2002 Fiscal Year Annual Research Report

抗原認識のシグナル変換機構

Research Project

Project/Area Number	12051101
Research Institution	Chiba University
Principal Investigator	斉藤隆千葉大学, 大学院・医学研究院, 教授 (50205655)
Co-Investigator(Kenkyū-buntansha)	渡邊武九州大学, 生体防御医学研究所, 教授 (40028684) 黒崎知博関西医科大学, 医学部, 教授 (50178125)
Keywords	シグナル変換機構 / 免疫シナプス / 抑制性アダプター分子 / BLNK / PLC活性化 / 遺伝子欠損マウス / アポトーシス / ヒスタミン受容体
Research Abstract	本調整班では、リンパ球が抗原認識した後に、機能発現・細胞分化などの様々な運命決定に導くための細胞内でのシグナル伝達系への情報変換機構の解析をT・B細胞において解析する事を目指した。 1)ラフト局在分子CbpがEBP50-ERM-Actinと会合して細胞骨格系にアンカーし、ラフトの膜状での可動性を調節するシステムが存在し、免疫シナプス形成をも制御することを発見した。Gab2がTCRシグナル系ではフィードバック抑制を担うアダプター分子であり、フォスファターゼをLAT/ラフトにリクルートする事によって抑制する機構を明らかにした。また、CTLA-4は主要な抑制性co-stimulationレセプターとしてT細胞分化においても抑制活性を示すことを示唆した。 2)BCRシグナル伝達における重要なアダプター分子BLNKとBCAPをクローニングし、その機能解析を、欠損細胞と欠損マウスを作製して行った。その結果、BLNKがPLCγ2を活性化させる上でラフトにリクルートされることが重要で、活性化BLNKはPLCγ2,Btkと複合体を形成し、BtkによってPLCγ2はリン酸化されることを示した。一方、BCAPは、Sykによりリン酸化され、P13Kのラフトへのリクルートを助け、PLCγ2に直接会合して活性化に関与していることを示唆した。 3)BCRシグナルで誘導される未熟B細胞の細胞死に必要な新規蛋白iWH37を単離した。iWH37はBCR刺激によって発現が誘導され、Mt膜のVDAC、Bacと結合し、高発現させると膜電位の低下を引き起こすことが判明した。一方、ヒスタミン受容体シグナルによるリンパ球の制御を欠損マウスを作製・解析し、アレルギー反応の惹起のみならず、TCR,BCRシグナル伝達系で重要な正の制御およびTH1,Th2細胞分化の制御に重要な役割を果たしていることを明らかにした。

Research Products

(19 results)

All Other

All Publications (19 results)

[Publications] Itoh, K.: "Negative regulation of immune synapse formation by anchoring lipid to cytoskeleton through Cbp-EBP50-ERM assembly"J. Immunol.. 168・2. 541-544 (2002)
[Publications] Azeredo da Silveira, S.: "Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody"J. Exp. Med.. 195・6. 665-672 (2002)
[Publications] Ioan-Facsinay, A.: "FcγRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses and protection from bacterial infection"Immunity. 16・3. 391-402 (2002)
[Publications] Yokosuka, T.: "Predominant role of T cell receptor α chain in forming preimmune TCR repertoire revealed by clonal TCR reconstitution system"J. Exp. Med.. 195・8. 991-1001 (2002)
[Publications] Murata, Y.: "The conversion of redox status of peritoneal macrophages during pathological progression of spontaneous inflammatory bowl disease in Janus family tyrosine kinase 3-/-and IL-2Rγ-/-mice."Int. Immunol.. 14・6. 627-636 (2002)
[Publications] Redegeld, F.A.: "Immunoglobulin free light chains elicit immediate hypersensitivity-like responses"Nat. Med.. 8・7. 694-701 (2002)
[Publications] Snell, D.C.: "Differential effects of reduced glycoprotein VI levels on activation of murine platelets by glycoprotein VI ligands"Biochem. J.. 368・Pt 1. 293-300 (2002)
[Publications] Tarzi, R.M.: "Nephrotoxic nephritis is mediated by Fcγ receptors on circulating leukocytes and not intrinsic renal cells"Kidney Int.. 62・6. 2087-2096 (2002)
[Publications] Matsumoto, K.: "Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL lpr mice"Arthritis. Rheum. 48・2. 486-494 (2003)
[Publications] Yamasaki, S.: "Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells"Moll. Cell. Biol. (in press).
[Publications] Arase, N.: "IgE-mediated activation of NK cells through FcγRIII"J. Immunol. (in press).
[Publications] Saito, T.: "Negative feedback of T cell activation through inhibitory adaptors and co-stimulatory receptors"Immunol. Rev. (in press).
[Publications] Inabe, K.: "Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation"J. Exp. Med.. 195. 189-200 (2002)
[Publications] Yamazaki, T.: "Essential immunoregulatory role for BCAP in B cell development and function"J. Exp. Med.. 195. 535-545 (2002)
[Publications] Kurosaki, T.: "Regulation of B-cell signal transduction by adaptor proteins"Nat. Immunol. Rev.. 2. 354-363 (2002)
[Publications] Himeji, D.: "Characterization of caspase-8L : a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade"Blood. 99. 4070-4078 (2002)
[Publications] Ma, R.Z.: "Identification of Bphs, an autoimmune disease locus, as histamine receptor H1"Science. 297. 620-623 (2002)
[Publications] Jutel, M.: "Immune regulation by histamine"Curr. Opin. Immunol.. 14. 735-740 (2002)
[Publications] Bahar, R.: "Growth retardation, polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulated protein"J. Biol. Chem.. (in press).

2002 Fiscal Year Annual Research Report

抗原認識のシグナル変換機構

Principal Investigator

斉藤 隆 千葉大学, 大学院・医学研究院, 教授 (50205655)

Research Products

[Publications] Itoh, K.: "Negative regulation of immune synapse formation by anchoring lipid to cytoskeleton through Cbp-EBP50-ERM assembly"J. Immunol.. 168・2. 541-544 (2002)

[Publications] Azeredo da Silveira, S.: "Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody"J. Exp. Med.. 195・6. 665-672 (2002)

[Publications] Ioan-Facsinay, A.: "FcγRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses and protection from bacterial infection"Immunity. 16・3. 391-402 (2002)

[Publications] Yokosuka, T.: "Predominant role of T cell receptor α chain in forming preimmune TCR repertoire revealed by clonal TCR reconstitution system"J. Exp. Med.. 195・8. 991-1001 (2002)

[Publications] Murata, Y.: "The conversion of redox status of peritoneal macrophages during pathological progression of spontaneous inflammatory bowl disease in Janus family tyrosine kinase 3-/-and IL-2Rγ-/-mice."Int. Immunol.. 14・6. 627-636 (2002)

[Publications] Redegeld, F.A.: "Immunoglobulin free light chains elicit immediate hypersensitivity-like responses"Nat. Med.. 8・7. 694-701 (2002)

[Publications] Snell, D.C.: "Differential effects of reduced glycoprotein VI levels on activation of murine platelets by glycoprotein VI ligands"Biochem. J.. 368・Pt 1. 293-300 (2002)

[Publications] Tarzi, R.M.: "Nephrotoxic nephritis is mediated by Fcγ receptors on circulating leukocytes and not intrinsic renal cells"Kidney Int.. 62・6. 2087-2096 (2002)

[Publications] Matsumoto, K.: "Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL lpr mice"Arthritis. Rheum. 48・2. 486-494 (2003)

[Publications] Yamasaki, S.: "Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells"Moll. Cell. Biol. (in press).

[Publications] Arase, N.: "IgE-mediated activation of NK cells through FcγRIII"J. Immunol. (in press).

[Publications] Saito, T.: "Negative feedback of T cell activation through inhibitory adaptors and co-stimulatory receptors"Immunol. Rev. (in press).

[Publications] Inabe, K.: "Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation"J. Exp. Med.. 195. 189-200 (2002)

[Publications] Yamazaki, T.: "Essential immunoregulatory role for BCAP in B cell development and function"J. Exp. Med.. 195. 535-545 (2002)

[Publications] Kurosaki, T.: "Regulation of B-cell signal transduction by adaptor proteins"Nat. Immunol. Rev.. 2. 354-363 (2002)

[Publications] Himeji, D.: "Characterization of caspase-8L : a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade"Blood. 99. 4070-4078 (2002)

[Publications] Ma, R.Z.: "Identification of Bphs, an autoimmune disease locus, as histamine receptor H1"Science. 297. 620-623 (2002)

[Publications] Jutel, M.: "Immune regulation by histamine"Curr. Opin. Immunol.. 14. 735-740 (2002)

[Publications] Bahar, R.: "Growth retardation, polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulated protein"J. Biol. Chem.. (in press).

斉藤隆千葉大学, 大学院・医学研究院, 教授 (50205655)