Involvement of altered B7 expression in dioxin immunotoxicity: B7 transfection restores the CTL but not the autoantibody response to the P815 mastocytoma.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic environmental contaminant, suppresses both CTL and cytotoxic alloantibody production in C57BL/6 mice challenged with allogeneic P815 tumor cells. Recent evidence suggests that TCDD interferes with the initial activation of CD4+ Th cells, possibly through an indirect mechanism. In this study, we examined the effect of TCDD on the expression of the important costimulatory molecules, B7-1 and B7-2, in P815 allograft immunity. Expression of B7-2, but not B7-1, was up-regulated on splenic B220+ and Mac-1+ cells in P815-challenged mice. Exposure to TCDD significantly decreased the expression of B7-2 on B220+ and Mac-1+ cells in P815-challenged mice. Providing exogenous B7-mediated costimulation, in the form of B7-transfected P815 tumor cells, induced CTL activity in TCDD-treated mice by a mechanism that was independent of CD4+ T cells. In contrast, B7-transfected P815 cells did not restore the cytotoxic alloantibody response in TCDD-treated mice. These results are consistent with a model in which MHC class II-, B7-transfected P815 tumor cells can directly activate CD8+ CTL precursors but cannot directly stimulate CD4+ T helper cells required for B cell activation. These results also demonstrate that CTL precursors in TCDD-treated mice are functional and able to differentiate into effector CTL provided they receive adequate costimulation via B7 and suggest that defective costimulation, through reduced B7-2 expression, may play a role in TCDD-induced immunotoxicity. In support of this hypothesis, we show that blocking B7-2/CD28 interactions, and to a lesser degree B7-1/CD28 interactions, suppressed the alloimmune responses to P815 tumor cells, which further indicates that B7-2 represents the dominant B7 molecule involved in the generation of an immune response to allogeneic P815 tumor cells.
Prell
R A
RA
Toxicology Program, Oregon State University, Corvallis 97331, USA.
Kerkvliet
N I
NI
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000961:Antilymphocyte Serum / Q000096:biosynthesis / Q000187:drug effects; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000235:genetics; D007518:Isoantibodies / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000187:drug effects; D008297:Male; D012515:Mast-Cell Sarcoma / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000961:Antilymphocyte Serum; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007518:Isoantibodies; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D000072317:Polychlorinated Dibenzodioxins; D017493:Leukocyte Common Antigens