2002 年度実績報告書

T細胞の抗原認識と活性化制御

研究課題

研究課題/領域番号	12051203
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	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・医学研究院, 教授 (50237468)
キーワード	部分アゴニストペプチド / T細胞エピトープ / 免疫シナプス形成 / 制御性アダプター分子 / インテグリン活性化 / 慢性骨髄性白血 / Th2分化 / ポリコーム遺伝子
研究概要	本研究においては、T細胞が抗原を認識して活性化され、機能分化や機能発現する際の、抗原ペプチド、抑制性アダプター分子、G蛋白、MAPKやCN系、などによるTCRシグナル伝達の制御を解析し、Th1/Th2分化やアナジー誘導などのT細胞機能調節系を解明した。 1)部分アゴニストペプチドによるT細胞応答は、ZAP70/LAT/SLP76などを活性化せずに、PKCm/Ras/B-raf/Erkの活性化に依存した増殖を誘導することが判明した。CLIPペプチドを置換するライブラリーを用いたT細胞エピトープの同定法を開発し、I型糖尿病関連自己抗原を同定した。 2)ラフト局在分子CbpがCbp-EBP50-ERM-Actinの会合によって細胞骨格系にアンカーし、ラフトの細胞膜状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していることを見いだした。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、その抑制機構を明らかにした。細胞表面抑制分子CTLA-4がT細胞分化選択でも抑制機能を有することを示した。 3)G蛋白Rap1がインテグリンの主要な活性化因子であることを見つけ、そのGAPであるSPA-1はRap1の制御を通して、免疫シナプス形成・活性化様式の決定に関わることを明らかにした。SPA-1欠損マウスを作製し、免疫応答不全とともに慢性骨髄性白血病を発症することから、SPA-1が癌抑制遺伝子であることを示した。 4)Th2への分化に必要なTCRシグナル伝達系を解析し、Lck,Ras/Erk,Calcineurinの強い活性化がTh2分化に必要なことを見いだした。実際にマウス喘息モデルにおいて、Th2のRas/MAPKによる亢進と、SHP-1による抑制を証明した。また、Th2分化におけるGATA3によるクロマチンリモデリングの分子機構を解明し、遺伝子発現制御に関与するポリコーム遺伝子がTh2分化に必須であることを明らかにした。

研究成果
(30件)

すべてその他

すべて文献書誌 (30件)

[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.. 195・6. 665-672 (2002)
[文献書誌] Ioan-Facsinay, A.: "FcγRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses and protection from bacterial infection"Immunity. 16・3. 391-402 (2002)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] Redegeld, F.A.: "Immunoglobulin free light chains elicit immediate hypersensitivity-like responses"Nat. Med.. 8・7. 694-701 (2002)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] Matsumoto, K.: "Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL lpr mice"Arthritis. Rheum.. 48・2. 486-494 (2003)
[文献書誌] Yamasaki, S.: "Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells"Moll. Cell. Biol. (in press).
[文献書誌] Arase, N.: "IgE-mediated activation of NK cells through FcγRIII"J. Immunol. (in press).
[文献書誌] Saito, T.: "Negative feedback of T cell activation through inhibitory adaptors and costimulatory receptors"Immunol. Rev.. (in press).
[文献書誌] Nakayama, T.: "The generation of mature, single-positive thymocytes in vivo is dysregulated by CD69 blockade or overexpression"J. Immunol.. 168. 87-94 (2002)
[文献書誌] Suto, A.: "CD4^+ CD25^+ T-cell development is regulated by at least 2 distinct mechanisms"Blood. 99. 555-560 (2002)
[文献書誌] Gonzalez-Aseguinolaza, G.: "Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines"J. Exp. Med.. 195. 617-624 (2002)
[文献書誌] Shibata, Y.: "Ras activation in T cells determines the development of antigen-induced airway hyperresponsiveness and eosinophilic inflammation"J. Immunol.. 196. 2134-2140 (2002)
[文献書誌] Yamashita, M.: "Identification of a conserved GATA3 response element upstream proximal of the IL-13 gene locus"J. Biol. Chem.. 277. 42399-42408 (2002)
[文献書誌] Kamata, T.: "src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation"J. Clin. Inv.. 111. 109-119 (2003)
[文献書誌] Iwai, Y.: "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade"Proc Natl Acad Sci U S A. 99・19. 12293-12297 (2002)
[文献書誌] Ishida, M.: "Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues"Immunol Lett.. 84・1. 57-62 (2002)
[文献書誌] Katagiri, K.: "Rap1 functions as a key regulator of T-cell and antigen-presenting cell interactions and modulates T-cell responses"Mol Cell Biol. 22・4. 1001-1015 (2002)
[文献書誌] Yamanaka, K.: "Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2"Nat Cell Biol.. (in press).
[文献書誌] Su, L.: "AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1"J Biol Chem.. (in press).
[文献書誌] Monji, M.: "Head and neck cancer antigens recognized by the humoral immune system"Biochem. Biophys. Res. Comm. 294. 734-741 (2002)
[文献書誌] Nakatsura, T.: "Cellular and humoral immune responses to a human pancreatic cancer antigen, clp, originally defined by the SEREX method"Eur. J. Immunol.. 32. 826-836 (2002)
[文献書誌] Uemura, Y.: "Systematic analysis of the combinatorial nature of epitopes recognized by TCR leads to identification of mimicry epitopes for GAD65 specific TCRs"J. Immunol.. 170. 947-960 (2003)
[文献書誌] Uemura, Y: "Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-class II restricted T cell receptors ; Implications for clinical medicine"Modern Rheumatology. (in press).
[文献書誌] Soejima, H: "The preference to a Th1-type response in patients with coronary spastic angina"Circulation. (in press).
[文献書誌] Senju, S.: "Generation and genetic modification of dendritic cells derived from mouse embryonic stem cells"Blood. (in press).
[文献書誌] Irie, A.: "Unique T cell proliferation dependent on PKCμ activation with impaired Zap-70 phosphorylation in recognition of over-expressed HLA-DR/partially agonistic peptide"Eur. J. Immunol.. (in press).

2002 年度 実績報告書

T細胞の抗原認識と活性化制御

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] 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.. 195・6. 665-672 (2002)

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

[文献書誌] 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)

[文献書誌] 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)

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

[文献書誌] 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)

[文献書誌] 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)

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

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

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

[文献書誌] Saito, T.: "Negative feedback of T cell activation through inhibitory adaptors and costimulatory receptors"Immunol. Rev.. (in press).

[文献書誌] Nakayama, T.: "The generation of mature, single-positive thymocytes in vivo is dysregulated by CD69 blockade or overexpression"J. Immunol.. 168. 87-94 (2002)

[文献書誌] Suto, A.: "CD4^+ CD25^+ T-cell development is regulated by at least 2 distinct mechanisms"Blood. 99. 555-560 (2002)

[文献書誌] Gonzalez-Aseguinolaza, G.: "Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines"J. Exp. Med.. 195. 617-624 (2002)

[文献書誌] Shibata, Y.: "Ras activation in T cells determines the development of antigen-induced airway hyperresponsiveness and eosinophilic inflammation"J. Immunol.. 196. 2134-2140 (2002)

[文献書誌] Yamashita, M.: "Identification of a conserved GATA3 response element upstream proximal of the IL-13 gene locus"J. Biol. Chem.. 277. 42399-42408 (2002)

[文献書誌] Kamata, T.: "src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation"J. Clin. Inv.. 111. 109-119 (2003)

[文献書誌] Iwai, Y.: "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade"Proc Natl Acad Sci U S A. 99・19. 12293-12297 (2002)

[文献書誌] Ishida, M.: "Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues"Immunol Lett.. 84・1. 57-62 (2002)

[文献書誌] Katagiri, K.: "Rap1 functions as a key regulator of T-cell and antigen-presenting cell interactions and modulates T-cell responses"Mol Cell Biol. 22・4. 1001-1015 (2002)

[文献書誌] Yamanaka, K.: "Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2"Nat Cell Biol.. (in press).

[文献書誌] Su, L.: "AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1"J Biol Chem.. (in press).

[文献書誌] Monji, M.: "Head and neck cancer antigens recognized by the humoral immune system"Biochem. Biophys. Res. Comm. 294. 734-741 (2002)

[文献書誌] Nakatsura, T.: "Cellular and humoral immune responses to a human pancreatic cancer antigen, clp, originally defined by the SEREX method"Eur. J. Immunol.. 32. 826-836 (2002)

[文献書誌] Uemura, Y.: "Systematic analysis of the combinatorial nature of epitopes recognized by TCR leads to identification of mimicry epitopes for GAD65 specific TCRs"J. Immunol.. 170. 947-960 (2003)

[文献書誌] Uemura, Y: "Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-class II restricted T cell receptors ; Implications for clinical medicine"Modern Rheumatology. (in press).

[文献書誌] Soejima, H: "The preference to a Th1-type response in patients with coronary spastic angina"Circulation. (in press).

[文献書誌] Senju, S.: "Generation and genetic modification of dendritic cells derived from mouse embryonic stem cells"Blood. (in press).

[文献書誌] Irie, A.: "Unique T cell proliferation dependent on PKCμ activation with impaired Zap-70 phosphorylation in recognition of over-expressed HLA-DR/partially agonistic peptide"Eur. J. Immunol.. (in press).

2002 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)