2001 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 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)	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)
Keywords	免疫シナプス / raft / アゴニストペプチド / ヒストンアセチル化 / Th1・Th2 / rap-1 / インテグリン / SPA-1
Research Abstract	本研究班は、今年度T細胞の抗原認識と活性化の制御機構に関して、(1)免疫シナプスの形成とラフト凝集の制御、(2)アンタゴニストペプチドによる活性化シグナルの相違、(3)Th2分化へのTCRシグナルによる制御、(4)Rap-1によるシナプス形成と活性化の制御、について解析した。 (1)Raftに局在し、Csk結合分子Cbpとの会合分子を解析し、EBP50をクローニングした。Cbp-EBP50の結合は細胞骨格と会合することによって、細胞表面のraftの動きを抑制する。T細胞活性化によってこの会合が離れ、raftが凝集し易くなり、活性化を誘導することが明らかになった。 (2)ヒトT細胞を用いて、アゴニストと部分アゴニストとが同様にIFNγ産生や増殖反応を誘導するにも拘わらず、ZAP70/LAT/SLP-76のリン酸化は抑えられ、MEK/ERKの活性化が抑制されており、PKCやSrcなどに対する種々の阻害剤への感受性が非常に高い、等ユニークなシグナル系を活性化している可能性を示した。 (3)ナイーブCD4T細胞がTh1/Th2細胞に分化する際、Th2サイトカインIL-4の遺伝子部位にヒストンアセチル化が誘導されることが判明した。その分子機構についてTCR下流のシグナル伝達経路を中心に解析し、ERK、MAPK系の活性化によりGATA3蛋白の安定性が上昇し、IL-4/IL-13の遺伝子部位に十分なヒストンアセチル化が起こることが分かった。 (4)Rap-1がインテグリンの主たる活性化因子であり、インテグリン依存性のT細胞と抗原提示細胞との免疫シナプス形成に必須であるのみならず、その後のT細胞の活性化様式(活性化、細胞死、あるいは免疫アナジー)を支配する重要な役割を果たすことを明らかにした。さらにRap-1制御因子SPA-1の遺伝子破壊マウスの解析から、Rap-1の異常な活性化により免疫アナージーと免疫記憶応答の喪失にいたることを個体レベルで証明した。

Research Products
(29 results)

All Other

All Publications (29 results)

[Publications] Arase, H.: "Negative regulation of expression and function of Fcγ RIII by CD3ζ in murine NK cells"J. Immunol.. 166・1. 21-25 (2001)
[Publications] Tomita, K.: "Cytokine-indepeudent Jak3 activation upon TCR stimulation through direct association of Jak3 and the TCR complex"J. Biol. Chem.. 276・27. 25378-25385 (2001)
[Publications] 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)
[Publications] Takeuchi, A.: "E2A and HEB activate the pre-TCRα promoter during immature T cell development"J. Immunol.. 167・4. 2157-2163 (2001)
[Publications] 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)
[Publications] 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)
[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.. (In press).
[Publications] Ioan-Facsinay, A.: "FcγRI(CD64) contributes substantially to severity of arthritis, hypersensitivity responses and protection from bacterial infection"Immunity. (In press).
[Publications] Yokosuka, T.: "Predominant role of TCRα chain in forming pre-immune TCR repertoire revealed by clonal TCR reconstitution system"J. Exp. Med.. (In press).
[Publications] Kimura, M.: "Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene"Immunity. 15. 275-287 (2001)
[Publications] Sharif, S.: "Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes"Nature Medicine. 7. 1057-1062 (2001)
[Publications] Nakayama, T.: "The generation of mature, single-positive thymocytes in vitro is dysregulated by CD69 blockade or overexpression"J. Immunol.. 168. 87-94 (2002)
[Publications] Suga, K.: "CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of Rap-1"FEBS Lett.. 489. 249-253 (2001)
[Publications] Nishimura, H.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice"Science. 291. 319-322 (2001)
[Publications] Miyagawa, F: "Essential requirement of antigen presentation by monocyte-lineage cells for the activation of primary human γδ T cells by aminobisphosphonate antigen"J. Immunol.. 166. 5508-5514 (2001)
[Publications] Kawakami, T.: "NEDD8 recruits E2-ubiquitin to SCF E3 ligase"EMBO J.. 20. 4003-4012 (2001)
[Publications] Kato, Y.: "Targeting of tumor cells for human gamma delta T cells by nonpeptide antigens"J. Immunol.. 167. 5092-5098 (2001)
[Publications] Miyagawa, F.: "Essential contribution of germline-encoded residues in Jg1.2 segment to the recognition of nonpeptide antigens by human γδ T cells"J. Immunol.. 167. 6773-6779 (2001)
[Publications] Okuda, H.: "The Von Hippel-Lindau (VHL) tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C"J. Biol Chem.. 276. 43611-44361 (2001)
[Publications] Katagiri, K.: "Rap1 functions as a key regulator of T cell and APC interactions and modulates cell -responses"Mol. Cell. Biol.. 22. 1001-1015 (2002)
[Publications] Nishimura, Y: "Molecular and cellular analyses of HLA class II-associated susceptibility to autoimmune diseases in the Japanese population"Modern Rheumatol.. 11. 103-112 (2001)
[Publications] Inoue, R.: "Identification of β lactoglobulin-derived peptides and class II HLA molecules recognized by T Cells from patients with milk allergy"Clin. Exp. Immunol.. 31. 1126-1134 (2001)
[Publications] Minohara, M.: "Differences between T cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls"Tissue Antigens. 57. 447-456 (2001)
[Publications] Yamada, K.: "Identification of a novel autoantigen UACA in patients with panuveitis"Biochem. Biophys. Res. Comm.. 280. 1169-1176 (2001)
[Publications] Maeda, A.: "Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, cancer-associated retinopathy antigen, to achieve a clinical better prognosis in a paraneoplastic syndrome"Eur. J. Immunol.. 31. 563-572 (2001)
[Publications] Nakatsura, T.: "Gene cloning of immunogenic antigens over-expressed in pancreatic cancer"Biochem. Biophys. Res. Comm.. 281. 936-944 (2001)
[Publications] Fujii, S.: "Establishment of an expression cloning system for CD4+ T cell epitopes"Biochem. Biophys. Res. Comm.. 284. 1140-1147 (2001)
[Publications] Masuda, M.: "Identification and immunocytochemical analysis of DCNP1, a dendritic cell-associated nuclear protein"Biochem. Biophys. Res. Comm.. (in press).
[Publications] Nakatsura, T.: "Cellular and humoral immune responses to a human pancreatic cancer antigen, CLP, originally defined by the SEREX method"Eur. J. Immunol.. (in press).

2001 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・医学研究院, 教授 (50205655)

Research Products

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

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[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.. (In press).

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

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

[Publications] Kimura, M.: "Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene"Immunity. 15. 275-287 (2001)

[Publications] Sharif, S.: "Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes"Nature Medicine. 7. 1057-1062 (2001)

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

[Publications] Suga, K.: "CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of Rap-1"FEBS Lett.. 489. 249-253 (2001)

[Publications] Nishimura, H.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice"Science. 291. 319-322 (2001)

[Publications] Miyagawa, F: "Essential requirement of antigen presentation by monocyte-lineage cells for the activation of primary human γδ T cells by aminobisphosphonate antigen"J. Immunol.. 166. 5508-5514 (2001)

[Publications] Kawakami, T.: "NEDD8 recruits E2-ubiquitin to SCF E3 ligase"EMBO J.. 20. 4003-4012 (2001)

[Publications] Kato, Y.: "Targeting of tumor cells for human gamma delta T cells by nonpeptide antigens"J. Immunol.. 167. 5092-5098 (2001)

[Publications] Miyagawa, F.: "Essential contribution of germline-encoded residues in Jg1.2 segment to the recognition of nonpeptide antigens by human γδ T cells"J. Immunol.. 167. 6773-6779 (2001)

[Publications] Okuda, H.: "The Von Hippel-Lindau (VHL) tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C"J. Biol Chem.. 276. 43611-44361 (2001)

[Publications] Katagiri, K.: "Rap1 functions as a key regulator of T cell and APC interactions and modulates cell -responses"Mol. Cell. Biol.. 22. 1001-1015 (2002)

[Publications] Nishimura, Y: "Molecular and cellular analyses of HLA class II-associated susceptibility to autoimmune diseases in the Japanese population"Modern Rheumatol.. 11. 103-112 (2001)

[Publications] Inoue, R.: "Identification of β lactoglobulin-derived peptides and class II HLA molecules recognized by T Cells from patients with milk allergy"Clin. Exp. Immunol.. 31. 1126-1134 (2001)

[Publications] Minohara, M.: "Differences between T cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls"Tissue Antigens. 57. 447-456 (2001)

[Publications] Yamada, K.: "Identification of a novel autoantigen UACA in patients with panuveitis"Biochem. Biophys. Res. Comm.. 280. 1169-1176 (2001)

[Publications] Maeda, A.: "Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, cancer-associated retinopathy antigen, to achieve a clinical better prognosis in a paraneoplastic syndrome"Eur. J. Immunol.. 31. 563-572 (2001)

[Publications] Nakatsura, T.: "Gene cloning of immunogenic antigens over-expressed in pancreatic cancer"Biochem. Biophys. Res. Comm.. 281. 936-944 (2001)

[Publications] Fujii, S.: "Establishment of an expression cloning system for CD4+ T cell epitopes"Biochem. Biophys. Res. Comm.. 284. 1140-1147 (2001)

[Publications] Masuda, M.: "Identification and immunocytochemical analysis of DCNP1, a dendritic cell-associated nuclear protein"Biochem. Biophys. Res. Comm.. (in press).

[Publications] Nakatsura, T.: "Cellular and humoral immune responses to a human pancreatic cancer antigen, CLP, originally defined by the SEREX method"Eur. J. Immunol.. (in press).

斉藤隆千葉大学, 大学院・医学研究院, 教授 (50205655)