IFN-γ controls the generation/activation of CD4+CD25 + regulatory T cells in antitumor immune response

Hiroyoshi Nishikawa, Takuma Kato, Isao Tawara, Hiroaki Ikeda, Kagemasa Kuribayashi, Paul M. Allen, Robert D. Schreiber, Lloyd J. Old, Hiroshi Shiku

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83 Scopus citations

Abstract

Immunization with serological identification of Ags by recombinant expression cloning (SEREX)-deflned self-Ags leads to generation/activation of CD4+CB25+ regulatory T cells with suppressive activities and enhanced expression of Foxp3. This is associated with increased susceptibility to pulmonary metastasis following challenge with syngeneic tumor cells and enhanced development of 3-methylcholanthrene-induced primary tumors. In contrast, coimmunization with the same SEREX-defined self-Ags mixed with a CTL epitope results in augmented CTL activity and heightened resistance to pulmonary metastasis, both of which depend on CD4+ Th cells. These active regulatory T cells and Th cells were derived from two distinct CD4 + T cell subsets, CD4+CD25+ T cells and CD4+CD25- T cells, respectively. In the present study, IFN-γ was found to abrogate the generation/activation of CD4 +CD25+ regulatory T cells by immunization with SEREX-deflned self-Ag. CD4+CD25+ T cells from these IFN-γ-treated mice failed to exhibit immunosuppressive activity as measured by 1) increased number of pulmonary metastasis, 2) enhanced development of 3-methylcholanthrene-induced primary tumors, 3) suppression of peptide-specific T cell proliferation, and 4) enhanced expression of Foxp3. The important role of IFN-γ produced by CD8+ T cells was shown in experiments demonstrating that CD4+CB25+ T cells cotransferred with CD8+ T cells from IFN-γ-/- mice, but not from wild-type BALB/c mice, became immunosuppressive and enhanced pulmonary metastasis when recipient animals were subsequently immunized with a SEREX-defined self-Ag and a CTL epitope. These findings support the idea that IFN-γ regulates the generation/activation of CD4+CD25 + regulatory T cells.

Original languageEnglish
Pages (from-to)4433-4440
Number of pages8
JournalJournal of Immunology
Volume175
Issue number7
StatePublished - Oct 1 2005

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    Nishikawa, H., Kato, T., Tawara, I., Ikeda, H., Kuribayashi, K., Allen, P. M., Schreiber, R. D., Old, L. J., & Shiku, H. (2005). IFN-γ controls the generation/activation of CD4+CD25 + regulatory T cells in antitumor immune response. Journal of Immunology, 175(7), 4433-4440.