2001 年度実績報告書

リンパ球の初期分化を誘導・制御するシグナル伝達機構

研究課題

研究課題/領域番号	12051243
研究機関	東京医科歯科大学
研究代表者	烏山一東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (60195013)
研究分担者	反町典子東京医科歯科大学, 大学院・医歯学総合研究科, 講師 (30217468) 生田宏一京都大学, 大学院・医学研究科, 助教授 (90193177) 塚田聡大阪大学, 大学院・医学研究科, 助手 (60273637)
キーワード	シグナル伝達 / B細胞分化 / Btk / PLCγ2 / IL-7レセプター / ヒストンアセチル化 / マクロファージ活性化 / Ly49Q
研究概要	(1)前年度の研究でクローニングに成功した新規分子(PP36)にはalternative splicingによる2つのvariant(分子量36kDと32kD)が存在することを明らかにした。プロB細胞上に発現するIgβ分子の架橋刺激によって両分子ともチロシンリン酸化を受けること、またそのリン酸化にはLynやSykなどのキナーゼが関与していることを明らかにした。さらにPP36に会合する分子を同定した。 (2)B細胞上の抗原受容体刺激後に細胞内カルシウムの動員が生じるためにはBtkが必須であり、その過程はホスホリパーゼCγ2(PLCγ2)の活性化を経て生じる。我々はBtkとアダプタ-分子BLNKの相互作用がPLCγ2の活性化に必須であることを報告したが、今回はBtkはPLCγ2の4つのチロシン残基をリン酸化し、PLCγ2の活性化はそれらのリン酸化が協調的に働いて生じることを明らかにした。 (3)IL-7レセプタ-のシグナル分子STAT5がTCRγ遺伝子座のJγプロモ-ターやエンハンサーに結合し、CBPやP300などの転写共役因子をリクルートし、ヒストンをアセチル化することを示した。IL-7レセプター欠損胸腺細胞に活性型STAT5を発現させるとTCRγ遺伝子座の転写とDNA組換えが回復した。STAT5はTCRγ遺伝子座のクロマチン構造変換を引き起こし、転写とDNA組換えを誘導すると考えられた。 (4)胎児肝臓内単核球より新規に同定した新規Ly49分子、Ly4gQはNK細胞ではなくGr-1陽性細胞に発現し、その発現がIFNγにより増強されることを明らかにした。抗Ly49Q抗体がマクロファージの細胞内タンパク質のチロシンリン酸化を誘導すること、またそれに伴い急激な形態変化と細胞接着の昂進が認められることから、Ly49Qはマクロファージの活性化制御に重要な役割を果たすことが強く示唆された。

研究成果
(27件)

すべてその他

すべて文献書誌 (27件)

[文献書誌] Toyama-Sorimachi, N., et al.: "Mouse CD94 participates in Qa-1-mediated self recognition by NK cells and delivers inhibitory signals independent of Ly49"J.Immunol.. 166. 3771-3779 (2001)
[文献書誌] Kouro, T., et al.: "Bruton's tyrosine kinase (Btk) is required for signaling the CD79b-mediated pro-B to pre-B cell transition"Int.Immunol.. 13. 485-493 (2001)
[文献書誌] Agematsu, K., et al.: "Complete arrest from pro-to pre-B cells in a case of B cell-negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations"Clin.Exp.Immunol. 124. 461-464 (2001)
[文献書誌] Kinoshita, T., et al.: "Oncostatin M suppresses generation of lymphoid progenitors in fetal liver by inhibiting the hepatic microenvironment"Exp.Hematol.. 299. 1091-1097 (2001)
[文献書誌] Kubo, S., et al.: "Drastic up-regulation of high affinity IgE receptor on mast cells is induced by IgE binding through stabilization and accumulation of the receptor on the cell surface"J.Immunol.. 167. 3427-3434 (2001)
[文献書誌] Stephan, R. P.: "Analysis of VpreB expression during B lineage differentiation in lambda5-deficient mice"J.Immunol. 167. 3734-3739 (2001)
[文献書誌] Wang, Y-H., et al.: "Differential surrogate light chain expression governs B cell differentiation"Blood. (in press). (2002)
[文献書誌] Honda, K., et al.: "Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis"J.Exp.Med.. 193. 621-630 (2001)
[文献書誌] Agata, Y., et al.: "Histone acetylation determines the developmentally regulated accessibility for T cell receptor-γ gene recombination"J.Exp.Med.. 193. 873-879 (2001)
[文献書誌] Lee, H.-C., et al.: "Induction of germline transcription in the human T cell receptor γ locus by STAT5"J.Immunol.. 167. 320-326 (2001)
[文献書誌] Ohba, Y., et al.: "Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis"EMBO J. 20. 3333-3341 (2001)
[文献書誌] Ye, S.-K., et al.: "Differential roles of cytokine receptors in the development of epidermal γ δ T Cells"J.Immunol.. 167. 1929-1934 (2001)
[文献書誌] Fagarasan, S., et al.: "In situ class switching and differentiation to IgA-producing cells in the gut lamina propria"Nature. 413. 639-643 (2001)
[文献書誌] Ye, S.-K., et al.: "The IL-7 receptor controls the accessibility of the TCR γ locus by Stat5 and histone acetylation"Immunity. 15. 813-823 (2001)
[文献書誌] Lee, H.-C., et al.: "Seeding of dendritic epidermal T cells in the neonatal skin is reduced in 129 strain of mice"Immunol.Lett.. (in press). (2002)
[文献書誌] Sakamoto, M., et al.: "Maternal germilne mosaicism of X-linked agammaglobulinemia"Am.J.Med Genet.. 99. 234-237 (2001)
[文献書誌] Baba, Y. et al.: "BLNK mediates Syk-dependent Btk activation"Proc.Natl.Acad.Sci.USA.. 98. 2582-2586 (2001)
[文献書誌] Usui, K., et al.: "Reccurent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults"Respir.Res.. 2. 188-192 (2001)
[文献書誌] Joe, E-K., et al.: "Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase (Btk) gene from seven Korean X-linked agammaglobulinemia families"J.Immunol.. 167. 4038-4045 (2001)
[文献書誌] Tsukada, S., et al.: "Btk and BLNK in B cell development"Adv.Immunol.. 77. 123-162 (2001)
[文献書誌] Kanegane, H., et al.: "Clinical and genetic characteristics of hypogammaglobulinemic males with Btk mutations detected by flow cytometric assay combined with genetic analysis"J.Allergy.Clin.Immunol.. 108. 1012-1020 (2001)
[文献書誌] Futatani, T., et al.: "Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinemia and carrier females"Br.J.Haematol.. 114. 141-149 (2001)
[文献書誌] Wang, Y., et al.: "Bruton's tyrosine kinase gene mutations in Turkish patients wuth presumed X-linked agammaglobulinemia"Hum.Mutat.. 18. 356 (2001)
[文献書誌] Watanabe, D., et al.: "Four tyrosine residues in phospholipase C-gamma2, identified as Btk-dependent phodphorylation sites, are required for B cell antigen receptor-coupled calcium signaling"J.Biol.Chem.. 276. 38595-38601 (2001)
[文献書誌] Wang, J.-W., et al.: "SHIP influences the NK repertoire and allogeneic marrow transplantation"Science. (In press). (2002)
[文献書誌] Toyama-Sorimachi, N., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 5 (2001)
[文献書誌] Maki, K., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 6 (2001)

2001 年度 実績報告書

リンパ球の初期分化を誘導・制御するシグナル伝達機構

研究代表者

烏山 一 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (60195013)

研究成果

[文献書誌] Toyama-Sorimachi, N., et al.: "Mouse CD94 participates in Qa-1-mediated self recognition by NK cells and delivers inhibitory signals independent of Ly49"J.Immunol.. 166. 3771-3779 (2001)

[文献書誌] Kouro, T., et al.: "Bruton's tyrosine kinase (Btk) is required for signaling the CD79b-mediated pro-B to pre-B cell transition"Int.Immunol.. 13. 485-493 (2001)

[文献書誌] Agematsu, K., et al.: "Complete arrest from pro-to pre-B cells in a case of B cell-negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations"Clin.Exp.Immunol. 124. 461-464 (2001)

[文献書誌] Kinoshita, T., et al.: "Oncostatin M suppresses generation of lymphoid progenitors in fetal liver by inhibiting the hepatic microenvironment"Exp.Hematol.. 299. 1091-1097 (2001)

[文献書誌] Kubo, S., et al.: "Drastic up-regulation of high affinity IgE receptor on mast cells is induced by IgE binding through stabilization and accumulation of the receptor on the cell surface"J.Immunol.. 167. 3427-3434 (2001)

[文献書誌] Stephan, R. P.: "Analysis of VpreB expression during B lineage differentiation in lambda5-deficient mice"J.Immunol. 167. 3734-3739 (2001)

[文献書誌] Wang, Y-H., et al.: "Differential surrogate light chain expression governs B cell differentiation"Blood. (in press). (2002)

[文献書誌] Honda, K., et al.: "Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis"J.Exp.Med.. 193. 621-630 (2001)

[文献書誌] Agata, Y., et al.: "Histone acetylation determines the developmentally regulated accessibility for T cell receptor-γ gene recombination"J.Exp.Med.. 193. 873-879 (2001)

[文献書誌] Lee, H.-C., et al.: "Induction of germline transcription in the human T cell receptor γ locus by STAT5"J.Immunol.. 167. 320-326 (2001)

[文献書誌] Ohba, Y., et al.: "Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis"EMBO J. 20. 3333-3341 (2001)

[文献書誌] Ye, S.-K., et al.: "Differential roles of cytokine receptors in the development of epidermal γ δ T Cells"J.Immunol.. 167. 1929-1934 (2001)

[文献書誌] Fagarasan, S., et al.: "In situ class switching and differentiation to IgA-producing cells in the gut lamina propria"Nature. 413. 639-643 (2001)

[文献書誌] Ye, S.-K., et al.: "The IL-7 receptor controls the accessibility of the TCR γ locus by Stat5 and histone acetylation"Immunity. 15. 813-823 (2001)

[文献書誌] Lee, H.-C., et al.: "Seeding of dendritic epidermal T cells in the neonatal skin is reduced in 129 strain of mice"Immunol.Lett.. (in press). (2002)

[文献書誌] Sakamoto, M., et al.: "Maternal germilne mosaicism of X-linked agammaglobulinemia"Am.J.Med Genet.. 99. 234-237 (2001)

[文献書誌] Baba, Y. et al.: "BLNK mediates Syk-dependent Btk activation"Proc.Natl.Acad.Sci.USA.. 98. 2582-2586 (2001)

[文献書誌] Usui, K., et al.: "Reccurent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults"Respir.Res.. 2. 188-192 (2001)

[文献書誌] Joe, E-K., et al.: "Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase (Btk) gene from seven Korean X-linked agammaglobulinemia families"J.Immunol.. 167. 4038-4045 (2001)

[文献書誌] Tsukada, S., et al.: "Btk and BLNK in B cell development"Adv.Immunol.. 77. 123-162 (2001)

[文献書誌] Kanegane, H., et al.: "Clinical and genetic characteristics of hypogammaglobulinemic males with Btk mutations detected by flow cytometric assay combined with genetic analysis"J.Allergy.Clin.Immunol.. 108. 1012-1020 (2001)

[文献書誌] Futatani, T., et al.: "Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinemia and carrier females"Br.J.Haematol.. 114. 141-149 (2001)

[文献書誌] Wang, Y., et al.: "Bruton's tyrosine kinase gene mutations in Turkish patients wuth presumed X-linked agammaglobulinemia"Hum.Mutat.. 18. 356 (2001)

[文献書誌] Watanabe, D., et al.: "Four tyrosine residues in phospholipase C-gamma2, identified as Btk-dependent phodphorylation sites, are required for B cell antigen receptor-coupled calcium signaling"J.Biol.Chem.. 276. 38595-38601 (2001)

[文献書誌] Wang, J.-W., et al.: "SHIP influences the NK repertoire and allogeneic marrow transplantation"Science. (In press). (2002)

[文献書誌] Toyama-Sorimachi, N., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 5 (2001)

[文献書誌] Maki, K., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 6 (2001)

2001 年度実績報告書

烏山一東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (60195013)