Aryl Hydrocarbon Receptor-Dependent Pathways in Immune Regulation

The idea of a possible involvement of the Aryl hydrocarbon Receptor (AhR) in transplant tolerance can be traced back to more than thirty years ago, when Clark and coworkers found that very low doses of dioxin, the most potent AhR ligand, markedly reduced the generation of cytotoxic T lymphocytes in response to alloantigen challenge in vivo. AhR is, indeed, a ligand-activated transcription factor that is activated by dioxins and other environmental pollutants. We now know that AhR can bind a broad variety of activating ligands, disparate in nature, including endogenous molecules and those formed in the gut from food and bacterial products. Therefore, in addition to its classical role as a toxicological signal mediator, AhR is emerging as a transcription factor involved in the regulation of both innate and adaptive immune responses in various immune cell types, including lymphocytes and antigen-presenting cells. Allograft rejection is mostly a T-cell-mediated alloimmune response, initiated by the recognition of alloantigens presented by donor and recipient antigen-presenting cells to recipient CD4+ and CD8+ T cells. Based on those findings, AhR may function as a critical sensor of the outside/inside environments, leading to changes in the immune system that may have relevance in transplantation.