1993 年度実績報告書

免疫制御の分子機構

研究課題

研究課題/領域番号	05272104
研究機関	九州大学
研究代表者	笹月健彦九州大学, 生体防御医学研究所, 教授 (50014121)
研究分担者	新井賢一東京大学, 医科学研究所, 教授 (00012782) 片桐一旭川医科大学, 医学部, 教授 (10041823) 吉開泰信名古屋大学, 医学部, 教授 (90158402) 谷口克千葉大学, 医学部, 教授 (80110310) 猪子英俊東海大学, 医学部, 教授 (10101932)
キーワード	免疫制御 / HLA / ペプチド / T細胞レパトワ / サイトカイン
研究概要	免疫制御の分子機構を、MHCを中心として、自己・非自己ペプチドのMHC分子への結合、T細胞の機能ならびにサイトカインネットワークの面より総合的に解析することを目的とした。まずHLA遺伝子領域の構造を詳細に解析するとともに、DP座のセントロメア側に存在する単球抗原遺伝子産物を認識すると考えられる単クローン抗体を作製し、これが新しい接着分子の遺伝子であることを見出した。HLA-B52分子およびDR4分子に結合する自己ペプチドのアミノ酸配列モチーフを抽出法および質量分析により決定した。さらに非自己ペプチドとHLA分子との結合およびT細胞の活性化に関わるモチーフの同定を目的として、溶連菌M蛋白とDP9分子、花粉抗原とDR9分子、インスリンとDR4分子の相互作用を、それぞれ合成ペプチドを用いた系で解析し、HLA分子の座位間ならびに対立遺伝子間で全く異なる結合モチーフが使用されることを示した。一方、マウスHSP60特異的gammadeltaリンパ球のT細胞レセプターが限られること、表面マーカーの発現からメモリー型と考えられること、リステリア等の感染症の初期防御に関わることを明らかにした。またdelta鎖遺伝子ノックアウトマウスでは、マクロファージのTNF産生誘導能が阻害されるがgammadelta型されるがgammadelta型リンパ球との共培養で回復することを見出した。マウスおよびヒトでは末梢リンパ球の1〜2%がCD4^-CD8^-T細胞であるが、この大半が特定のValphaおよびJalpha遺伝子を発現していること、またこれらは胸腺外組織(肝・骨髄・消化管など)で分化することを証明した。一方、GM-CSF、IL-3、IL-4およびIL-5の活性化T細胞における発現誘導に関わると考えられるNF-AT活性を有する転写因子をそれぞれ精製し、対応する数種のcDNAクローンを単離しその構造を決定した。

研究成果
(24件)

すべてその他

すべて文献書誌 (24件)

[文献書誌] Yoshizumi H: "Generation of a novel CD8^+cytotoxic T lymphocyte that requires soluble factor to lyse autologous antigen-presenting cells" Eur.J.Immunol.23. 3173-3180 (1993)
[文献書誌] Fukui Y: "Restricted expression of transgenic HLA-DRA gene in thymic epithelial cells and its role in aquisition of T cell tolerance to self-superantigens and processed DRalpha-derived peptide" Eur.J.Immunol.23. 1678-1686 (1993)
[文献書誌] Yao Z: "Polymorphism of the DQA1 promoter region (QAP) and DRB1,QAP,DQA1,DQB1 haplotypes in systemic lupus erythematosus" Immunogenetics. 38. 430-436 (1993)
[文献書誌] Tamai H: "Resistance to autoimmune thyroid disease is associated with HLA-DQ" J.Clin.Endocrinol.Metab.78. 94-97 (1993)
[文献書誌] Sugimura K: "Analysis of genes within the HLA region affecting susceptibility to Ulcerative Colitis" Hum.Immunol.36. 112-118 (1993)
[文献書誌] Nakanishi K: "Association of HLA-A24 with complete beta-cell destruction in IDDM" Diabetes. 42. 1086-1093 (1993)
[文献書誌] Kimoto H: "The fetal thymus stores immature hemopoietic cells capable of defferentiating into non-T lineage cells constituting the thymus atromal element" Intl.Immunol.5. 1535-1540 (1993)
[文献書誌] Sydora BC: "Intestinal intraepithelial lymphocytes preferentially home to the intestinal epithelium" Intl.Immunol.5. 743-751 (1993)
[文献書誌] Makino Y: "Extrathymic development of Valpha14 positive T cells" J.Exp.Med.177. 1399-1408 (1993)
[文献書誌] Matsuzaki G: "Characterization of T-cell receptor deltadelta T cells appearing at the early phase of murine Listeria monocytogenes infection" Immunology. 78. 22-27 (1993)
[文献書誌] Emoto M: "Different appearance of deltadelta T cells during salmonellosis between Ity^r and Ity^s mice" J.Immunol.150. 3411-3420 (1993)
[文献書誌] Kondo M: "Sharing of the Interleukin-2(IL-2)receptor delta chain between receptors for IL-2 and IL-4" Science. 262. 1874-1877 (1993)
[文献書誌] Sato K: "Evolution of the MHC: Isolation of class II beta-chain cDNA clones from the amphibian xenopus laevis" J.Immunol.150. 2831-2843 (1993)
[文献書誌] Esaki Y: "Role of human major histocompatibility complex DQ molecules in superantigenicity of Streptococcus-derived protein" Infect.Immun.62. 1228-1235 (1994)
[文献書誌] Tashiro H: "Monitoring for rejection and engraftment following rat orthotopic liver transplantation by polymerase chain reaction" Transplantation. (in press).
[文献書誌] Makino Y: "Extrathymic differentiation of a T cell bearing invariant Valpha14Jalpha281 TCR" Intern.Rev.Immunol.(in press).
[文献書誌] Tomida S: "ICAM-1 and LFA-1 are involved in protection mediated by deltadelta T Cells at the early stage after infection with Listeria monocytogenes in rats" Inter.Immunol.(in press).
[文献書誌] Ogasawara T: "Sendai virus pneumonia:early appearance of deltadelta T cells in viral infection" J.Virol.(in press).
[文献書誌] watanabe S: "Regulation of cytokine production and cell proliferation in a human T cell clone by prostaglandin E2 involves cAMP and IL-2 dependent signaling pathways" Int.Immunol.(in press).
[文献書誌] Nakagawa Y: "Structure of the gene encoding the a subunit of the human granulocyte macrophage colony stimulating factor receptor:implications for the evolution of the cytokine receptor superfamil" J.Biol.Chem.(in press).
[文献書誌] Matsuda I: "Characterization of NF(P),the nuclear factor that interacts with the regulatory P sequence (5′-CGAAAATTTCC-3′) of the human interleukin-4 gene: relationship to NF-KB and NF-AT" Biochem.Biophys.Res.Commun.(in press).
[文献書誌] Koyano-Nakagawa N: "Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the interleukin 3 promoter" Mol.Cell.Biol.(in press).
[文献書誌] Ando A: "Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region" Immunogenetics. (in press).
[文献書誌] Onuma H: "Association of HLA-DPB1^*0501 with early-onset Graves′ disease in Japanese" Hum.Immunol.(inpress).

1993 年度 実績報告書

免疫制御の分子機構

研究代表者

笹月 健彦 九州大学, 生体防御医学研究所, 教授 (50014121)

研究成果

[文献書誌] Yoshizumi H: "Generation of a novel CD8^+cytotoxic T lymphocyte that requires soluble factor to lyse autologous antigen-presenting cells" Eur.J.Immunol.23. 3173-3180 (1993)

[文献書誌] Fukui Y: "Restricted expression of transgenic HLA-DRA gene in thymic epithelial cells and its role in aquisition of T cell tolerance to self-superantigens and processed DRalpha-derived peptide" Eur.J.Immunol.23. 1678-1686 (1993)

[文献書誌] Yao Z: "Polymorphism of the DQA1 promoter region (QAP) and DRB1,QAP,DQA1,DQB1 haplotypes in systemic lupus erythematosus" Immunogenetics. 38. 430-436 (1993)

[文献書誌] Tamai H: "Resistance to autoimmune thyroid disease is associated with HLA-DQ" J.Clin.Endocrinol.Metab.78. 94-97 (1993)

[文献書誌] Sugimura K: "Analysis of genes within the HLA region affecting susceptibility to Ulcerative Colitis" Hum.Immunol.36. 112-118 (1993)

[文献書誌] Nakanishi K: "Association of HLA-A24 with complete beta-cell destruction in IDDM" Diabetes. 42. 1086-1093 (1993)

[文献書誌] Kimoto H: "The fetal thymus stores immature hemopoietic cells capable of defferentiating into non-T lineage cells constituting the thymus atromal element" Intl.Immunol.5. 1535-1540 (1993)

[文献書誌] Sydora BC: "Intestinal intraepithelial lymphocytes preferentially home to the intestinal epithelium" Intl.Immunol.5. 743-751 (1993)

[文献書誌] Makino Y: "Extrathymic development of Valpha14 positive T cells" J.Exp.Med.177. 1399-1408 (1993)

[文献書誌] Matsuzaki G: "Characterization of T-cell receptor deltadelta T cells appearing at the early phase of murine Listeria monocytogenes infection" Immunology. 78. 22-27 (1993)

[文献書誌] Emoto M: "Different appearance of deltadelta T cells during salmonellosis between Ity^r and Ity^s mice" J.Immunol.150. 3411-3420 (1993)

[文献書誌] Kondo M: "Sharing of the Interleukin-2(IL-2)receptor delta chain between receptors for IL-2 and IL-4" Science. 262. 1874-1877 (1993)

[文献書誌] Sato K: "Evolution of the MHC: Isolation of class II beta-chain cDNA clones from the amphibian xenopus laevis" J.Immunol.150. 2831-2843 (1993)

[文献書誌] Esaki Y: "Role of human major histocompatibility complex DQ molecules in superantigenicity of Streptococcus-derived protein" Infect.Immun.62. 1228-1235 (1994)

[文献書誌] Tashiro H: "Monitoring for rejection and engraftment following rat orthotopic liver transplantation by polymerase chain reaction" Transplantation. (in press).

[文献書誌] Makino Y: "Extrathymic differentiation of a T cell bearing invariant Valpha14Jalpha281 TCR" Intern.Rev.Immunol.(in press).

[文献書誌] Tomida S: "ICAM-1 and LFA-1 are involved in protection mediated by deltadelta T Cells at the early stage after infection with Listeria monocytogenes in rats" Inter.Immunol.(in press).

[文献書誌] Ogasawara T: "Sendai virus pneumonia:early appearance of deltadelta T cells in viral infection" J.Virol.(in press).

[文献書誌] watanabe S: "Regulation of cytokine production and cell proliferation in a human T cell clone by prostaglandin E2 involves cAMP and IL-2 dependent signaling pathways" Int.Immunol.(in press).

[文献書誌] Nakagawa Y: "Structure of the gene encoding the a subunit of the human granulocyte macrophage colony stimulating factor receptor:implications for the evolution of the cytokine receptor superfamil" J.Biol.Chem.(in press).

[文献書誌] Matsuda I: "Characterization of NF(P),the nuclear factor that interacts with the regulatory P sequence (5′-CGAAAATTTCC-3′) of the human interleukin-4 gene: relationship to NF-KB and NF-AT" Biochem.Biophys.Res.Commun.(in press).

[文献書誌] Koyano-Nakagawa N: "Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the interleukin 3 promoter" Mol.Cell.Biol.(in press).

[文献書誌] Ando A: "Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region" Immunogenetics. (in press).

[文献書誌] Onuma H: "Association of HLA-DPB1^*0501 with early-onset Graves′ disease in Japanese" Hum.Immunol.(inpress).

1993 年度実績報告書

笹月健彦九州大学, 生体防御医学研究所, 教授 (50014121)