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リンパ球の初期分化を誘導・制御するシグナル伝達機構

Research Project

Project/Area Number 12051243
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo Medical and Dental University

Principal Investigator

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)

Co-Investigator(Kenkyū-buntansha) 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, ウイルス研究所, 教授 (90193177)
塚田 聡  大阪大学, 大学院・医学研究科, 助手 (60273637)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥165,500,000 (Direct Cost: ¥165,500,000)
Fiscal Year 2002: ¥57,200,000 (Direct Cost: ¥57,200,000)
Fiscal Year 2001: ¥58,500,000 (Direct Cost: ¥58,500,000)
Fiscal Year 2000: ¥49,800,000 (Direct Cost: ¥49,800,000)
KeywordsB細胞分化 / チロシンリン酸化 / Btk / Sab / T細胞レセプター遺伝子 / ヒストンアセチル化 / 抗原提示細胞 / Ly49Q / シグナル伝達 / PLCγ2 / IL-7レセプター / マクロファージ活性化 / プレB細胞レセプター / BLNK / サイトカイン / STAT / NK細胞 / CD94
Research Abstract

(1)プロB細胞よりクローニングしたTPP36とそのアイソフォームであるTPP32がともにチロシンキナーゼAb1によって効率よくチロシンリン酸化されること、しかも120番目チロシン残基のリン酸化によって立体構造変化がひきおこされることが判明した。両分子ともN末端近傍に典型的な核移行シグナル配列をもつが、核ではなく細胞質に局在しており、リン酸化にともなう核移行の可能性が示唆された。
(2)我々は以前、BtkのSH3ドメインに結合し、Btkの活性を抑制する新規分子Sab (SH3BP5)を同定したが、今回はSabがミトコンドリア内に局在し、活性型のJNKと会合し、さらにJNKによってリン酸化される事を示した。これらのことにより、B細胞のアポトーシスに機能すると考えられるBtkとJNKの両分子のクロストークにおけるSabの介在の可能性を示した。
(3)TCRγ遺伝子座において、サイトカイン非刺激下では調節領域のヒストンH3Lys9がメチル化されていたが、刺激後数日間で徐々に低下し、代わりにアセチル化レベルが上昇した。この時、Jγ領域のgermline転写とクロマチンのaccessibilityも同様に上昇した。以上の結果からTCRγ遺伝子座のクロマチンの閉じた状態とヒストンH3Lys9のメチル化が良く相関することが示された。
(4)マクロファージおよび未熟樹状細胞に発現する新規抑制性レセプターLy49Qの性状解析を行った。Ly49Qは細胞内ITIMのリン酸化依存的にSHP-2を会合した。マクロファージおよびプラスマ細胞様樹状細胞は抗Ly49Q抗体処理により速やかに接着伸展し、極性を形成した。さらにLy49Qの過剰発現によって、細胞接着が抑制されたことから、Ly49Qはこれらの細胞で細胞接着能の制御に関与することが示唆された。

Report

(3 results)
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (53 results)

All Other

All Publications (53 results)

  • [Publications] Wang, Y-H., et al.: "Differential surrogate light chain expression governs B cell differentiation"Blood. 99. 2459-2467 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taguchi, T., et al.: "Pre-BCR-mediated signal inhibits CD24-induced apoptosis in human pre-B cells"J. Immunol. 170. 252-260 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kubo, S., et al.: "Long-term maintenance of IgE-mediated memory in mast cells in the absence of detectable serum IgE"J. Immunol.. 170. 775-780 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sato, E., et al.: "Chronic inflammation in skin can be induced in IgE transgenic mice by a single challenge of multivalent antigen"J. Allergy Clin. Immunol.. 111. 143-148 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Saijo, K., et al.: "Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development"Nature Immunol.. 4. 274-279 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuchiya, K., et al.: "Molecular cloning and characterization of TPP36 and its isoform TPP32,_novel substrates of Abl tyrosine kinase"FEBS lett.. 537. 203-209 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 烏山 一: "プレB細胞レセプターを介するB細胞分化誘導"蛋白質核酸酵素増刊号. 47. 2182-2187 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 烏山 一: "B細胞発生・分化の分子制御機構とその破綻"感染炎症免疫. 32. 18-27 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Wiltshire, C., et al.: "A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab(SH3BP5), associates with mitochondria"Biochem J.. 367. 577-585 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Agematsu, K., et al.: "Absence of memory B cells in patients with common variable immunodeficiency"Clin Immunol.. 103. 34-42 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Inabe, K., et al.: "Bruton's tyrosine kinase regulates B cell antigen receptor-mediated JNK1 response through Rac1 and phospholipase C-gamma2 activation"FEBS Lett.. 514. 260-262 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Lee, H.-C., et al.: "Seeding of dendritic epidermal T cells in the neonatal skin is reduced in 129 strain of mice"Immunol. Lett.. 81. 211-216 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Han, H., et al.: "Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision"Int. Immunol.. 14. 637-645 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Watanabe, N., et al.: "Activation and differentiation of autoreactive B-1 cells by interleukin-10 induce autoimmune hemolytic anemia in Fas-deficient anti-erythrocyte immunoglobulin transgenic mice"J. Exp. Med.. 196. 141-146 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Lahn, M., et al.: "MHC class I-dependent Vγ4^+ pulmonary T cells regulate αβ T cell-independent airway responsiveness"Proc. Natl. Acad. Sci. USA.. 99. 8850-8855 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Wang, J.W, et al.: "Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation"Science. 15. 2094-2097 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 反町典子: "NK細胞の系統発生-missing self認識の起源を求めて 動物界における免疫系の進化 別冊医学のあゆみ"医歯薬出版株式会社. 5 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 反町典子: "抑制性レセプターによる細胞接着制御 蛋白質核酸酵素増刊号 免疫研究の最前線"共立出版. 5 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 反町典子: "NKレセプターファミリー分,CD94とLy49Qの機能 Molecular Medicine増刊号 免疫2002"中山書店. 9 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 烏山 一: "「B細胞の初期分化」標準免疫学第2版(谷口克、宮坂昌之編)"医学書院. 9 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Stephan, R. P.: "Analysis of VpreB expression during B lineage differentiation in lambda5-deficient mice"J.Immunol. 167. 3734-3739 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wang, Y-H., et al.: "Differential surrogate light chain expression governs B cell differentiation"Blood. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Honda, K., et al.: "Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis"J.Exp.Med.. 193. 621-630 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ohba, Y., et al.: "Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis"EMBO J. 20. 3333-3341 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fagarasan, S., et al.: "In situ class switching and differentiation to IgA-producing cells in the gut lamina propria"Nature. 413. 639-643 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakamoto, M., et al.: "Maternal germilne mosaicism of X-linked agammaglobulinemia"Am.J.Med Genet.. 99. 234-237 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Baba, Y. et al.: "BLNK mediates Syk-dependent Btk activation"Proc.Natl.Acad.Sci.USA.. 98. 2582-2586 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Usui, K., et al.: "Reccurent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults"Respir.Res.. 2. 188-192 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsukada, S., et al.: "Btk and BLNK in B cell development"Adv.Immunol.. 77. 123-162 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wang, Y., et al.: "Bruton's tyrosine kinase gene mutations in Turkish patients wuth presumed X-linked agammaglobulinemia"Hum.Mutat.. 18. 356 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wang, J.-W., et al.: "SHIP influences the NK repertoire and allogeneic marrow transplantation"Science. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toyama-Sorimachi, N., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 5 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maki, K., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 6 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maki,K., et al.: "Immunoglobulin β signaling regulates locus accessibility for ordered Ig gene rearrangements."J.Exp.Med.. 191. 1333-1340 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nomura,K., et al.: "Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway."Blood. 96. 610-617 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kurosaki,T.and Tsukada,S.: "Connecting Syk and Btk to calcium signals."Immunity. 12. 1-5 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Baba,Y., et al.: "BLNK mediates Syk-dependent Btk activation."Proc.Natl.Acad.Sci.USA.. (In press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Agata,Y., et al.: "Histone acetylation determines the developmentally regulated accessibility for T cell receptor-γ gene recombination."J.Exp.Med.. (In press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Toyama-Sorimachi,N., et al.: "Mouse CD94 participates in Qa-1-mediated self recognition by NK cells and delivers inhibitory signals independent of Ly-49."J.Immunol.. (In press).

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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