1995 Fiscal Year Annual Research Report

T細胞活性化のシグナル伝達

Research Project

Project/Area Number	07274102
Research Institution	Chiba University
Principal Investigator	斉藤隆千葉大学, 医学部, 教授 (50205655)
Co-Investigator(Kenkyū-buntansha)	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) 南康博神戸大学, 医学部, 助教授 (70229772) 藤原大美大阪大学, バイオメディカル教育センター, 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細胞レセプター / Co-stimulation / IL-2レセプター / シグナル伝達 / 抗腫瘍免疫 / CD3結合分子 / セリン・スレオニンキナーゼ / Jak3欠損マウス
Research Abstract	癌免疫の中心を担うT細胞の活性化と制御のシグナル伝達系を明らかにするため、TCRを介する認識シグナル、接着分子による副シグナル、サイトカインレセプターによる増殖シグナル、の各々のシグナル伝達系とその相互作用を解析した。TCR-CD3複合体で形成する2つのシグナルユニットの一方CD3ζを介するシグナル伝達分子として90kdを同定した。p90は、活性化早期に、TCR刺激特異的に、ζ鎖構造に依存してチロシンリン酸化を受ける。他方、CD3_<ζε>に結合する分子も新たに2分子をクローニングできた。担癌状態に伴うTCR構造異常、特にζ鎖消失は、細胞内でも実際にマクロファージ様細胞との相互作用によって誘導されることを証明し、細胞内レドックス調節に関与することを示唆した。一方、CD28を介してする-stimulationを実際の抗腫瘍免疫へ応用し、B7導入メラノーマでは顕著に転移がなくなり、肝癌では、B7導入細胞で誘導したキラーT細胞が、元のB7-腫瘍も傷害できることを明らかにし、ワクチン療法への展望を拓いた。また、B7-CD28のシグナルが関与しないT_<H1>細胞の系でも、IL-12が増殖及びIFNγなどのリンホカイン産生の活性化を誘導できることが判明した。IL-2レセプターを介して増殖シグナルの解析では、変異Jak3を用いた解析から、Jak3が増殖シグナルに不可欠であり、Jak3およびStat5の活性化に必要なIL-2Rの領域を決定した。また、IL-2Rに会合するセリン・スレオニンキナーゼを新たに同定した。さらに、Jak3のin vivoでの役割を明らかにするために、Jak3欠損マウスを樹立した。このマウスでは、B細胞、NK細胞、リンパ節、γδ細胞などがほとんど分化しなかったが、T細胞は数は少ないが分化し、末梢CD4^+T細胞では活性化マーカーを発現しており、増殖シグナルと分化・活性化との関連を解析する上で興味深い。T細胞クローンのTCR刺激による増殖阻害においても、Jak3の減少が観察され、TCRシグナルと増殖シグナルの相互作用の解析をさらに進める必要がある。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Aoe, T.: "Activated macrophares induce structural abnormalities of the T cell receptor-CD3 complex." J. Exp. Med.181. 1881-1886 (1995)
[Publications] Ono, S.: "Rapid turnover of the CD3ζ chain independent of the TCR-CD3 complex in normal T cells." Immunity. 2. 639-644 (1995)
[Publications] Park, S. Y.: "Differential Contribution of the FcRγ chain for the surface TCR expression among T cells localized in epithelia: Analysis of FcRγ-deficient mice." Eur. J. Immunol.25. 2107-2110 (1995)
[Publications] Miyateke, S.: "Induction of growth arrest by down-regulation of cyclin D3 in T cell hybridomas." J. Exp. Med.182. 401-408 (1995)
[Publications] Arase, H.: "Developmental arrest of NK1.1^+TRC^+ T cells and expansion of NK1.1^+ TCRγδ^+ T cell development in CD3ζ-deficient mice." J. Exp. Med.182. 891-4895 (1995)
[Publications] Park, S. Y.: "Developmental defects of lymphoid cell in Jak3 kinase-deficient mice." Immunity. 3. 1-20 (1995)
[Publications] Nakano, H.: "Specific interaction between topoisomerase IIβ and CD3ε chain of the T cell receptor compex." J. Biol. Chem.271. 6483-6489 (1996)
[Publications] Tezuka, T.: "Physical and functional association of the cbl proto-oncogene product with a Src-family protein tyrosine kinase, p53/56 ^<lyn>, in the B cell antigen receptor-mediated signaling." J. Exp. Med.(in press).
[Publications] Fusaki, N.: "Physical and functional interactions of protein tyrosine kinases, p59^<fyn> and ZAP-70, in T cell signaling." J. Immunol.(in press).
[Publications] Kong, Y. -Y.: "Differential requirements of CD45 for lymphocyte development and function." Eur. J. Immunol.25. 3431-3436 (1995)
[Publications] Kong, Y. -Y.: "Deneration of T cells with differential responses to alloantigens in CD45 exon 6-deficient mice." J. Immunol.154. 5725-5735 (1995)
[Publications] Zou, J-P.: "Systemic administration of rIL-12 induces complete tumor regression and protective immunity: Response is corelated with a striking reversal of supppressed interferon-g production by anti-tumor T cells." Int. Immunol.7. 1135-1145 (1995)
[Publications] Toyooka, K.: "CD28 costimulatory signals induce IL-2 receptor expression on antigenstimulated virgin T cells by an IL-2-independent mechanisms." Int. Immunol.(in press).
[Publications] Maruo, S.: "IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones." J. Immunol.(in press).
[Publications] Fujii, H.: "Vaccination of tumor cells transfected with B7-1(CD80)gene induces the antimetastatic effect and tumor immunity in mice." Int. J. Cancer. (in press).
[Publications] Takeshita, T.: "Molecular analysis of the same HIV peptide functionally binding to both a class I and a class II MHC molecule." J. Immunol.154. 1973-1986 (1995)
[Publications] Takahashi, H.: "Inactivation of HIV-1 envelope-specific CD8^+ cytotoxic T lymphocytes by free antigenic peptide: A self veto mechanisms?" J. Exp. Med.(in press).
[Publications] Miyazaki, T.: "Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation." Cell. 81. 223-231 (1995)
[Publications] Fujii, H.: "Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor β chain but is not essential for the proliferative signal transmission." Proc. Natl. Acad. Sci. USA. 92. 5482-5486 (1995)
[Publications] Kawahara, A.: "Critical role of the interleukin 2(IL-2)receptor γ-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction,." Proc. Natl. Acad. Sci. USA. 92. 5482-5486 (1995)

1995 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] Aoe, T.: "Activated macrophares induce structural abnormalities of the T cell receptor-CD3 complex." J. Exp. Med.181. 1881-1886 (1995)

[Publications] Ono, S.: "Rapid turnover of the CD3ζ chain independent of the TCR-CD3 complex in normal T cells." Immunity. 2. 639-644 (1995)

[Publications] Park, S. Y.: "Differential Contribution of the FcRγ chain for the surface TCR expression among T cells localized in epithelia: Analysis of FcRγ-deficient mice." Eur. J. Immunol.25. 2107-2110 (1995)

[Publications] Miyateke, S.: "Induction of growth arrest by down-regulation of cyclin D3 in T cell hybridomas." J. Exp. Med.182. 401-408 (1995)

[Publications] Arase, H.: "Developmental arrest of NK1.1^+TRC^+ T cells and expansion of NK1.1^+ TCRγδ^+ T cell development in CD3ζ-deficient mice." J. Exp. Med.182. 891-4895 (1995)

[Publications] Park, S. Y.: "Developmental defects of lymphoid cell in Jak3 kinase-deficient mice." Immunity. 3. 1-20 (1995)

[Publications] Nakano, H.: "Specific interaction between topoisomerase IIβ and CD3ε chain of the T cell receptor compex." J. Biol. Chem.271. 6483-6489 (1996)

[Publications] Tezuka, T.: "Physical and functional association of the cbl proto-oncogene product with a Src-family protein tyrosine kinase, p53/56 ^<lyn>, in the B cell antigen receptor-mediated signaling." J. Exp. Med.(in press).

[Publications] Fusaki, N.: "Physical and functional interactions of protein tyrosine kinases, p59^<fyn> and ZAP-70, in T cell signaling." J. Immunol.(in press).

[Publications] Kong, Y. -Y.: "Differential requirements of CD45 for lymphocyte development and function." Eur. J. Immunol.25. 3431-3436 (1995)

[Publications] Kong, Y. -Y.: "Deneration of T cells with differential responses to alloantigens in CD45 exon 6-deficient mice." J. Immunol.154. 5725-5735 (1995)

[Publications] Zou, J-P.: "Systemic administration of rIL-12 induces complete tumor regression and protective immunity: Response is corelated with a striking reversal of supppressed interferon-g production by anti-tumor T cells." Int. Immunol.7. 1135-1145 (1995)

[Publications] Toyooka, K.: "CD28 costimulatory signals induce IL-2 receptor expression on antigenstimulated virgin T cells by an IL-2-independent mechanisms." Int. Immunol.(in press).

[Publications] Maruo, S.: "IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones." J. Immunol.(in press).

[Publications] Fujii, H.: "Vaccination of tumor cells transfected with B7-1(CD80)gene induces the antimetastatic effect and tumor immunity in mice." Int. J. Cancer. (in press).

[Publications] Takeshita, T.: "Molecular analysis of the same HIV peptide functionally binding to both a class I and a class II MHC molecule." J. Immunol.154. 1973-1986 (1995)

[Publications] Takahashi, H.: "Inactivation of HIV-1 envelope-specific CD8^+ cytotoxic T lymphocytes by free antigenic peptide: A self veto mechanisms?" J. Exp. Med.(in press).

[Publications] Miyazaki, T.: "Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation." Cell. 81. 223-231 (1995)

[Publications] Fujii, H.: "Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor β chain but is not essential for the proliferative signal transmission." Proc. Natl. Acad. Sci. USA. 92. 5482-5486 (1995)

[Publications] Kawahara, A.: "Critical role of the interleukin 2(IL-2)receptor γ-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction,." Proc. Natl. Acad. Sci. USA. 92. 5482-5486 (1995)

斉藤隆千葉大学, 医学部, 教授 (50205655)