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.