Sensitivity to suppression of cytotoxic T cell generation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on the Ah genotype of the murine host

Nagarkatti, Mitzi; Sweeney, George D.; Gauldie, Jack; Clark, David A.

doi:10.1016/0041-008x(84)90261-8

Cited by 102 publications

(39 citation statements)

References 17 publications

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“…TCDD-mediated immunotoxicity has been well characterized in various animal models (Faith and Luster, 1979;Nagarkatti et al, 1984;Greenlee et al, 1985;Fine et al, 1990;Lundberg et al, 1990a,b;Holladay et al, 1991;Esser, 1994;Kerkvliet et al, 2002). Currently, the consensus is that TCDD-mediated toxicity is initiated by TCDD-AhR interaction, AhR-ARNT interaction with DRE present in regulatory regions of TCDD-sensitive genes, their induction, and resultant immunotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

Singh

Nagarkatti²,

Nagarkatti

2008

Mol Pharmacol

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Although the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T cells in vivo have been well characterized, attempts to reproduce these findings in vitro have not been successful. In the current study, we examined whether activation or the presence of dendritic cells (DCs) would make primary naive T cells from C57BL/6 mice susceptible to TCDD-induced apoptosis in vitro. Although nonactivated primary T cells cultured with 10 to 1000 nM TCDD were relatively resistant to apoptosis, they became sensitive to apoptosis upon activation with concanavalin A (ConA). Moreover, ConA-activated T cells cultured in the presence of DCs showed highest levels of TCDD-induced apoptosis. Likewise, primary T cells from OT.II.2a mice cultured with specific ovalbumin peptide and syngeneic DCs showed higher levels of apoptosis compared with similar nonactivated T cells. T-cell activation led to up-regulation of aryl hydrocarbon receptor (AhR), Fas, and Fas-ligand (FasL) expression. In addition, DC maturation and culture with TCDD caused significant induction of FasL. TCDD-mediated apoptosis in activated peripheral T cells was AhR-dependent. Analysis of why nonactivated T cells are more resistant, whereas activated T cells are sensitive to TCDD-induced apoptosis revealed that TCDD treatment of activated but not nonactivated T cells led to down-regulation of cellular FLICE inhibitory protein (c-FLIP), an inhibitor of apoptosis. Moreover, down-regulation of c-FLIP using small interfering RNA in nonactivated T cells made them sensitive to TCDDinduced apoptosis. The current study demonstrates for the first time that TCDD can induce apoptosis in vitro in peripheral T cells upon activation and in the presence of DCs and that this may be mediated by down-regulation of c-FLIP.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant that mediates toxicity through activation of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor and member of the basic helix-loop-helix-Per/Arnt/Sim (periodicity/aryl hydrocarbon receptor nuclear translocator/simple-minded) gene family (Marlowe and Puga, 2005;Bock and Kohle, 2006;Harper et al., 2006). TCDD binds and activates cytosolic AhR attached to 90-kDa heat shock protein; and upon activation, AhR dissociates from 90-kDa heat shock protein, migrates to the nucleus, dimerizes with AhR nuclear translocator (ARNT), and forms AhR/ARNT heterodimer. This in turn binds to dioxin-response elements (DRE), present as cis-acting elements in the regulatory regions of dioxin-responsive genes, and it up-regulates a large set of genes that directly or indirectly participate in TCDD-induced toxicity (Schmidt and

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Section: Discussionmentioning

confidence: 99%

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

Singh

Nagarkatti²,

Nagarkatti

2008

Mol Pharmacol

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“…T cells are a possible direct target for TCDD, as evidenced by the presence of the AhR in T cells, and inhibition of T cell growth by the expression of a constitutively active AhR mutant in AhRnull Jurkat T cells or following TCDD treatment (1,41). It has been demonstrated that expression of AhR in both CD4 ϩ and CD8 ϩ T cells is required for a full suppression of an allospecific CTL response by TCDD, indicating a direct role for AhR in these TCDD-induced immunosuppressive effects (1,42). However, the relationship between in vivo TCDD exposure and breakdown in T cell tolerance has not been well defined.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance

Ishimaru

Takagi

Kohashi

et al. 2009

The Journal of Immunology

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Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to influence immune responses, the effects of low-dose TCDD on the development of autoimmunity are unclear. In this study, using NFS/sld mice as a model for human Sjögren’s syndrome, in which the lesions are induced by the thymectomy on day 3 after birth, the autoimmune lesions in the salivary glands, and in later phase, inflammatory cell infiltrations in the other organs were developed by neonatal exposure to nonapoptotic dosage of TCDD without thymectomy on day 3 after birth. We found disruption of thymic selection, but not thymic atrophy, in TCDD-administered mice. The endogenous expression of aryl hydrocarbon receptor in the neonatal thymus was significantly higher than that in the adult thymus, suggesting that the neonatal thymus may be much more sensitive to TCDD compared with the adult thymus. In addition, the production of TH1 cytokines such as IL-2 and IFN-γ from splenic CD4+ T cells and the autoantibodies relevant for Sjögren’s syndrome in the sera from TCDD-exposed mice were significantly increased compared with those in control mice. These results suggest that TCDD/aryl hydrocarbon receptor signaling in the neonatal thymus plays an important role in the early thymic differentiation related to autoimmunity.

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“…However, what appears to be a dose-related pattern of immunotoxic eects among the three groups (Atlantic < Baltic < TCDD) may suggest a similar mechanism of immunotoxic action in the Baltic and TCDD groups. Immunotoxicity by organochlorines has been shown to be largely mediated by the Ah receptor (Safe 1990;Nagarkatti et al 1984). The TCDD group of rat pups was exposed to the Ah-prototype immunotoxicant, 2,3,7,8-TCDD (a very small amount of other organochlorines were present in the relatively uncontaminated Atlantic herring oil), while the Baltic group was exposed to a complex mixture of lipophilic PHAH compounds.…”

Section: Discussionmentioning

confidence: 99%

Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or 2,3,7,8-TCDD

Ross¹,

Swart²,

Vliet

et al. 1997

Archives of Toxicology

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While the immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established, the eects of complex environmental mixtures of polyhalogenated aromatic hydrocarbons (PHAHs) are poorly understood. Many PHAHs, including the polychlorinated-biphenyls (PCBs), -dibenzofurans (PCDFs), and dibenzo-p-dioxins (PCDDs), possess`dioxin-like' activities, and accumulate in the aquatic food chain. Organisms occupying high trophic levels may therefore be exposed to concentrations which may present an immunotoxic risk. In this study, pregnant PVG rats were administered a daily oral dose of 1 ml of the following during pregnancy and lactation: (1) oil extracted from herring caught in the relatively uncontaminated Atlantic Ocean; (2) oil extracted from herring caught in the contaminated Baltic Sea; or (3) the Atlantic herring oil extract spiked with 2,3,7,8-TCDD. The daily intakes of aryl hydrocarbon (Ah)-receptor dependent toxic equivalents (TEQ) for mothers were 0.3 in the Atlantic group, 2.1 in the Baltic group, and 134 ng/kg body wt. in the 2,3,7,8-TCDD positive control group. Immune function and host resistance to rat cytomegalovirus (RCMV) were assessed in ospring aged 11, 25, 46 or 59 days. Rat pups in the positive control TCDD-spiked group exhibited immunosuppression characterized by reduced thymus weight and cellularity, reduced thymocyte and splenocyte proliferative responses to T-dependent mitogens in vitro, reduced virus-associated natural killer (NK) cell and speci®c antibody responses. While less pronounced, a similar pattern of eects was observed in the rat pups exposed only to the Baltic Sea herring oil. These immunotoxic eects were transient in both exposure groups, with a time-related recovery in immune function possibly due to the half-life of TCDD in rats and the waning exposure levels in the rapidly growing pups. We previously demonstrated that the same Baltic Sea herring led to impaired natural killer cell and Tlymphocyte function in harbour seals during the course of a long-term captive feeding study. The collective results of these studies in rats and seals indicate the immunotoxic potential of environmental mixtures at current levels in the aquatic environment, and suggest that the developing immune system of young mammals may be at particular risk.

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Sensitivity to suppression of cytotoxic T cell generation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on the Ah genotype of the murine host

Cited by 102 publications

References 17 publications

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance

Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or 2,3,7,8-TCDD

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