br Regulation of AHR Activity AHR

Regulation of AHR Activity AHR activity is regulated in various ways. First, AHR protein levels are controlled via ubiquitin-mediated proteosomal degradation: Ligand binding induces AHR ubiquitination and subsequent degradation by the proteasome [5]. AIP, a component of the AHR chaperone complex, stabilizes AHR by inhibiting its ubiquitination [40–42]. Second, an auto-regulatory feedback loop is in place, in which AHR induces the expression of negative regulators that in turn prevent excessive AHR activation. AHR repressor (AHRR), encoded by a target gene of AHR, is a member of the bHLH protein family and is structurally similar to AHR but lacks a ligand-binding domain (PAS-B domain) and an activation domain [43]. AHRR is thought to disrupt the interaction between AHR and ARNT complex to inhibit AHR–ARNT binding to DNA, although the precise mechanisms involved are not fully understood [44]. TIPARP (TCDD-inducible poly-ADP-ribose polymerase, also known as ARTD14) is a mono-ADP-ribosyltransferase and a ligand-induced negative regulator of AHR transactivation, which may play a role in regulating the AHR protein levels [45–47]. Third, AHR activity can be regulated indirectly, through availability of its ligands. Induction of CYP enzymes (e.g., CYP1A1) which degrade AHR ligands prevents prolonged AHR activation [11]. AHR binding partners present another level of regulation. RORγt can facilitate the binding of AHR to its target gene Il22, potentiating transcription [48]. Although activation of liver X receptors (LXRs) by metabolites of cholesterol leads to decreased Ahr transcription in T cells, LXR-induced SREBP-1 (sterol regulatory Z-VEID-FMK binding transcription factor 1) has been shown to physically interact with AHR and to prevent AHR-mediated Il17 transcription by interfering with DNA binding [49]. ID (inhibitor of DNA binding) proteins inhibit E protein-mediated transcription by interfering with DNA binding [50]. ID2-deficient ILC3s have reduced amounts of AHR [51]. E2A protein (E2A immunoglobulin enhancer binding factor, also known as transcription factor 3, TF3) has been shown to interact with AHR in the mouse EL4 cell lines, and suppresses AHR binding to the Il22 locus, presumably by interfering with the RORγt–AHR complex. These data are consistent with the reduced levels of IL-22 produced by ID2-deficient ILC3s in which E2A protein transcriptional activity is enhanced [51].
Variety of AHR Ligands The impact of xenobiotic ligands (e.g., TCDD) on AHR function in the immune system has been reviewed elsewhere [52,53]. I focus here on endogenous and physiological AHR ligands generated by cells, the microbiota, or from dietary sources that have been shown to impact on lymphocyte development and function. The high-affinity AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) is an ultraviolet photoproduct of L-tryptophan [54]. Recent data suggest that FICZ can also be generated by other metabolic pathways, including enzymatic deamination of tryptamine and oxidation of tryptophan by intracellular oxidants [9]. FICZ promotes Th17 differentiation in vitro and in vivo, and treatment with FICZ results in increased numbers of gut ILC3s via an AHR-dependent pathway [22–24,48]. Another high-affinity AHR ligand, indolo-[3,2-b]-carbazole (ICZ), is generated with 3,3′-diindolylmethane (DIM) from indole-3-carbinal (I3C) under acidic conditions in the stomach [55]. I3C is enzymatically generated from glucobrassicin, an L-tryptophan-derived glucosinolate that is enriched in cruciferous vegetables, suggesting a mechanism for immune regulation by dietary components. Indeed, mice fed a diet that lacks AHR ligand have reduced AHR activity and concomitant reduction of immune cell compartments including γδT cells and ILC3s in the gut. Restoration of these compartments could be achieved by I3C dietary supplementation [7,56]. Kynurenine, an AHR agonist, is a tryptophan metabolite generated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). IDO expression is induced by AHR [57,58], suggesting positive feedback in this pathway. It has been proposed that activation of AHR by different ligands can lead to different cell fates depending on the surrounding milieu [23]. Consistent with this notion, FICZ and kynurenine have different effects on T cell differentiation in vitro. FICZ, but not kynurenine, promotes Th17 cell differentiation [22–24]; kynurenine promotes TGF-β-induced Treg (iTreg) cell differentiation whereas FICZ is inhibitory [27]. Different effects of FICZ and TCDD in Th17 and Treg lineage specification in vitro and in vivo have also been reported [23]. Although concerns regarding toxicity and long-term/secondary effects of TCDD should be taken into account [11], it will nevertheless be important to examine the impact of different AHR ligands in vivo, in a cell type-specific manner.