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

Abstract
Immunization with serological identification of Ags by recombinant expression cloning (SEREX)-defined self-Ags leads to generation/activation of CD4+ CD25+ 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-gamma was found to abrogate the generation/activation of CD4+ CD25+ regulatory T cells by immunization with SEREX-defined self-Ag. CD4+ CD25+ T cells from these IFN-gamma-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-gamma produced by CD8+ T cells was shown in experiments demonstrating that CD4+ CD25+ T cells cotransferred with CD8+ T cells from IFN-gamma(-/-) 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-gamma regulates the generation/activation of CD4+ CD25+ regulatory T cells.
AuthorsHiroyoshi Nishikawa, Takuma Kato, Isao Tawara, Hiroaki Ikeda, Kagemasa Kuribayashi, Paul M Allen, Robert D Schreiber, Lloyd J Old, Hiroshi Shiku
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 7 Pg. 4433-40 (Oct 01 2005) ISSN: 0022-1767 [Print] United States
PMID16177085 (Publication Type: Journal Article)
Chemical References
  • Epitopes
  • Heat-Shock Proteins
  • Receptors, Interleukin-2
  • Interferon-gamma
Topics
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Epitopes (immunology)
  • Female
  • Heat-Shock Proteins (immunology)
  • Interferon-gamma (deficiency, genetics, physiology)
  • Lung Neoplasms (immunology, prevention & control, secondary)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Receptors, Interleukin-2 (biosynthesis, metabolism)
  • Sarcoma, Experimental (immunology, pathology, prevention & control)
  • T-Lymphocyte Subsets (immunology)
  • T-Lymphocytes, Cytotoxic (immunology)
  • T-Lymphocytes, Regulatory (immunology)

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