2004 Fiscal Year Final Research Report Summary
Augmented Induction of CD8+ Cytotoxic T cell Response and Antitumor Resistance by Thl-inducing peptide
| Project/Area Number |
12213025
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | University of Tokyo |
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Principal Investigator |
TAKATSU Eyoshi Institute of Medical Science, Division of Immunology, Professor, 医科学研究所, 教授 (10107055)
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| Co-Investigator(Kenkyū-buntansha) |
TAMURA Toshiki Institute of Medical Science, Division of Immunology, Research Associate, 医科学研究所, 助手 (40291306)
KARIYONE Ai Institute of Medical Science, Division of Immunology, Research Associate, 医科学研究所, 助手 (50114450)
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| Project Period (FY) |
2000 – 2004
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| Keywords | Ag85B / Peptide-25 / Thl-indicing Peptide / I-A restriction / IFN-γ / Adjuvant Activity / Transgenic mice / Cytotoxic Activity |
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| Research Abstract |
The effector CD8^+ T cells recognize MHC class I binding altered self-peptides expressed in tumor cells. Although the requirement for CD4^+ Th1 cells in regulating CD8^+ T cells has been documented, their target epitopes and functional impact in antitumor responses remain unclear. We examined whether a potent immunogenic peptide of Mycobacterium (M.) tuberculosis eliciting Thl immunity contributes to the generation of CD8^+ T cells and to protective antitumor immune responses to unrelated tumor-specific antigens. Peptide-25, a major Th epitope of Ag85B from M. tuberculosis preferentially induced CD4^+ Thl cells in C57BL/6 mice and showed an augmenting effect on Thl generation for coimmunized unrelated antigenic peptides. Coimmunization of mice with Peptide-25 and OVA or Peptide-25 and B16 melanoma peptide (TRP-2) for MHC class I led to a profound increase in CD8^+ T cells specific for OVA and TRP-2 peptides, respectively. This heightened response depended on Peptide-25 specific CD4^+ I
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FN-y-producing Th1 cells. In tumor protection assays, immunization with Peptide-25 and OVA resulted in the enhancement of CD8^+ cytotoxic cell generation specific for OVA and the growth inhibition of EL-4 thymoma expressing OVA peptide leading to the tumor rejection, that were not achieved by immunization with OVA alone. Peptide-25 reactive Thl cells counteractivated dendritic cells (DCs) in the presence of Peptide-25 leading them to activate and present OVA peptide to CD8^+ cytotoxic T cells. This result indicates that Peptide-25 not only induces a Thl-response by itself but also induces Thl-inducing activation of DCs through interactions with CD4^+ T cells. Therefore, we generated TCR transgenic mice (P25 TCR-Tg) expressing TCR a-and β-chains of Peptide-25-reactive cloned T cells and analyzed Thl development of CD4^+ T cells from P25 TCR-Tg to elucidate cellular and molecular mechanisms of the induction of Thl differentiation by Peptide-25. Naive CD4^+ T cells from P25 TCR-Tg preferentially develop Thl cells upon Peptide-25 stimulation in the presence of I-A^b splenic antigen-presenting cells under neutral conditions. Peptide-25-induced Thl differentiation is observed even in the presence of anti-IFN-y and anti-IL-12. Furthermore, Peptide-25-loaded I-A^b-transfected Chinese hamster ovary cells (Peptide-25-I-A^b-CHO) induce Thl differentiation of naive CD4^+ T cells from P25 TCR-Tg in the A^bsence of IFN-y or IL-12. Three hours after the TCR stimulation with Peptide-25-I-A^b-CHO, transient T-bet up-regulation and suppression of GATA-3 expression were observed by quantitative RT-PCR, both of which were independent of IFN-y and IL-12. These results imply that interaction between Peptide-25/I-A^b and TCR may primarily influence determination of the fate of naive CD4^+ T cells in their differentiation towards the Th1 subset. Taken together, these results indicate that Peptide-25 exerts potent adjuvant activity and provides efficient help for CTL induction against tumor antigen. Less
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[Journal Article] The role of antigenic peptide in CD4+ T helper phenotype development in a T cell receptor transgenic model.2004
Author(s)
Tamura, T., Ariga, H., Kinashi, T., Uehara, S., Kikuchi, T., Nakada, M., Tokunaga, T., Xu, W., Kariyone, A., Saito, T., Kitamura, T., Maxwell, G., Takaki, S., Takatsu, K.
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Journal Title
International Immunology 16(12)
Pages: 1691-1699
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Immunogenicity of Peptide-25 of Ag85B in Thl development : role of IFN-y.2003
Author(s)
Kariyone, A., Tamura, T., Kano, H., Iwakura, Y., Takeda, K., Akira, S., Takatsu, K.
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Journal Title
International Immunolology 15(10)
Pages: 1183-1194
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] PI3K and Btk differentially regulate B cell antigen receptor- mediated signal transduction.2003
Author(s)
Suzuki, H., Matsuda, S., Terauchi, Y., Fujiwara, M., Ohteki, T., Asano, T., Behrens, TW., Kouro, T., Takatsu, K., Kadowaki, T., Koyasu, S.
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Journal Title
Nature Immunology. 4(3)
Pages: 280-286
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Impairment in the expression and activity of Fyn during differentiation of naive CD4+ T cells into the Th2 subset.2001
Author(s)
Tamura, T., Igarashi, 0., Hino, A., Yamane, H., Aizawa, S., Kato, T., Nariuchi, H.
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Journal Title
Journal of Immunolology 167(4)
Pages: 1962-1969
Description
「研究成果報告書概要(欧文)」より
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