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Elucidation of T cell subset Th1 differentiation by IL-12

Research Project

Project/Area Number 09470090
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionThe University of Tokyo

Principal Investigator

NARIUCHI Hideo  Institute of Medical Science, The University of Tokyo, Professor, 医科学研究所, 教授 (10012741)

Co-Investigator(Kenkyū-buntansha) TAMURA Toshiki  Institute of Medical Science, The University of Tokyo, Assistant, 医科学研究所, 助手 (40291306)
YOSHIMOTO Takayuki  Institute of Medical Science, The University of Tokyo, Assistant, 医科学研究所, 助手 (80202406)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥9,300,000 (Direct Cost: ¥9,300,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1997: ¥4,400,000 (Direct Cost: ¥4,400,000)
KeywordsIL-12p35 / IL-2p40 / MHC class II / B7 / CD28 / CD152 / IL-12 independent TH1 differentiation / IL-12受容体 / IL-12Rβ2 / B7刺激 / トランスジェニックマウス / 副刺激 / T細胞抗原受容体 / T細胞上B7-2発現
Research Abstract

Differentiation and activation of Th cell sub Th1 is mainly regulated by IL-12. We, therefore, designed the present project to elucidate the regulation of IL-12 production and IL-12 receptor expression. IL-12 is composed of p35 and p40. We and other groups had shown that antigen-presenting cells (APC) produced p40 upon CD40 stimulation. In the present studies, we tried to identify the molecules on APC playing an important role in the p35 production. MHC class II molecules are revealed to be the molecule and p35 produced by the calss II stimulation contributed the bioactive IL-12 production. IL-12 receptor is also composed of β1 and β2 heterodimer. These components, especially β2, are expressed in T cells by B7 costimulation along with TCR ligation. The counter receptor for B7 on T cells playing a critical role in IL-12R expression was shown to be CD28. CD152, in contrast, was revealed to down regulate the expression. We also demonstrated that there is an IL-12 independent pathway for Th1 subset differentiation, that is, CD152 stimulation polarized naive T cells toward Th1 subset. CD152 was indicated to induce Th1 subset differentiation via unknown mechanism in addition to the suppression of IL-4 production and induction of TGF- β Production. We also examined whether IL-12 dependent Th1 polarization occurr in vivo by producing p40 transgenic mice. These mice showed the phenotype with Th2, dominant and impaired resistancy to malarial infection. These results showed that IL-12 actually, plays an important role in Th1 subset differentiation in vivo.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (53 results)

All Other

All Publications (53 results)

  • [Publications] Hideki Nakano: "Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes."Eur. J. Immunol.. 27. 215-221 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takuma Kato: "Costimulatory effect of IL-12 on the activation of naive memory CD4+ T cells, and Th1 clone."Cell. Immunol.. 176. 50-58 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masanori Utsuyama: "Impairment of signal transduction in T cells from old mice."Mech. Ageing Develop. 93. 131-144 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takuma Kato: "Differential effects of LPS and CD40 ligand stimulations on the induction of IL-12 production by dendritic cell and macrophages."Cell. Immunol.. 181. 59-67 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayuki Yoshimoto: "Induction of interleukin-12 p40 transcript by CD40 ligation via activation of nuclear factor-kB."Eur. J. Immunol.. 27. 3461-3470 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayuki Yoshimoto: "Reduced Th1 responses in interleukin-12 p40 transgenic mice."J. Immunol.. 160. 588-594 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hisashi Nagase: "Novel mutant mice secreting soluble CD4 without expression of membrane-bound CD4."Eur. J. Immunol.. 28. 403-412 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Osamu Igarashi: "IL-12R expression and accumulation of IL-12Rb1 and IL-12Rb2 mRNAs in CD4+ T cells by the costimulation with B7-2 molecules."J. Immunol.. 160. 1638-1646 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sachiko Yamanouchi: "T cell activation antigen Ly6C induced on CD4+ Th1 cells mediates an inhibitory signal for secretion of IL-2 and proliferation in peripheral immune response."Eur. J. Immunol.. 28. 696-707 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Rie Hakamada-Taguchi: "Expression and costimulatory function of B7-2 on murine CD4+ T cells."Eur. Immunol.. 28. 865-873 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hideki Nakano: "A novel-mutant gene involved in T lymphocyte specific homing into peripheral lymphoid organs on murine chromosome 4."Blood. 91. 2886-2895 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayuki Yoshimoto: "IL-12 dependent mechanisms in the clearance of blood-stage murine malaria Plasmodium berghei XAT, an attenuated variant of Plasmodium berghei NK65."J. Infect. Dis.. 177. 1674-1681 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hisashi Saito: "Generation of intestinal T cells from progenitors residing in gut cryptopatches."Science. 280. 275-278 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayuki Yoshimoto: "A pathogenic role of IL-12 in blood -stage murine malaria lethal strain Plasmodium berghei NK65 infection."J. Immunol.. 160. 5500-5505 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masaya Takamoto, Eosinophilia: "IgE production, and cytokine production by lung T cells in surface CD4-deficient mutant mice infected with Toxocara canis."Immunology. 95. 97-104 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayuki Yoshimoto: "Interleukin-12 expression in B cells by transformation with Epstein-Barr virus."B.B.R.C.. 252. 556-560 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Toshihiko Yoneto: "Gamma interferon production is critical for protective immunity to infection with blood-stage Plasmodium berghei XAT but neither NO production nor NK cell activation is critical."Infect. Immun.. 67. 2349-2356 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ayako Hino: "Interferon-g priming is not critical for IL-12 production of murine spleen cells."Cytokines.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hidehiro Yamane: "Effective stimulation for IL-12 p35 mRNA accumulation and bioactive IL-12 production of antigen-presenting cells interacted with T helper cells."J. Immunol.. 162. 6433-6441 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yuji Yamanashi: "Role of the rasGAP-associated docking protein p62dok in negative regulation of B cell receptor-mediated signaling."Genes Develop.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takashi Kosuge: "Effect of inhibitors of glycoprotein processing on cytokine secretion and production in anti-CD3-stimulated T cells."Biol. Pharm. Bull.. 23. 1-5 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayuki Yoshimoto: "A role of IL-16 in delayed-type hypersensitivity."Blood. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takuma Kato: "Polarization of naive CD4+ T cells toward TH1 subset by CTLA-4 costimulation."J. Immunol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chrong-Reen Wang: "Impaired delayed-type hypersensitivity response in mutant mice secreting soluble CD4 without expression of membrane-bound CD4."Immunology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takuma Kato: "Costimulatory eggect of IL-12 on the activation of naive, memory CD4^+T cells. and Th1 clone"Cellular Immunology. 176. 50-58 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "Induction of interleukin-12 p40 transcript by CD40 ligation via actibation of nuclear factor-κB"European Journal of Immunology. 27. 3461-3470 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "Reduction Thl responses in interleukin-12 p40 transgenic mice"Journal of Immunology. 160. 588-594 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hisashi Nagase: "Novel mutant mice secreting soluble CD4 without expression of membrane-bound CD4"European Journal of Immunology. 28. 403-412 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Osamu Igarashi: "IL-12R expression and accumulation of IL-12Rβ1 and IL-12Rβ2 mRNAs in CD4^+T cells by the costimulation with B7-2 molecules"Journal of Immunology. 160. 1638-1646 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Rie Hakamada-Taguchi: "Expression and costimulatory function of B7-2 on murine CD4_+T cells."European Journal of Immunology. 28. 865-873 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "IL-12 dependent mechanisms in the clearance of blood-stage murine Plasmodium berghei XAT. an attenuated variant of Plasmodium berghei"Journal of Infectious Diseases. 177. 1674-1681 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hisashi Saito: "Generation of intestinal T cells from progenitors residing in gut cryptopatches"Science. 280. 275-278 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection"Journal of Immunology. 160. 5500-5505 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masaya Takamoto: "Eosinophilia, IgE production, and cytokine production by lung T cells surface CD4-deficient mutant mice infected with Toxocara canis"Immunology. 95. 97-104 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "Interleukin-12 expression in B cells by transformation with Epstein-Barr virus"Biochem. Biophys. Res. Commun.. 252. 556-560 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Toshihiko Yoneto: "Gamma interferon production is critical for protective immunity toinfectio with blood-stage Plasmodium berghei XAT but neither NO production nor・・・"Infection and Immunity. 28. 403-412 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ayako Hino: "Interferon-γpriming is not critical for IL-12 production of murine spleen cells"Cytokines.. 12. 10-15 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hiehiro Yamane: "Effective stimulation for IL-12 p35 mRNA accumulation and bioactive IL-12 production of antigen-presenting cells interacted with T helper cell"Journal of Immunology. 162. 6433-6441 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yuji Yamanashi: "Role of the ras GAP-associated docking protein p62^<dok> in negative ragulation of B cell receptor-mediated signaling"Genes and Development. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "A role of IL-16 in delayed-type hypersensitivity"Blood. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takumi Kato: "Polarization of naive CD4^+T cells toward Thl subset by CTLA-4 costimulation"Journal of Immunology. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Osamu Igarashi: "IL-12R expression and accumulation of IL-12Rb1 and b2 mRNA in CD4 Tcells by the costimulation with B7-2 molecules" Journal of Immunology. 160. 1638-1646 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "Reduced Th1 responses in interleukin-12 p40 transgenic mice" Journal of Immunology. 160. 588-594 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "IL-12-depmdent mechanisms in the clearance of blood-stage murine malaria Plasmodium berghei XAT,an attenuated variant…" Journal of Infectious Diseases. 177. 1674-1681 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "A pathogenic role of IL-12 in blood-stage murine malaria lethal" Journal of Immunology. 160. 5500-5505 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hisashi Saito: "Genaration of intestinal T cells from progenitors residing gut cryptopaches" Science. 280. 275-278 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hisashii Nagase: "Novel mutant mice secreting soluble CD4 without expression of membrane-bound CD4" European Journal of Immunology. 28. 403-412 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Osamu Igarashi,: "IL-12R expression and accumulation of IL-12Rβ1 and IL-12Rβ12 mRNAs in CD4^+T cells by the costimulation with B7-2 molecules." Journal of Immunology. 140. 1638-1646 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Rie Hakamada,: "Expression and costimulatory function of B7-2 on murine CD4_+T cells." European Journal of Immunology. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hisashi Nagase: "Novel mutant mice secreting soluble CD4 without expression of membrane-bound CD4" European Journal of Immunology. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "Reduced Th1 responses in interleukin-12 p40 transgenic mice" Journal of Immunology. 160. 588-594 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takuma Kato: "Differential effects of LPS and CD40 ligand stimulations on the induction of IL-12 production by dendritic cells and macrophages" Cellular Immunology. 181. 59-67 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takayuki Yoshimoto: "Induction of interleukin-12 p40 transcript by CD40 ligation via activation of nuclear factor-κB" European Journal of Immunology. 27. 3461-3470 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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