2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules.
Primary T cell-mediated immune responses are highly susceptible to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, yet direct effects of TCDD on T cells have been difficult to demonstrate. Since the activation of naive T cells has been shown to be initiated primarily by dendritic cells (DC), these cells represent a potential target for TCDD immunotoxicity. In this report, we have examined the influence of TCDD exposure on splenic DC phenotype and function in the absence of antigenic stimulation. Results showed that DC from TCDD-treated mice expressed higher levels of several accessory molecules including ICAM-1, CD24, B7-2, and CD40, whereas the expression of LFA-1 was significantly reduced. These effects were dose-dependent and persisted for at least 14 days after exposure. The effects were also dependent upon the aryl hydrocarbon receptor (AhR), as similar effects were observed in AhR+/+ C57Bl/6 and Balb/c mice but not in AhR-/- mice. When DC from TCDD-treated mice were cultured with allogeneic T cells, the proliferative response and production of IL-2 and IFN-gamma by the T cells were increased. Production of IL-12 by the DC was likewise enhanced in comparison to cells from vehicle-treated mice. Interestingly, however, the number of DC recovered from TCDD-treated mice was significantly decreased. Taken together, these results suggest that, in the absence of antigen, TCDD provides an activation stimulus to DC that may lead to their premature deletion. Since the survival of DC has been shown to influence the strength and duration of the immune response, these results suggest a possible novel mechanism for TCDD-induced immune suppression.
Vorderstrasse
B A
BA
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
Kerkvliet
N I
NI
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D051940:B7-2 Antigen; D051927:CD24 Antigen; D019013:CD40 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002452:Cell Count; D002455:Cell Division; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007165:Immunosuppression Therapy; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D018655:Lymphocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000502:physiology; D013154:Spleen / Q000166:cytology*; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D051940:B7-2 Antigen; D051927:CD24 Antigen; D019013:CD40 Antigens; C497890:Cd24a protein, mouse; C497965:Cd86 protein, mouse; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma