2000 Fiscal Year Annual Research Report

T細胞の抗原認識と活性化制御

Research Project

Project/Area Number	12051203
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (A)
Research Institution	Chiba University
Principal Investigator	斉藤隆千葉大学, 大学院・医学研究科, 教授 (50205655)
Co-Investigator(Kenkyū-buntansha)	西村泰治熊本大学, 大学院・医学研究科, 教授 (10156119) 湊長博京都大学, 大学院・生命科学研究科, 教授 (40137716) 中山俊憲千葉大学, 大学院・医学研究科, 助教授 (50237468)
Keywords	Gab-2 / CTLA-4 / Rap-1 / Spa-1 / Th1 / Th2 / カルシニューリン / シグナルクロストーク / 部分アゴニスト
Research Abstract	T細胞の抗原認識シグナルの伝達機構とその制御系について解析した。ヒトT細胞クローンを用いることにより、溶連菌由来ペプチドの一残基置換による部分アゴニストが引き起こす反応は、増殖反応を誘導するにも関わらず、ZAP-70やLATの活性化を伴わないことが判明し、部分ペプチドによる未知のT細胞活性化経路の存在を示唆した(西村)。TCRシグナル下流の調節分子として、small G蛋白rap-1とアダプター分子Gab-2を解析した。Rap-1はβ1-integrinのみでなく、β2-integrin,LFA-1の活性化に重要であることが、rap-1GAPであるSPA-1に解析から明らかになり、inside-outのシグナル伝達を主要に担うことが判明した(湊)。サイトカインシグナルではMAPK活性化に働くGab-2が、TCRシグナルにおいては抑制シグナルを伝え、SHP-2をリクルートしてCD3ζ脱リン酸化を誘導することが判明した(斉藤)。また、ナイーブT細胞からTh2への分化には、TCRシグナル伝達系としてカルシニューリンの活性化が重要であることが判明した(中山)。一方、TCRシグナルを制御する他のレセプター、co-stimulationシグナル、およびサイトカインシグナルとの相互制御の解析も進んだ。抑制レセプターCTLA-4の細胞内局在と発現制御を調べ、CD4^+T細胞ではCTLA-4はリソソームに蓄積しており、TCR刺激に伴ってリソソームが分泌されることによって細胞表面CTLA-4の昂進が起こる、ユニークな制御系を発見した(斉藤)。Th2分化にはIL-4レセプターのシグナル伝達に重要なJak3の転写誘導とSTAT5のIL-4レセプターへの会合が重要であり、TCRシグナルによるサイトカインシグナルの調節というクロストークが明らかになった(中山)。

Research Products
(34 results)

All Other

All Publications (34 results)

[Publications] Suzuki,K.: "Janus kinase 3 (Jak 3) is essential for common cytokine receptor γ chain(γc)-dependen signaling : comparative analysis of γc, Jak 3, and γc and Jak 3 double deficient mice."Int.Immunol.. 12. 123-132 (2000)
[Publications] Fossati-Jimack,L.: "Markedly different pathogenicity of four immunoguloblin Gisotype-switch variants o an antierythrocyte autoantibody is based on their capacity to interact in vivo with low-affinity Fcγ receptor III."J.Exp.Med.. 191. 1293-1302 (2000)
[Publications] Hamano,Y.: "Immune complex and Fc receptor-mediated augmentation of antigen presentation for in vivo helper T cell responses."J.Immunol.. 164. 6113-6119 (2000)
[Publications] Nakatsu,F.: "A di-leucine signal in the ubiquitin moiety : possible involvement in ubiquitination-mediated endocytosis."J.Biol.Chem.. 275. 26213-26219 (2000)
[Publications] Tsujino,S.: "Differential requirement of the cytoplasmic subregions of γc chain in T cell development and function."Proc.Natl.Acad.Sci.USA. 97. 10514-10519 (2000)
[Publications] Suzuki,K.: "Role of common cytokine receptor γ chain (γc)-and Jak3-dependent signaling in the proliferation and survival of murine mast cells."Blood. 96. 2172-2180 (2000)
[Publications] Iida,T.: "Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosmes upon activation of CD4^+ T cells."J.Immunol.. 165. 5062-5068 (2000)
[Publications] Okazaki,Y.: "Cell surface expression of calnexin, a molecular chaperone in the endoplasmic reticulum."J.Biol.Chem.. 275. 35751-35758 (2000)
[Publications] Watanabe,N.: "The quantity of TCR signaling determines positive selection and commitment of cells."J.Immunol.. 165. 6252-6261 (2000)
[Publications] Arase,H.: "Negative regulation of expression and function of Fcγ RIII by CD3ζ in murine NK cells."J.Immunol.. 166. 21-25 (2001)
[Publications] Okada,T.: "BCAP : The tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation."Immunity. 13. 817-827 (2000)
[Publications] Ishiai,M.: "Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane."J.Exp.Med.. 192. 847-856 (2000)
[Publications] Hashimoto,A.: "Essential role of phospholopase C-γ 2 in B cell development and function."J.Immunol.. 165. 1738-1742 (2000)
[Publications] Yasuda,T.: "Cb1 suppresses B cell receptor-mediated phospholipase C (PLC)-γ 2 activation by regulating B cell linker protein-PLC-γ 2 binding."J.Exp.Med.. 191. 641-650 (2000)
[Publications] Kurosaki,T.: "BLNK : Connecting Syk and Btk to calcium signals."Immunity. 12. 1-5 (2000)
[Publications] Kurosaki,T.: "Functional dissection of BCR signaling pathways"Curr.Opin.Immunol.. 12. 276-281 (2000)
[Publications] Liou,J.: "HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1."Immunity. 12. 399-408 (2000)
[Publications] Wong,J.: "Functional complementation of BLNK by SLP-76 and LAT linker proteins."J.Biol.Chem.. 275. 33116-33122 (2000)
[Publications] Pogue,S.L.: "B cell antigen receptor-induced activation of Akt promotes B cell survival and is dependent on Syk kinase."J.Immunol.. 165. 1300-1306 (2000)
[Publications] Grishin,A.: "Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signalling pathways for G-CSF."Oncogene. 19. 97-105 (2000)
[Publications] Burrows,P.D.: "Activation of self-reactive B cells and autoimmune diseases."Reviews in Immunogenetics. 2. 38-51 (2000)
[Publications] Yayoshi-Yamamoto,S.: "FRL, a novel member of Formin-related proteins, that binds to Rac and regulates cell motility and survival of macrophages."Mol.Cet.Biol.. 20. 6872-6881 (2000)
[Publications] Ochi,H.: "Negative regulation of BCR-mediated signaling in B-1 cells through CD5 and Ly49 coreceptors via Lyn kinase activity."Int.Immunol.. 12. 1417-1423 (2000)
[Publications] Kondo,S.: "Suppression of insulitis and diabetes in B cell-deficient mice treated with streptozocin : b cells are essential for the T cell receptor clonotype spreading of islet-infiltrating T cells."Int.Immunol.. 12. 1075-1083 (2000)
[Publications] Kobayashi,T.: "Abnormal functional and morphological regulation of the gastric mucosa in histamine H2 receptor-dificient mice."J.Clin.Invest.. 105. 1741-1749 (2000)
[Publications] Marguet,D.: "Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26."Proc.Natl.Acad.Sci.USA. 97. 6874-6879 (2000)
[Publications] Sonoda,K.: "The clinical significance of tumor-associated antigen RCAS1 expression in the normal, hyperplastic, and malignant uterine endometrium"Gynecol.Oncol.. 79. 424-429 (2000)
[Publications] Iwasaki,T.: "The expression of human tumor-associated antigen RCAS1 and the prognostic significance in lung cancer."Int.J.Cancer. 89. 488-493 (2000)
[Publications] Nakahara,H.: "Vascular permeability in allergic conjunctivitis in mice lacking histamine H1 receptors."Eur.J.Pharmacol.. 409. 313-317 (2000)
[Publications] Izumizaki,M.: "Lack of temperature-induced polypnea in histamine H1 receptor-deficient mice."Neurosci.Lett. 284. 139-142 (2000)
[Publications] Mobarakeh,J.I.: "Role of histamine H1 receptor in pain perception : a study of the receptor gene knockout mice."Eur.J.Pharmacol.. 391. 81-89 (2000)
[Publications] Ohshima,K.: "Expression of RCAS1 and FasL in human trophoblasts and uterine glands during pregnancy ; the possible role in immune privilege."Clin.Exp.Immunol.. (In press).
[Publications] Masaki,T.: "Targeted disruption of histamine H1 receptor attenuated regulatory effect of leptin on feeding behavior, adiposity and UCP family expression in mice."Diabetes. (In press).
[Publications] Masaki,T.: "Central infusion of hitamine reduced fat accumulation and increased UCP family expression in leptin resistant obese mice."Diabetes. (In press).

2000 Fiscal Year Annual Research Report

T細胞の抗原認識と活性化制御

Principal Investigator

斉藤 隆 千葉大学, 大学院・医学研究科, 教授 (50205655)

Research Products

[Publications] Suzuki,K.: "Janus kinase 3 (Jak 3) is essential for common cytokine receptor γ chain(γc)-dependen signaling : comparative analysis of γc, Jak 3, and γc and Jak 3 double deficient mice."Int.Immunol.. 12. 123-132 (2000)

[Publications] Fossati-Jimack,L.: "Markedly different pathogenicity of four immunoguloblin Gisotype-switch variants o an antierythrocyte autoantibody is based on their capacity to interact in vivo with low-affinity Fcγ receptor III."J.Exp.Med.. 191. 1293-1302 (2000)

[Publications] Hamano,Y.: "Immune complex and Fc receptor-mediated augmentation of antigen presentation for in vivo helper T cell responses."J.Immunol.. 164. 6113-6119 (2000)

[Publications] Nakatsu,F.: "A di-leucine signal in the ubiquitin moiety : possible involvement in ubiquitination-mediated endocytosis."J.Biol.Chem.. 275. 26213-26219 (2000)

[Publications] Tsujino,S.: "Differential requirement of the cytoplasmic subregions of γc chain in T cell development and function."Proc.Natl.Acad.Sci.USA. 97. 10514-10519 (2000)

[Publications] Suzuki,K.: "Role of common cytokine receptor γ chain (γc)-and Jak3-dependent signaling in the proliferation and survival of murine mast cells."Blood. 96. 2172-2180 (2000)

[Publications] Iida,T.: "Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosmes upon activation of CD4^+ T cells."J.Immunol.. 165. 5062-5068 (2000)

[Publications] Okazaki,Y.: "Cell surface expression of calnexin, a molecular chaperone in the endoplasmic reticulum."J.Biol.Chem.. 275. 35751-35758 (2000)

[Publications] Watanabe,N.: "The quantity of TCR signaling determines positive selection and commitment of cells."J.Immunol.. 165. 6252-6261 (2000)

[Publications] Arase,H.: "Negative regulation of expression and function of Fcγ RIII by CD3ζ in murine NK cells."J.Immunol.. 166. 21-25 (2001)

[Publications] Okada,T.: "BCAP : The tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation."Immunity. 13. 817-827 (2000)

[Publications] Ishiai,M.: "Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane."J.Exp.Med.. 192. 847-856 (2000)

[Publications] Hashimoto,A.: "Essential role of phospholopase C-γ 2 in B cell development and function."J.Immunol.. 165. 1738-1742 (2000)

[Publications] Yasuda,T.: "Cb1 suppresses B cell receptor-mediated phospholipase C (PLC)-γ 2 activation by regulating B cell linker protein-PLC-γ 2 binding."J.Exp.Med.. 191. 641-650 (2000)

[Publications] Kurosaki,T.: "BLNK : Connecting Syk and Btk to calcium signals."Immunity. 12. 1-5 (2000)

[Publications] Kurosaki,T.: "Functional dissection of BCR signaling pathways"Curr.Opin.Immunol.. 12. 276-281 (2000)

[Publications] Liou,J.: "HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1."Immunity. 12. 399-408 (2000)

[Publications] Wong,J.: "Functional complementation of BLNK by SLP-76 and LAT linker proteins."J.Biol.Chem.. 275. 33116-33122 (2000)

[Publications] Pogue,S.L.: "B cell antigen receptor-induced activation of Akt promotes B cell survival and is dependent on Syk kinase."J.Immunol.. 165. 1300-1306 (2000)

[Publications] Grishin,A.: "Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signalling pathways for G-CSF."Oncogene. 19. 97-105 (2000)

[Publications] Burrows,P.D.: "Activation of self-reactive B cells and autoimmune diseases."Reviews in Immunogenetics. 2. 38-51 (2000)

[Publications] Yayoshi-Yamamoto,S.: "FRL, a novel member of Formin-related proteins, that binds to Rac and regulates cell motility and survival of macrophages."Mol.Cet.Biol.. 20. 6872-6881 (2000)

[Publications] Ochi,H.: "Negative regulation of BCR-mediated signaling in B-1 cells through CD5 and Ly49 coreceptors via Lyn kinase activity."Int.Immunol.. 12. 1417-1423 (2000)

[Publications] Kondo,S.: "Suppression of insulitis and diabetes in B cell-deficient mice treated with streptozocin : b cells are essential for the T cell receptor clonotype spreading of islet-infiltrating T cells."Int.Immunol.. 12. 1075-1083 (2000)

[Publications] Kobayashi,T.: "Abnormal functional and morphological regulation of the gastric mucosa in histamine H2 receptor-dificient mice."J.Clin.Invest.. 105. 1741-1749 (2000)

[Publications] Marguet,D.: "Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26."Proc.Natl.Acad.Sci.USA. 97. 6874-6879 (2000)

[Publications] Sonoda,K.: "The clinical significance of tumor-associated antigen RCAS1 expression in the normal, hyperplastic, and malignant uterine endometrium"Gynecol.Oncol.. 79. 424-429 (2000)

[Publications] Iwasaki,T.: "The expression of human tumor-associated antigen RCAS1 and the prognostic significance in lung cancer."Int.J.Cancer. 89. 488-493 (2000)

[Publications] Nakahara,H.: "Vascular permeability in allergic conjunctivitis in mice lacking histamine H1 receptors."Eur.J.Pharmacol.. 409. 313-317 (2000)

[Publications] Izumizaki,M.: "Lack of temperature-induced polypnea in histamine H1 receptor-deficient mice."Neurosci.Lett. 284. 139-142 (2000)

[Publications] Mobarakeh,J.I.: "Role of histamine H1 receptor in pain perception : a study of the receptor gene knockout mice."Eur.J.Pharmacol.. 391. 81-89 (2000)

[Publications] Ohshima,K.: "Expression of RCAS1 and FasL in human trophoblasts and uterine glands during pregnancy ; the possible role in immune privilege."Clin.Exp.Immunol.. (In press).

[Publications] Masaki,T.: "Targeted disruption of histamine H1 receptor attenuated regulatory effect of leptin on feeding behavior, adiposity and UCP family expression in mice."Diabetes. (In press).

[Publications] Masaki,T.: "Central infusion of hitamine reduced fat accumulation and increased UCP family expression in leptin resistant obese mice."Diabetes. (In press).

斉藤隆千葉大学, 大学院・医学研究科, 教授 (50205655)