2001 年度実績報告書

抗原認識のシグナル変換機構

研究課題

研究課題/領域番号	12051101
研究機関	千葉大学
研究代表者	斉藤隆千葉大学, 大学院・医学研究院, 教授 (50205655)
研究分担者	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)
キーワード	免疫シナプス / シグナル伝達 / 抗原受容体 / アダプター分子 / アポトーシス / 負の制御 / 細胞骨格 / フォスファターゼ
研究概要	調整班は、抗原認識の機構とそのシグナル伝達・細胞内変換機構の解明を目指し、リンパ球における活性化シグナル系と、アポトーシスを含む負のシグナル調節系を解析した。 (1)T細胞と抗原提示細胞のインターフェイスに作る免疫シナプスの形成の制御機構を解析した。Raftに局在するCbpとの会合分子EBP50を同定し、Cbp-EBP50-ERMの会合を通して、raftを細胞骨格に結合させ、raft凝集を負に制御していることが判明した。また、アダプター分子Gab2によるT細胞活性化の抑制機構として、SHP-2をリクルートする事と共に、活性化アダプターとLAT結合を競合する事も明らかにした。 (2)B細胞の活性化制御に関して、チロシンキナーゼ群とエフェクター群をカップルする役割を担うアダプター分子として、BLNK, BCAPを単離し、その役割解明を行った。BLNKはBCR刺激依存性に細胞膜の特殊な分画であるGEM分画に移行することがより下流のシグナル伝達、特にPLC-γ2の活性化に必須であること、および、新規のアダプター分子BCAPは、チロシン燐酸化されることがPI3K活性化に必須であることを明らかにした。 (3)BCRシグナルによるB細胞活性化の負の制御機構について解析を行った。未熟B細胞株ではBCR刺激によりアポトーシスが誘導されるが、その際、新規分子iWH37の合成が必須であることを見出した。iWH37はアポトーシスの際にミトコンドリアに局在し、VDAC, Bakと結合する。ミトコンドリアにiWH37が局在すると細胞死が誘導される。iWH37はBCR刺激により誘導されることから、未熟B細胞の細胞死に関与する新規分子と考えられる。一方、Bリンパ球においてSHP-1は抑制性共受容体により活性化され、BCRや近傍シグナル分子のリン酸化を負に制御して活性化を負に制御することを明らかにした。

研究成果

(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Arase, H.: "Negative regulation of expression and function of FcγRIII by CD3ζ in murine NK cells"J. Immunol.. 166・1. 21-25 (2001)
[文献書誌] Tomita, K.: "Cytokine-independent Jak3 activation upon TCR stimulation through direct association of Jak3 and the TCR complex"J. Biol. Chem.. 276・27. 25378-25385 (2001)
[文献書誌] Arase, H.: "The mouse NK cell-associated antigen recognized by DX5 mAb is CD49β (α_2 integrin, VLA-2)"J. Immunol.. 167・3. 1141-1144 (2001)
[文献書誌] Takeuchi, A.: "E2A and HEB activate the pre-TCRα promoter during immature T cell development"J. Immunol.. 167・4. 2157-2163 (2001)
[文献書誌] Yamasaki, S.: "Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell recepor signaling by recruitment of inhibitory molecules"J. Biol. Chem.. 276・48. 45175-45183 (2001)
[文献書誌] Itoh, K.: "Negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly"J. Immunol.. 168・2. 541-544 (2002)
[文献書誌] 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.. (in press).
[文献書誌] Ioan-Facsinay, A.: "FcγRI(CD64) contributes substantially to severity of arthritis, hypersensitivity responses and protection from bacterial infection"Immunity. (in press).
[文献書誌] Yokosuka, T.: "Predominant role of TCRα chain in forming pre-immune TCR repertoire revealed by clonal TCR reconstitution system"J. Exp. Med.. (in press).
[文献書誌] Kurosaki, T: "Regulation of phospholipase C-γ2 and phosphoinositide 3-kinase pathways by adaptor proteins in B lymphocytes"Int. Rev. Immunol.. 20. 23-37 (2001)
[文献書誌] Inabe, K.: "Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement"Blood. 99. 584-589 (2002)
[文献書誌] Inabe, K.: "Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation"J. Exp. Med.. 195. 189-200 (2002)
[文献書誌] Yamazaki, T.: "Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high-affinity anti-erythrocyte autoantibody"J. Exp. Med.. 195. 535-545 (2002)
[文献書誌] Jutel, M.: "Histamine regulates T cell and antibody responses by differential expression of H1 and H2 receptors"Nature. 413. 420-425 (2001)
[文献書誌] Huang, Z-L.: "Arousal effect of orexin A depends on activation of the histaminergic system"Proc. Natl. Acad. Sci. USA.. 98. 9965-9970 (2001)
[文献書誌] Kubokawa, M.: "Aberrant intracellular localization of RCAS1 is associated with tumor progression of gastric cancer"Int. J. Oncology.. 19. 695-700 (2001)
[文献書誌] Izumi, M.: "Expression of tumor associated antigen RCAS1 is significantly correlated with poor prognosis in non small cell lung cancer"Cancer. 92・2. 46-451 (2001)
[文献書誌] Oshima, K.: "Expression of human tumor-associated antigen RCAS1 in Reed-Sternberg cells in association with Epstein-Barr virus infection. A potential mechanism of immune evasion"Int. J. Cancer. 93. 91-96 (2001)
[文献書誌] Yuasa, T.: "Lyn is essential for Fcγ receptor III-mediated systemic anaphylaxis but not for the Arthus reaction"J. Exp. Med.. 193・5. 563-571 (2001)
[文献書誌] Matsushima, T.: "RCAS1 : A novel regulator of apoptosis of erythroid progenitor cells"Blood. 96. 313-321 (2001)
[文献書誌] Ohshima, K.: "Expression of RCAS1 and FasL in human trophoblasts and uterine glands during pregnancy ; the possible role in immune privilege"Clin. Exp. Immunol.. 123. 481-486 (2001)

2001 年度 実績報告書

抗原認識のシグナル変換機構

研究代表者

斉藤 隆 千葉大学, 大学院・医学研究院, 教授 (50205655)

研究成果

[文献書誌] Arase, H.: "Negative regulation of expression and function of FcγRIII by CD3ζ in murine NK cells"J. Immunol.. 166・1. 21-25 (2001)

[文献書誌] Tomita, K.: "Cytokine-independent Jak3 activation upon TCR stimulation through direct association of Jak3 and the TCR complex"J. Biol. Chem.. 276・27. 25378-25385 (2001)

[文献書誌] Arase, H.: "The mouse NK cell-associated antigen recognized by DX5 mAb is CD49β (α_2 integrin, VLA-2)"J. Immunol.. 167・3. 1141-1144 (2001)

[文献書誌] Takeuchi, A.: "E2A and HEB activate the pre-TCRα promoter during immature T cell development"J. Immunol.. 167・4. 2157-2163 (2001)

[文献書誌] Yamasaki, S.: "Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell recepor signaling by recruitment of inhibitory molecules"J. Biol. Chem.. 276・48. 45175-45183 (2001)

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

[文献書誌] 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.. (in press).

[文献書誌] Ioan-Facsinay, A.: "FcγRI(CD64) contributes substantially to severity of arthritis, hypersensitivity responses and protection from bacterial infection"Immunity. (in press).

[文献書誌] Yokosuka, T.: "Predominant role of TCRα chain in forming pre-immune TCR repertoire revealed by clonal TCR reconstitution system"J. Exp. Med.. (in press).

[文献書誌] Kurosaki, T: "Regulation of phospholipase C-γ2 and phosphoinositide 3-kinase pathways by adaptor proteins in B lymphocytes"Int. Rev. Immunol.. 20. 23-37 (2001)

[文献書誌] Inabe, K.: "Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement"Blood. 99. 584-589 (2002)

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

[文献書誌] Yamazaki, T.: "Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high-affinity anti-erythrocyte autoantibody"J. Exp. Med.. 195. 535-545 (2002)

[文献書誌] Jutel, M.: "Histamine regulates T cell and antibody responses by differential expression of H1 and H2 receptors"Nature. 413. 420-425 (2001)

[文献書誌] Huang, Z-L.: "Arousal effect of orexin A depends on activation of the histaminergic system"Proc. Natl. Acad. Sci. USA.. 98. 9965-9970 (2001)

[文献書誌] Kubokawa, M.: "Aberrant intracellular localization of RCAS1 is associated with tumor progression of gastric cancer"Int. J. Oncology.. 19. 695-700 (2001)

[文献書誌] Izumi, M.: "Expression of tumor associated antigen RCAS1 is significantly correlated with poor prognosis in non small cell lung cancer"Cancer. 92・2. 46-451 (2001)

[文献書誌] Oshima, K.: "Expression of human tumor-associated antigen RCAS1 in Reed-Sternberg cells in association with Epstein-Barr virus infection. A potential mechanism of immune evasion"Int. J. Cancer. 93. 91-96 (2001)

[文献書誌] Yuasa, T.: "Lyn is essential for Fcγ receptor III-mediated systemic anaphylaxis but not for the Arthus reaction"J. Exp. Med.. 193・5. 563-571 (2001)

[文献書誌] Matsushima, T.: "RCAS1 : A novel regulator of apoptosis of erythroid progenitor cells"Blood. 96. 313-321 (2001)

[文献書誌] Ohshima, K.: "Expression of RCAS1 and FasL in human trophoblasts and uterine glands during pregnancy ; the possible role in immune privilege"Clin. Exp. Immunol.. 123. 481-486 (2001)

2001 年度実績報告書

斉藤隆千葉大学, 大学院・医学研究院, 教授 (50205655)