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Controls the Generation/Activation of CD4+CD25+ Regulatory T Cells in Antitumor Immune Response1
* Second Department of Internal Medicine and
Department of Bioregulation, Mie University School of Medicine, Mie, Japan;
Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110; and
Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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-
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--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- produced by CD8+ T cells was shown in experiments demonstrating that CD4+CD25+ T cells cotransferred with CD8+ T cells from IFN-–/– 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- regulates the generation/activation of CD4+CD25+ regulatory T cells.
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