Aryl hydrocarbon receptor control of adaptive immunity

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that belongs to the family of basic helix-loop-helix transcription factors. Although the AhR was initially recognized as the receptor mediating the pathologic effects of dioxins and other pollutants, the activation of AhR by endogenous and environmental factors has important physiologic effects, including the regulation of the immune response. Thus, the AhR provides a molecular pathway through which environmental factors modulate the immune response in health and disease. In this review, we discuss the role of AhR in the regulation of the immune response, the source and chemical nature of AhR ligands, factors controlling production and degradation of AhR ligands, and the potential to target the AhR for therapeutic immunomodulation.

Fig. 1.

AhR signaling pathways. AhR ligands, or precursors to AhR ligands, are derived from industrial waste or by-products (pollutants), cruciferous plants (diet), or commensal flora. Several endogenous ligands also are proposed. Upon interaction with its ligands, the AhR undergoes conformational changes that result in its translocation to the nucleus and the dissociation of the AhR/HSP90/c-SRC complex. Once in the nucleus, the AhR establishes protein-protein interactions with the AhR nuclear translocator (ARNT) and with additional coactivators and transcription factors (TF) to control the transcriptional activity of target genes. In addition, the conformational changes induced by ligand binding result in the release of active c-SRC, which then targets multiple cellular targets. AhR is also a ligand-dependent E3 ubiquitin ligase that directs the ubiquitination and degradation of target proteins by the proteasome.

Fig. 2.

Endogenous AhR ligands and amplification of AhR activation with positive feedback loops. Exogenous ligands derived from the diet or commensal flora may initiate AhR activation. Within any given cell, heme-, arachidonic acid-, or tryptophan-derived metabolites bind to and activate the AhR. Activated AhR transcriptionally upregulates expression of genes encoding enzymes involved in arachidonic acid (CYP1A1, Cox-2) and tryptophan (CYP1A1, CYP1A2, CYP1B1) metabolism, producing AhR ligands in a localized positive feedback loop. AhR upregulation of genes encoding enzymes that degrade heme-derived [CYP1A1, CYP1A2, UDP-glucuronosyl-transferase (UDT)] and tryptophan-derived (CYP1A1, CYP1A2, CYP1B1) AhR ligands represents a negative feedback loop.

Fig. 3.

Bifunctional nanoparticles for the induction of antigen-specific immune tolerance. Gold nanoparticles coated with polyethylene glycol (PEG) are engineered ligand ITE and the central nervous system antigen myelin oligodendrocyte protein (MOG) to dendritic cells in vivo. Dendritic cells that produce kynurenines (postulated tryptophan-derived endogenous AhR ligands) and retinoic acid induce and/or expand MOG-specific regulatory T cells (Treg) through retinoic acid receptor- and AhR-dependent signaling pathways. Treg cells actively suppress effector T-cell function (Teff), thereby inhibiting central nervous system autoimmunity.