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

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 WN-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.