Mechanism of TCDD-Induced Suppression of Antibody Production: Effect on T Cell-Derived Cytokine Production in the Primary Immune Reaction of Mice

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to suppress antigen-specific antibody production in humoral immune reactions, but the precise mechanism remains unclear. Since T cell activation and subsequent production of type 2 helper T (Th2) cell-derived cytokines are required for antigen-specific antibody production in humoral immunity, we examined the effects of TCDD on splenic T cell numbers, T cell growth factor IL-2 production, and Th2 cell-derived cytokine production. C57BL/6N mice were orally given TCDD (20 microg/kg) or vehicle, and immediately intraperitoneally immunized with ovalbumin (OVA) adsorbed to alum, and cellular changes in the spleen and cytokine production by spleen cells were investigated from Day 1 to Day 14. In vehicle-control mice the numbers of splenic CD3(+) T cells increased from Day 7 onward, but no increase was observed in the TCDD-exposed mice. When spleen cells from control mice were cultured and restimulated with OVA ex vivo, a significant amount of IL-2 was found from Day 1, but it decreased on Day 7, whereas TCDD exposure promptly suppressed the increase on Day 4. TCDD exposure significantly suppressed the production of Th2 cell-derived cytokines IL-4, IL-5, and IL-6, which were prominently increased from Day 4 onward in control mice. The dose-dependent study showed that IL-5 production was significantly suppressed in a dose-dependent manner starting at 1 microg/kg TCDD. Moreover, separation and reconstitution studies showed that the TCDD-induced suppression of IL-5 production was due to the impaired function of T cells rather than that of antigen-presenting cells. The results of this study suggest that TCDD-induced suppression of T cell activation and Th2-type cytokine production is involved in the impairment of antigen-specific antibody production.

Constitutively Active Aryl Hydrocarbon Receptor Expressed Specifically in T-Lineage Cells Causes Thymus Involution and Suppresses the Immunization-Induced Increase in Splenocytes

“…We previously reported finding that TCDD administration to mice immunized with OVA suppressed the immunization-induced increase in spleen weight and splenocyte number (27,34). Consistent with these findings, the increase in spleen weight and splenocyte number observed in wild-type mice after immunization with OVA was suppressed in line A Tg mice (Fig.…”

“…Alum-precipitated OVA (OVA/alum) was prepared as follows (27,34). OVA (1 mg/ml) in PBS was mixed with an equal volume of 9% (w/v) AlK(SO 4 ) 2 , and pH of the mixture was adjusted to 6.5 with KOH.…”

“…A recent study by Kerkvliet et al (26) in a mouse graft-vs-host model injected with AhR ϩ/ϩ or AhR Ϫ/Ϫ T cells showed that AhR activation in T cells is critical to the suppression of CTL activity by TCDD. In our own study examining the effect of TCDD on OVA-specific Ab production in mice (27), TCDD exposure suppressed the increase in T cell number in the spleen and production of IL-2 and Th2-type cytokines before the inhibition of Ag-induced Ab production, suggesting that the AhR activation in T cells causes suppression of T cell activation and subsequent immune reactions leading to Ab production. However, it is difficult to determine the specific role of AhR activation in T cells alone in TCDD-exposed mice, because the AhR in all cell types, including B cells and APCs, is simultaneously activated, and indirect effects cannot be excluded.…”

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

“…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.…”

Cancer immunoediting and dioxin-activating aryl hydrocarbon receptor: a missing link in the shift toward tumor immunoescape?

“…[57][58][59] Exposure to dioxin leads to profound suppression of both humoral and cellular immune responses. 60 Dioxin-activated AhR suppresses T-cells, which are its primary targets, and mediates B-cell antibody response inhibition [61][62][63] and thymic involution, with consequent thymocyte loss, premature migration of T-cell progenitors, [64][65][66] and overexpression of FAS-L in thymic stromal cells, resulting in Tcell apoptosis induction. 67,68 Alterations in thymocytes appear transient, as adult mice exposed developmentally to dioxin do not exhibit thymic atrophy or alterations in the proportion of thymocyte subpopulations, and skewing of T-cell subpopulations is not observed in secondary lymphoid organs.…”