• Open Access

Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy

Authors

  • Kenji Chamoto,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Akemi Kosaka,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Takemasa Tsuji,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Junko Matsuzaki,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Takeshi Sato,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Tsuguhide Takeshima,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Kenji Iwakabe,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Yuji Togashi,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Toshiaki Koda,

    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
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  • Takashi Nishimura

    Corresponding author
    1. Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Sapporo 060-0815
      To whom correspondence should be addressed. E-mail: tak24@imm.hokudai.ac.jp
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To whom correspondence should be addressed. E-mail: tak24@imm.hokudai.ac.jp

Abstract

Th1 and Th2 cells obtained from OVA-specific T cell receptor transgenic mice completely eradicated the tumor mass when transferred into mice bearing A20-OVA tumor cells expressing OVA as a model tumor antigen. To elucidate the role of Tc1 or Tc2 cells during tumor eradication by Th1- or Th2-cell therapy, spleen cells obtained from mice cured of tumor by the therapy were restimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1-cell therapy produced high levels of IFN-γ, while spleen cells from mice cured by Th2-cell therapy produced high levels of IL-4. Intracellular staining analysis demonstrated that a high frequency of IFN-γ-producing Tc1 cells was induced in mice given Th1-cell therapy. In contrast, IL-4-producing Tc2 cells were mainly induced in mice after Th2-cell therapy. Moreover, Tc1, but not Tc2, exhibited a tumor-specific cytotoxicity against A20-OVA but not against CMS-7 fibrosarcoma. Thus, immunological memory essential for CTL generation was induced by the Th1/Tc1 circuit, but not by the Th2/Tc2 circuit. We also demonstrated that Th1-cell therapy is greatly augmented by combination therapy with cyclophosphamide treatment. This finding indicated that adoptive chemoimmuno-therapy using Th1 cells should be applicable as a novel tool to enhance the Th1/Tc1 circuit, which is beneficial for inducing tumor eradication in vivo.

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