title: 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.
authors.affiliation: Second Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Takuma
authors.initials: T
authors.lastname: Kato
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Kagemasa
authors.initials: K
authors.lastname: Kuribayashi
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology; D005260:Female; D006360:Heat-Shock Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000939:Epitopes; D006360:Heat-Shock Proteins; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma