Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on anti-CD3-induced changes in T-cell subsets and cytokine production

doi:10.1016/0192-0561(95)00080-1

International Journal of Immunopharmacology

Volume 17, Issue 11, November 1995, Pages 951-961

International Journa...

https://doi.org/10.1016/0192-0561(95)00080-1 Get rights and content

Abstract

The influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on the cytokine-dependent toxicity syndrome induced by the injection of 145-2C11 (anti-CD3), a hamster monoclonal antibody to the CD3 epsilon portion of the murine T-cell receptor, was studied. This syndrome has been attributed to the transient release of several cytokines including TNF-α, IFN-γ, IL-2, IL-3, IL-6, and GM-CSF. Exposure of C57B1/6 mice to TCDD (15 μg/kg) 2 days prior to anti-CD3 injection exacerbated anti-CD3-induced toxicity as evidenced by significantly enhanced and prolonged body weight loss and lymphoid tissue atrophy. Unexpectedly, TCDD exposure did not alter plasma levels of TNF or IL-2 at any time after anti-CD3 injection. However, plasma IFN-γ was significantly reduced at 24 h and plasma IL-6 levels were elevated 48 h after anti-CD3 injection in TCDD-treated mice. In addition, TCDD exposure resulted in elevated levels of plasma GM-CSF at 24 and 48 h. Since the body weight of TCDD-treated mice diverged from vehicle-treated mice at 48 h, it suggests that the increased IL-6 and GM-CSF may have contributed to the prolonged loss of body weight. The ability of spleen cells from vehicle- and TCDD-treated mice to produce cytokines was evaluated in vitro at various times after anti-CD3 injection. TCDD treatment resulted in reduced IL-2 and GM-CSF production at 90 min but increased GM-CSF production at 48 h post-anti-CD3 injection. In contrast, TCDD exposure did not influence cytokine production by spleen cells from mice injected with a control IgG and activated in vitro with anti-CD3. Flow cytometric analysis showed that the percentage of CD4⁺ cells in the draining lymph nodes from TCDD-treated mice was reduced 48–144 h post-anti-CD3 injection. In contrast, the percentage of CD8⁺ cells was not affected by TCDD exposure. A high fraction of lymph node cells (LNC) from TCDD-treated animals showed decreased forward angle light scatter and increased 90° light scatter following anti-CD3 injection, which is a pattern characteristic of cells undergoing apoptosis. In contrast, few LNC from vehicle-treated animals showed this light scatter profile. These data suggest that TCDD may be targeting T-helper cells during activation resulting in activation-driven cell death (apoptosis) rather than differentiation.

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Halogenated aromatic hydrocarbons (HAHs) persist in the environment and pose a threat to human health. The immune system is a sensitive target of HAHs. Over the past several decades, research in animal models and in human populations supports that HAHs are immunotoxic. The effects of some HAHs have been studied very broadly, whereas other effects have been interrogated in detail. The complex nature of the immune system involves many different cell types, such as T cells, dendritic cells, macrophages, natural killer cells, and neutrophils, which originate from hematopoietic stem cells and lineage-specific precursors. HAH immunotoxicity to cells of the primary immune organs, and to specific adaptive and innate immune cells, has been reported. Given that HAH immunotoxicity has been known for about 40 years, the main focus of this article is to summarize the recent findings and to discuss how this emerging information suggests possible cellular and molecular mechanisms of HAH immunotoxicity. The article will also present an overview of emerging data that point to HAH-mediated changes in innate immunity, immunological memory, as well as new information regarding HAH developmental immunotoxicity.
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The outcome of perinatal low-level TCDD exposure on the T-cell-mediated contact hypersensitivity (CHS) response in adult F344 rats was investigated. Suppression of the 2,4-dinitrofluorobenzene (DNFB)-specific contact hypersensitivity reponse occurred in mature offspring of dams dosed by gavage with 1 μg or 3 μg TCDD/kg on gestation day (GD) 14. To determine if this effect was correlated with altered distribution or activation of major T-cell subtypes, cells of the auricular lymph node draining the hapten-treated skin were evaluated by flow cytometry for expressed phenotype, including activation markers, 24 h after challenge. Six-month-old female offspring with significantly decreased CHS and born to dams given 3 μg TCDD/kg, had significantly greater proportion of CD4⁺ T cells expressing a naive phenotype marker, CD45RC^hi, in their draining nodes. The greater relative frequency of this CD4⁺ subset in peripheral lymphoid tissues associated with a reduced CHS in these rats may be attributed to a reduction in the proportion of CD4⁺ T cells maintaining or recruited into an activated state. The CHS proved to be a valuable bioassay for investigating long-term immunotoxic effects of perinatal TCDD exposure in rats.
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Exposure to TCDD has been shown to alter the expression of genes encoding anti-viral cytokines [45,46,48,53,54]. In fact, the idea that activation of the AhR dysregulates cytokine production and that these defects underlie the immunomodulatory activity of AhR ligands is supported by a large number of studies [23,55–58]. Therefore, a cytokine-mediated compensatory mechanism was logical.
Activation of the aryl hydrocarbon receptor (AhR) causes numerous defects in anti-viral immunity, including suppressed CTL generation and impaired host resistance. However, despite a reduced CTL response, mice that survive infection clear the virus. Therefore, we examined the contribution of NK cells and pro-inflammatory cytokines to viral clearance in influenza virus-infected mice exposed to TCDD, the most potent AhR agonist. Infection caused transient increases in pulmonary TNFα, IL-1, and IFNα/β levels, but neither the kinetics nor magnitude of this response was affected by AhR activation. No IL-18 was detected at any time point examined. Exposure to TCDD enhanced NK cell numbers in the lung but did not affect their IFNγ production. Furthermore, depletion of NK cells did not alter anti-viral cytolytic activity. In contrast, removal of CD8⁺ T cells ablated virus-specific cytolytic activity. These results demonstrate that the pulmonary CTL response to influenza virus is robust and few CTL are necessary for viral clearance.
Functional alterations in CD11b+Gr-1+ cells in mice injected with allogeneic tumor cells and treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin
2003, International Immunopharmacology
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure results in an increased percentage of CD11b⁺ (Mac-1⁺) cells in the spleens of mice challenged with P815 tumor cells, coincident with a failure of the mice to generate allospecific CD8⁺ CTL activity. Since CD11b⁺Gr-1⁺ myeloid suppressor cells (MSC) have been described as that which prevent cytotoxic T lymphocyte (CTL) development in a variety of disease states, we hypothesized that TCDD promoted MSC development, leading to suppression of CTL activity. The purpose of the present studies was to compare the phenotypic and functional characteristics of CD11b⁺ cells in vehicle- and TCDD-treated mice during the P815 tumor allograft response to determine their potential to function as MSC. Initial studies showed that virtually all splenic CD11b⁺ cells in both vehicle- and TCDD-treated mice co-expressed Gr-1. Consistent with MSC activity, CD11b⁺Gr-1⁺ cells isolated from TCDD- but not vehicle-treated mice suppressed the development of CTL activity when added in vitro to mixed lymphocyte–P815 tumor cell cultures. Also consistent with MSC activity, this suppressive effect in vitro required cell-to-cell contact. Surprisingly, however, in vivo depletion of CD11b⁺Gr-1⁺ cells failed to affect TCDD-induced suppression of the CTL response, arguing against an immunoregulatory role for the cells in vivo. Immunohistochemical analysis of the spleen showed that CD11b⁺Gr-1⁺ cells were localized in the red pulp, and physically separated from the T cells in the white pulp. The localization of CD11b⁺Gr-1⁺ cells in the red pulp was indicative of extramedullary myelopoiesis and suggested that TCDD enhanced myelopoiesis. A significantly enhanced neutrophilia in the blood of TCDD-treated mice supported this conclusion. CD11b⁺Gr-1⁺ cells isolated from the blood or spleen of TCDD-treated mice produced up to fivefold higher levels of superoxide following PMA stimulation when compared with cells from vehicle-treated mice. However, unlike vehicle-treated mice, CD11b⁺Gr-1⁺ cells from TCDD-treated mice were unable to kill YAC-1 target cells. These results indicate that TCDD exposure alters the host response to allogeneic tumor growth, resulting in enhanced myelopoiesis perhaps as a compensatory response to the suppressed T cell-mediated immunity in the face of an increasing P815 tumor burden. Furthermore, within the context of the P815 response, TCDD appears to alter the functional capabilities of mature neutrophils, by enhancing their oxidative burst capacity but reducing their tumoricidal response.
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The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppresses T cell functions and reduces T cell numbers in multiple models of immune stimulation. However, the underlying mechanism(s) by which TCDD induces these changes has yet to be elucidated. We hypothesized that TCDD affects T cells through the induction or augmentation of apoptosis. In these studies, we used antibody to CD4, annexin V, and 7-AAD in three-color flow cytometric analyses to examine the relationship between the decrease in CD4⁺ T cells and cell death in mice treated with anti-CD3 and TCDD. In addition, we examined two signaling pathways, Fas and TNF, in order to elucidate a potential mechanism by which TCDD increases cell death. Our results show that the TCDD-induced decrease in CD4⁺ T cell number correlated with an increase in the percentage of dead cells, but not with cells expressing an early apoptotic phenotype. The TCDD-induced decrease in CD4⁺ T cells was attenuated in Fas- and FasL-deficient mice (lpr and gld, respectively), but not by treatment with a neutralizing antibody to TNF. While these results suggest that the Fas pathway may be important in TCDD-induced T cell death, however, the effect of TCDD on the Fas pathway remains unclear. Taken together, our data suggest that TCDD-induced suppression of CD4⁺ T cells involves, in part, increased cell death that may be mediated by Fas/FasL interaction.

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ImmunotoxicologyEffect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on anti-CD3-induced changes in T-cell subsets and cytokine production

Abstract

Toxic. appl. Pharmac.

Toxic. appl. Pharmac.

Biochim. biophys. Acta

Clin. Immun. Immunopath.

J. immun. Meth.

Fund. appl. Toxic.

Cell

Toxic. appl. Pharmac.

Int. J. Immunopharmac.

Int. J. Immunopharmac.

J. immun. Meth.

Toxic. appl. Pharmac.

Toxic. Lett.

Cytokine release syndrome induced by the 145-2C11 anti-CD3 monoclonal antibody in mice: prevention by high doses of methylprednisolone

J. Immun.

Hypothermia and hypoglycemia induced by anti-CD3 monoclonal antibody in mice: role of tumor necrosis factor

Eur. J. Immun.

2,3,7,8-Tetrachlorodibenzo-p-dioxin causes elevation of the levels of the protein tyrosine kinase pp60c-src

J. Biochem. Toxic.

Enhanced suppressor cell activity as a mechanism of immunosuppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Tumor necrosis factor involvement in the toxicity of TCDD: the role of endotoxin in the response

Exp. clin. Immunogenet.

Anti-tumor necrosis factor modulates anti-CD3-triggered T-cell cytokine gene expression in vivo

J. clin. Invest.

Immunotoxicology
Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on anti-CD3-induced changes in T-cell subsets and cytokine production

2,3,7,8-Tetrachlorodibenzo-p-dioxin causes elevation of the levels of the protein tyrosine kinase pp60^c-src