Constitutively active aryl hydrocarbon receptor expressed in T cells increases immunization-induced IFN-  production in mice but does not suppress Th2-cytokine production or antibody production

Abstract

The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) has been implicated in various immune functions. Our previous studies have shown that AhR activation by exposure of ovalbumin (OVA)-immunized mice to the potent ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases immunization-induced IFN-gamma production in the spleen and suppresses the production of T(h)2 cytokines and OVA-specific antibodies. In the present study, we used transgenic (Tg) mice that express a constitutively active mutant of aryl hydrocarbon receptor (CA-AhR) specifically in T-lineage cells to clarify the role of AhR activation in T cells in these reactions. The results of this study clearly demonstrated that AhR activation only in the T cells augments IFN-gamma production upon OVA immunization. By contrast, production of T(h)2 cytokines and antibodies were not significantly suppressed by CA-AhR in the T cells. These results suggest that suppression of T(h)2 cytokines and antibodies production require AhR activation not only in T cells but also in other cell types as caused by TCDD exposure. Alternatively, these results may indicate that IFN-gamma augmentation and T(h)2 cytokines and antibodies suppression depend on different ways of functions of AhR in the T cells and that CA-AhR does not replicate the suppressive effect of TCDD-activated AhR on T(h)2 cytokines and antibodies. Expression of CA-AhR in the T cells was also shown to increase the percentage of CD25(+) cells among CD4(+) cells in the thymus and spleen. Thus, studies using T-cell-specific CA-AhR Tg mice provide a way to dissect the role of AhR in individual cell types and how the AhR functions.

The aryl hydrocarbon receptor: fine-tuning the immune-response

“…AhR-dependent induction of iTreg is in contrast with studies using a T cell-specific constitutively active form of AhR, which does not result in increased Treg differentiation or development [34,35]. Importantly, increases in Treg in vivo have only been reported proportionally and not in absolute numbers, whilst other ligands such as FICZ reduce in vitro TGFb-dependent iTreg differentiation [31 ].…”

Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders

“…3,70 Many review articles on the mechanism of TCDD-mediated immunosuppression have been published in recent years, 71,72 and therefore such mechanisms will not be further elaborated here. Overall, the mechanisms could be summarized into the ability of TCDD to induce apoptosis in immune cells, 70,[73][74][75][76] to alter cytokines, 77 and to directly affect various cellular components such as Th cells, cytotoxic T lymphocytes, B cells, thymocytes, and dendritic cells, as detailed in recent reviews. 72 In addition, TCDD has been shown to induce transforming growth factor-b, which facilitates the generation of suppressor T cells or Foxp3 + regulatory T cells (Tregs).…”