Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Suppresses the Humoral and Cell-Mediated Immune Responses to Influenza A Virus without Affecting Cytolytic Activity in the Lung

Abstract

The immune response to influenza virus is exquisitely sensitive to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); however, the cellular mechanisms underlying the suppressive effects of TCDD are unknown. Mice exposed to TCDD exhibited a dose-responsive increase in mortality following an otherwise non-lethal influenza virus infection. Given that cytotoxic T lymphocytes (CTL) are generally thought to resolve primary infections in the lung, we tested the hypothesis that exposure to TCDD suppresses T-cell responsiveness, leading to decreased CTL in the lung. After infection with influenza virus, naive CD8+ lymphocytes are activated and differentiate in the mediastinal lymph node (MLN). In mice exposed to TCDD and infected with influenza virus, the number of CD8+ MLN cells was reduced 60% compared to vehicle-treated mice. Moreover, MLN cells from TCDD-treated mice failed to develop cytolytic activity, and the production of interleukin (IL)-2 and interferon (IFN)-gamma was suppressed. Exposure to TCDD also altered the production of virus-specific antibodies, decreased the recruitment of CD8+ cells to the lung, reduced the percentage and number of bronchoalveolar lavage cells bearing a CTL phenotype (CD8+CD44hiCD62L(l) degrees ), and suppressed IL-12 levels in the lung. Despite our findings that exposure to TCDD suppressed T cell-dependent functions, the cytolytic activity of lung lavage cells from TCDD and vehicle treated mice was equivalent, and IFN gamma levels in the lungs of mice treated with TCDD were enhanced 10-fold. Thus, while exposure to TCDD suppressed a number of responses associated with the development of adaptive immunity to influenza virus, a direct link between these effects and enhanced susceptibility to influenza remains unclear.

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

“…Previous reports have shown that exposure to TCDD suppresses IL-12 production (25,58), and affects the expression of costimulatory and adhesion molecules on DC, macrophages, and B cells (23,53,59,60). Suppressed IL-12 production and changes in DC number and phenotype were not observed in TCDD-treated AhR Ϫ/Ϫ mice (60) (our unpublished observations), indicating that that these changes are AhR dependent.…”

“…Previous reports have shown that exposure to the potent AhR agonist TCDD suppresses the expansion and differentiation of CD8 ϩ T cells (17,25,30). However, it is not known whether this effect is limited to specific CD8 ϩ T cell epitopes or whether it alters the anatomical distribution of virus-specific CD8 ϩ T cells during the response.…”

“…Although very little is known about the endogenous function of the AhR in the immune system, TCDD has a very profound effect on immune function. In fact, T cell-dependent responses and host resistance to infection are extremely sensitive targets for modulation by AhR agonists (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Although the molecular mechanisms that underlie these effects are not entirely clear, epidemiological data suggest that exposure to pollutants that contain AhR agonists correlates with diminished host resistance, altered immune function, and an increased incidence of influenza and other respiratory infections (27)(28)(29), suggesting a possible cause and effect relationship between exposure to AhR ligands and altered host resistance to infection.…”

“…We have investigated the mechanisms underlying the immunosuppressive effects of TCDD, and have shown previously that exposure of mice to TCDD impairs multiple facets of the immune response to influenza A virus, resulting in suppressed virus-specific IgG levels, enhanced pulmonary inflammation, and altered cytokine production in the lung and draining lymph nodes (25,30,31). Importantly, we have found that during primary infection, exposure to a single dose of TCDD suppresses the proliferation of CD8 ϩ T cells in the mediastinal lymph nodes (MLN), reduces their production of IFN-␥, and impairs the generation of CTL (25,30).…”

“…Importantly, we have found that during primary infection, exposure to a single dose of TCDD suppresses the proliferation of CD8 ϩ T cells in the mediastinal lymph nodes (MLN), reduces their production of IFN-␥, and impairs the generation of CTL (25,30). In addition to suppressive effects on the response of endogenous CD8 ϩ T cells, exposure to TCDD impairs expansion, differentiation, and IFN-␥ production by influenza virus-specific TCR transgenic CD8 ϩ T cells that have been adoptively transferred into wild-type recipients (32).…”