IFN-gamma regulates donor CD8 T cell expansion, migration, and leads to apoptosis of cells of a solid tumor.
We previously reported that IFN-gamma secreted by donor cytotoxic T cell 1 (Tc1) cells was the most important factor in promoting EG7 (an OVA transfection the EL4 thymoma) rejection in mice. In this study, we show that the ability of the host to respond to Tc1-secreted IFN-gamma is critical for promoting acute tumor rejection, while host production of IFN-gamma is not important. CFSE-labeled wild-type and IFN-gamma-deficient Tc1 cells divide rapidly in secondary lymphoid organs, indicating no defect in rate of cell division. However, wild-type Tc1 cells accumulate to significantly greater numbers in the tumor than deficient Tc1 cells. Hosts injected with wild-type Tc1 effectors had more T cells within the tumor at day 4, had higher levels of MCP-1, IFN-gamma-inducible protein-10, MIP-1alpha, and MIP-1beta mRNA transcripts, had greater numbers of CD11b+ and Gr-1+ cells within the tumor, and had massive regions of tumor cell apoptosis as compared with IFN-gamma knockout Tc1 cell-treated hosts. NO has a cytostatic effect on EG7 growth in vitro, and NO is important for tumor eradication by day 22. These observations are compatible with a model in which the donor CD8 Tc1 effectors expand rapidly in the host, migrate to the tumor site, and induce the secretion of a number of chemokines that in turn recruit host cells that then attack the tumor.
Hollenbaugh
Joseph A
JA
Trudeau Institute, Saranac Lake, NY 12983, USA.
Dutton
Richard W
RW
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
D018925:Chemokines; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II