publications] Narumiya,S.: "Pre-B cells adhere to fibronectin via interactions of VLA-5/vitronectin receptor with RGDS as well as of VLA-4 with V region sequences at its different binding sites." Int.Immunol.6. 139-147 (1994)

[Publications] Mizuhara,H.: "T cell activation associated hepatic injury: Mediation by tumor necrosis factor and protection by interleukin-6." J.Exp. Med.179. 1529-1537 (1994)

[Publications] Yamamoto,N.: "Regulatory mechanisms for production of interferon-γ and tumor necrosis factor by anti-tumor T cells or macrophages in the tumor-bearing state" J.Immunol.(in press).

[Publications] Ninami,Y.: "Signal transduction mediated by the reconstituted IL-2 receptor: Evidence for cell type-specific function of IL-2 receptor β-chain." J.Immunol.152. 5680-5690 (1994)

[Publications] Kawahara,A.: "Evidence for a critical role for the cytoplasmic region of the interleukin 2(IL-2) receptor γ chain in IL-2, IL-4 and IL-7 signalling." Mol. Cell. Biol.14. 5433-5440 (1994)

[Publications] Miyazaki,T.: "Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits." Science. 266. 1045-1047 (1994)

[Publications] Minami,Y.: "Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: Possible link with the c-mycinduction pathway." Immunity. 2. 89-100 (1995)

[Publications] Minami,Y.: "The IL-2 signaling rccruitment and activation of multiple protein tyrosine kinases by the IL-2 receptor components" Curr. Opin. Cell. Biol.(in press).

斉藤隆千葉大学, 医学部, 教授 (50205655)