promotion information Previous studies to investigate the fu

Previous studies to investigate the functions of AHR in Treg promotion information have employed a loss-of-function approach, using AHR complete-null mice, or a gain-of-function approach by ligand administration. However, these approaches may confound the interpretation of the results. For example, the broad expression of AHR in other cell types will most likely influence Treg cell development and/or function. For example, it has been shown that lipopolysaccharide (LPS) induces AHR expression in macrophages, and that AHR-deficient macrophages produce more IL-6 [28], a cytokine known to suppress FOXP3 expression [82]. In addition, our group has recently shown that AHR deficiency in group 3 innate lymphoid cells (ILC3s) leads to aberrant outgrowth of gut commensal segmented filamentous bacteria (SFB) and elevated intestinal Th17 cells [95] that have a reciprocal relationship with Tregs during differentiation [82,96]. It is worth mentioning that not only are the identities of endogenous ligands for AHR elusive [17], but also that administration of ligands to activate AHR may result in the production of downstream metabolites that exert indirect effects on the immune system [16]. Thus, elucidating the cell-autonomous role of AHR in Treg cells is crucial for future targeted manipulation of the AHR pathway in the treatment of human disease (e.g., inflammatory bowel disease, IBD).
AHR in Tr1 Development and Function Type 1 regulatory T (Tr1) cells are characterized by the expression of IL-10 but not FOXP3 and are prominent in chronic infections and following specific immune manipulations in vivo (e.g., peptide immunization or activation by anti-CD3) [97]. Because a lineage-specific transcription factor has yet to be identified for Tr1 cells, and IL-10 is a common cytokine that can be produced by different subsets of CD4+ T helper cells (e.g., Th17 cells), it is debatable whether Tr1 cells represent a bona fide independent T helper subset or whether they are derived from other lineages as a result of CD4+ T cell plasticity [11,98]. It was reported that IL-27 promotes Tr1 cell differentiation in vitro and the production of IL-10 [99–101]. In Tr1-skewing conditions, AHR induced by IL-27 physically interacts with MAF and cooperatively transactivates the human and mouse IL-10 and IL-21 gene promoters, which results in generation of Tr1 cells and amelioration of experimental autoimmune encephalomyelitis [90,102]. Considering the cooperativity between AHR and MAF in promoting IL-10 expression, the mechanism for the inverse regulation of IL-22 by AHR in Th17 cells remains unknown [77]. It has recently been reported that Th17 cells can trans-differentiate into Tr1 cells in the presence of TGF-β, and AHR activation promotes this conversion [103]. Metabolic stress hypoxia through HIF1α activation suppresses Tr1 cell differentiation [104]. AHR was shown to control the metabolism of Tr1 cells and reduce HIF1α cellular levels, participating in the late stages of Tr1 cell differentiation [104].
AHR in Innate-Like Lymphocytes The role of AHR in ILC3s has been discussed extensively in a previous review [83]. I mainly focus here on the AHR-mediated crosstalk between T cells and ILC3s. RORγt-expressing ILCs (also known as ILC3s) strikingly resemble Th17 and Th22 cells in their cytokine profile (e.g., production of IL-22 and IL-17). Coevolution of two systems may be a fail-safe mechanism to implement redundancy in host immunity to specific infections, especially at mucosal surfaces, and especially during different stages of the infection. It has been shown that intestinal Th17/22 responses are enhanced by Citrobacter rodentium, a murine pathogen that models human enterohemorrhagic Escherichia coli and enteropathogenic E. coli infections. Most recently, our group and others have shown that ILC-produced IL-22 is essential for the clearance of C. rodentium in the intestines [48,105]. Interestingly, even in the lymphocyte-replete hosts, mice lacking ILC3s died from the infection, highlighting an essential role for ILCs in gut immunity [105]. However, the molecular mechanism underlying the development and function of ILC3s regulated by AHR is incompletely understood. At least three mechanisms of action of AHR in ILC3s have been described. Although AHR is dispensable for T cell survival, AHR can increase ILC3 survival via the IL-7/IL-7R pathway and anti-apoptotic gene expression, and thus promote ILC3 maintenance [48]. AHR can enhance ILC3 proliferation, leading to expansion of this cell type in the gut [56]. AHR has also been shown to directly regulate the transcription of Notch 1 and Notch 2, which are important for ILC3 development [6]. AHR is important for all ILC3 subsets including lymphoid tissue-inducer (LTi)-like ILC3s and NKp46+ ILC3s [6,48,56]. However, the precise function of each subset in gut immunity and inflammation could not be addressed until conditional knockout mice were used to delete AHR or RORγt in RORγt- and NKp46-expressing cells, thus lacking all ILC3s or NKp46+ ILC3s, respectively [106]. NKp46+ILC3s are sufficient to promote inflammatory monocyte accumulation in the anti-CD40-induced colitis model. By contrast, NKp46+ILC3s are not necessary to resist C. rodentium infection even in the absence of T cells, presumably because LTi-like ILC3s provide sufficient protection [105,106].