title: T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): AhR expression in both CD4+ and CD8+ T cells is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD.
abstract: The cellular basis for the potent suppression of T cell-mediated immune responses in mice following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is not fully understood. Although activation of the aryl hydrocarbon receptor (AhR) is required, the specific AhR+ cells that transduce the suppression have been difficult to identify in vivo. The recent availability of AhR-/- mutant mice has provided a resource for novel approaches to investigate the direct targets of TCDD. In our studies, we used an in vivo acute graft versus host (GVH) model of T cell immunity to address the direct AhR-dependent effects of TCDD on T cells. In this model, T cells from C57B1/6 mice are injected into C57B1/6 x DBA/2 F1 host mice. The injected T cells recognize the MHC disparity of the host cells, resulting in the generation of an antihost cytotoxic T lymphocyte (CTL) response. By comparing the ability of TCDD to suppress the CTL response of T cells obtained from AhR+/+ and AhR-/- C57B1/6 mice, the need for AhR expression in T cells themselves could be assessed. The results of these studies showed that the CTL response of T cells from AhR+/+ mice was highly suppressed when the F1 host mice were treated with 15 microg/kg TCDD. TCDD treatment also protected the F1 host mice from the loss of body weight that accompanies the induction of the GVH response. In contrast, when grafted T cells were derived from AhR-/- mice, there was no suppression of the CTL response by TCDD, and the host animals lost significant body weight. Furthermore, when T cells from AhR+/+ and AhR-/- mice were separated into CD4+ and CD8+ subsets and recombined using one subset from each donor prior to injection into the F1 host, suppression of the CTL response by TCDD was still apparent, but the degree of suppression was significantly reduced when either subset was AhR-/-. These results indicate that direct AhR-dependent effects of TCDD occur in both CD4+ and CD8+ T cell subsets and both T cell subsets contribute to the full suppression of the CTL response by TCDD.
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA. Nancy.kerkvliet@oregonstate.edu
authors.forename: Nancy I
authors.initials: NI
authors.lastname: Kerkvliet
authors.forename: David M
authors.initials: DM
authors.lastname: Shepherd
authors.forename: Linda
authors.initials: L
authors.lastname: Baecher-Steppan
mesh_terms: D000818:Animals; D001835:Body Weight; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006789:Host vs Graft Reaction / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon