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

Cancer Sci. 2003 Oct;94(10):924-8. doi: 10.1111/j.1349-7006.2003.tb01377.x.


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 re-stimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1-cell therapy produced high levels of IFN-gamma, 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-gamma-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 chemoimmunotherapy 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell- and Tissue-Based Therapy / methods*
  • Cells, Cultured
  • Flow Cytometry
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / metabolism
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Spleen / cytology
  • Survival Rate
  • Th1 Cells / immunology*
  • Th1 Cells / transplantation*
  • Th2 Cells / immunology
  • Th2 Cells / transplantation


  • Interleukin-4
  • Interferon-gamma