Functional alterations in CD11b(+)Gr-1(+) cells in mice injected with allogeneic tumor cells and treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure results in an increased percentage of CD11b(+) (Mac-1(+)) cells in the spleens of mice challenged with P815 tumor cells, coincident with a failure of the mice to generate allospecific CD8(+) CTL activity. Since CD11b(+)Gr-1(+) myeloid suppressor cells (MSC) have been described as that which prevent cytotoxic T lymphocyte (CTL) development in a variety of disease states, we hypothesized that TCDD promoted MSC development, leading to suppression of CTL activity. The purpose of the present studies was to compare the phenotypic and functional characteristics of CD11b(+) cells in vehicle- and TCDD-treated mice during the P815 tumor allograft response to determine their potential to function as MSC. Initial studies showed that virtually all splenic CD11b(+) cells in both vehicle- and TCDD-treated mice co-expressed Gr-1. Consistent with MSC activity, CD11b(+)Gr-1(+) cells isolated from TCDD- but not vehicle-treated mice suppressed the development of CTL activity when added in vitro to mixed lymphocyte-P815 tumor cell cultures. Also consistent with MSC activity, this suppressive effect in vitro required cell-to-cell contact. Surprisingly, however, in vivo depletion of CD11b(+)Gr-1(+) cells failed to affect TCDD-induced suppression of the CTL response, arguing against an immunoregulatory role for the cells in vivo. Immunohistochemical analysis of the spleen showed that CD11b(+)Gr-1(+) cells were localized in the red pulp, and physically separated from the T cells in the white pulp. The localization of CD11b(+)Gr-1(+) cells in the red pulp was indicative of extramedullary myelopoiesis and suggested that TCDD enhanced myelopoiesis. A significantly enhanced neutrophilia in the blood of TCDD-treated mice supported this conclusion. CD11b(+)Gr-1(+) cells isolated from the blood or spleen of TCDD-treated mice produced up to fivefold higher levels of superoxide following PMA stimulation when compared with cells from vehicle-treated mice. However, unlike vehicle-treated mice, CD11b(+)Gr-1(+) cells from TCDD-treated mice were unable to kill YAC-1 target cells. These results indicate that TCDD exposure alters the host response to allogeneic tumor growth, resulting in enhanced myelopoiesis perhaps as a compensatory response to the suppressed T cell-mediated immunity in the face of an increasing P815 tumor burden. Furthermore, within the context of the P815 response, TCDD appears to alter the functional capabilities of mature neutrophils, by enhancing their oxidative burst capacity but reducing their tumoricidal response.
Choi
Jin-Young
JY
Department of Environmental and Molecular Toxicology, Agricultural Life Sciences Building, Room 1007 Oregon State University, Corvallis, OR 97331, USA.
Oughton
Julie A
JA
Kerkvliet
Nancy I
NI
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D039481:CD11b Antigen / Q000096:biosynthesis* / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D008297:Male; D012515:Mast-Cell Sarcoma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D039481:CD11b Antigen; D000072317:Polychlorinated Dibenzodioxins