Infiltration of a mesothelioma by IFN-gamma-producing cells and tumor rejection after depletion of regulatory T cells.
Depletion of CD4+CD25+Foxp3+ regulatory T cells (CD25+ T(reg)) with an anti-CD25 Ab results in immune-mediated rejection of tolerogenic solid tumors. In this study, we have examined the immune response to a mesothelioma tumor in mice after depletion of CD25+ cells to elucidate the cellular mechanisms of CD25+ T(reg), a subject over which there is currently much conjecture. Tumor rejection was found to be primarily due to the action of CD8+ T cells, although CD4+ cells appeared to play some role. Depletion of CD25+ cells resulted in an accumulation in tumor tissue of CD4+ and CD8+ T cells and NK cells that were producing the potent antitumor cytokine IFN-gamma. Invasion of tumors by CD8+ T cells was partially dependent on the presence of CD4+ T cells. Although a significant increase in the proliferation and number of tumor-specific CD8+ T cells was observed in lymph nodes draining the tumor of anti-CD25-treated mice, this effect was relatively modest compared with the large increase in IFN-gamma-producing T cells found in tumor tissue, which suggests that the migration of T cells into tumor tissue may also have been altered. Depletion of CD25+ cells did not appear to modulate antitumor CTL activity on a per cell basis. Our data suggests that CD25+ T(reg) limit the accumulation of activated T cells producing IFN-gamma in the tumor tissue and, to a lesser extent, activation and/or rate of mitosis of tumor-specific T cells in lymph nodes.
Rudge
Geordie
G
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
Barrett
Simon P
SP
Scott
Bernadette
B
van Driel
Ian R
IR
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007371:Interferon-gamma / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008654:Mesothelioma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma