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

H Nishikawa, T Kato, I Tawara, H Ikeda… - The Journal of …, 2005 - journals.aai.org
H Nishikawa, T Kato, I Tawara, H Ikeda, K Kuribayashi, PM Allen, RD Schreiber, LJ Old…
The Journal of Immunology, 2005journals.aai.org
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 …
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-γ 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-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+ CD25+ 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.
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