Involvement of altered B7 expression in dioxin immunotoxicity: B7 transfection restores the CTL but not the autoantibody response to the P815 mastocytoma

• Published in: The Journal of immunology (1950) Vol. 158; no. 6; pp. 2695 - 2703
• Main Authors: Prell, RA, Kerkvliet, NI
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.03.1997
• Subjects: Animals; Antigens, CD - biosynthesis; Antilymphocyte Serum - biosynthesis; Antilymphocyte Serum - drug effects; B7-1 Antigen - biosynthesis; B7-1 Antigen - drug effects; B7-1 Antigen - genetics; B7-2 Antigen; CD4-Positive T-Lymphocytes - immunology; Cytotoxicity, Immunologic - drug effects; Cytotoxicity, Immunologic - genetics; Isoantibodies - biosynthesis; Leukocyte Common Antigens - drug effects; Macrophage-1 Antigen - drug effects; Male; Mast-Cell Sarcoma - genetics; Mast-Cell Sarcoma - immunology; Membrane Glycoproteins - biosynthesis; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Transplantation; Polychlorinated Dibenzodioxins - toxicity; Spleen - cytology; Spleen - immunology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Transfection; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.158.6.2695

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.