Activation of the Aryl Hydrocarbon Receptor Suppresses Sensitization in a Mouse Peanut Allergy Model

Abstract

Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 μg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

“…Strikingly, FICZ-dependent formation of ROS observed in our experiments would also be in accordance and contribute to the enhancement of the overall inflammatory acute response observed in young allergic patients (32). Alternatively, repetitive exposure to AhR-ligand pollutants could suppress MC degranulation and attenuate the allergic response in favor of other types MCmediated responses (e.g., inflammatory responses) by directly acting on AhR-mediated MC responsiveness (10). Consistently, MC "desensitization" through a repetitive AhR activation may suggest an association with approaching therapies to desensitize patients (especially children) that develop severe IgE-mediated anaphylactic responses against dietary compounds (33).…”

“…Therefore, AhR expression and its possible role in modulating MC functions may have significant implications for the outcome of inflammatory pathologies where effector T cell/Treg cell balance is compromised. Interestingly, a recent study shows that the activation of AhR suppresses the development of Th2-mediated food allergic response by inducing Treg cell skewing (10). However, these data do not exclude that AhR engagement could directly affect the function of allergy effector cells, namely MCs, beyond T cells.…”

Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

“…TCDD treatment only weakly affected the number of Tregs, consistent with the literature (Kerkvliet, 2009b;Negishi et al, 2005). We also found that TCDD exposure decreased the levels of pro-inflammatory cytokines IL-6 and IL-22 and increased the levels of the anti-inflammatory cytokines IL-13 and IL-12p70 (Table 2), consistent with TCDD-induced suppression of immune hypersensitivity phenotype in the mouse model of peanut allergy (Schulz et al, 2011).…”

Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function

“…13,14 In the context of allergic hypersensitivity, AhR agonists inhibit Th2-mediated cytokine production and allergic responses in mouse models of atopic dermatitis, food allergy and asthma-like disease. 10,15,16 However, when using whole animal models, it is difficult to determine whether the effects of AhR ligands are due to direct effects on T cells or to effects on T-cell programming by antigen-presenting cells. Interestingly, wild-type recipients of adoptively transferred AhR-deficient T cells displayed TCDD-induced inhibition of T-cell proliferation in response to influenza virus, 11,17 suggesting that antigenpresenting cells play a key a role in AhR modulation of T-cell function.…”