The aryl hydrocarbon receptor: a novel target for immunomodulation in organ transplantation

Abstract

The aryl hydrocarbon receptor (AHR), which has been central to studies in toxicology for years as the receptor for the toxicant dioxin, is rapidly gaining interest in immunology based on its ability to influence T-cell differentiation. Multiple studies have documented that binding of this receptor with certain ligands favors T-cell differentiation toward regulatory T cells, and paradoxically, binding of this same receptor with different ligands enhances Th17 effector cell differentiation. This finding has been confirmed in both in vitro and in vivo models, where different ligands are able to either ameliorate or conversely aggravate autoimmunity in experimental autoimmune encephalomyelitis. The AHR has both an endogenous role that is important in development and normal physiology and an exogenous role as a receptor for manmade toxicants, with their binding leading to transcription of cytochrome P450 enzymes that metabolize these same ligands. Based on recent reports that will be summarized in this overview, we will consider the role that the AHR might play as a sensor to the outside environment, leading to alteration of the acquired immune system that might have relevance in transplantation or other medical conditions. In addition to describing the data in normal physiology and T-cell differentiation, we will present examples of the importance of this receptor in preclinical models of disease and highlight specific ligands that target the AHR and will have efficacy in treating transplant rejection and in tolerance protocols.

Figure 1. AHR/ARNT signaling pathway

The AHR is a cytosolic receptor that is bound to a chaperone protein. When a ligand goes across the cell membrane and binds to the AHR, it sheds its chaperone and goes to the nucleus, where it associates with ARNT and binds to the Dioxin Response Element (DRE), becoming a transcription factor. It induces transcription of the cytochrome P450 enzymes including cyp1a1, cyp1a2, cyp1b1 and other metabolizing enzymes including glutathione S-transferase Ya (GSTYa) and aldehyde-3-dehydrogenase (ALDH-3). Reprinted with permission from (7). Copyright 2008 American Chemical Society.

Figure 2. The AHR in T cell differentiation

The AHR is represented in the cytosol of both DCs and T cells. In the top part of the figure, which represents the endogenous pathway, ligands including TCDD, SU5416, ITE, VAV347, and kynurenine bind to the AHR on DCs, leading to IDO generation. IFN-γ can generate IDO irrespective of the AHR. This leads to the metabolism of tryptophan to kynurenine, which itself is a ligand for the AHR that binds to the receptor on T cells to generate Regulatory T cells. The bottom part of the figure represents the exogenous pathway, where ligands like FICZ or polycyclic aromatic hydrocarbons bind directly to the AHR on T cells to favor Th17 differentiation under the right conditions. This AHR binding also leads to the transcription of metabolizing enzymes, most notably the cytochrome P450 enzymes. The two pathways potentially function together in a feedback loop, where the AHR metabolizes compounds that then themselves become ligands that can shift the T cell differentiation response when the inflammation abates. Modified and reprinted from (57) with permission from the publisher, Taylor & Francis Ltd, http://www.tand.co.uk/journals).