TY - JOUR
T1 - IFN-γ controls the generation/activation of CD4+CD25 + regulatory T cells in antitumor immune response
AU - Nishikawa, Hiroyoshi
AU - Kato, Takuma
AU - Tawara, Isao
AU - Ikeda, Hiroaki
AU - Kuribayashi, Kagemasa
AU - Allen, Paul M.
AU - Schreiber, Robert D.
AU - Old, Lloyd J.
AU - Shiku, Hiroshi
PY - 2005/10/1
Y1 - 2005/10/1
N2 - Immunization with serological identification of Ags by recombinant expression cloning (SEREX)-deflned self-Ags leads to generation/activation of CD4+CB25+ 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-deflned 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+CB25+ 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.
AB - Immunization with serological identification of Ags by recombinant expression cloning (SEREX)-deflned self-Ags leads to generation/activation of CD4+CB25+ 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-deflned 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+CB25+ 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.
UR - http://www.scopus.com/inward/record.url?scp=25444439253&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.175.7.4433
DO - 10.4049/jimmunol.175.7.4433
M3 - Article
C2 - 16177085
AN - SCOPUS:25444439253
SN - 0022-1767
VL - 175
SP - 4433
EP - 4440
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -