Increasing evidence indicates that ILCs participate in

Increasing evidence indicates that ILCs participate in a dialog with CD4+ T 69 6 [107–110]. This dialog is mediated, in part, through the expression of type II major histocompatibility complex (MHCII) molecules on ILC3s [107]. Depending on the expression of co-stimulatory molecules, MHCII:TCR interaction can result in T cell activation, anergy, or deletion [107,108,111]. ILC3s in the intestine express MHCII molecules, but lack expression of CD80 and CD86 co-stimulatory molecules [107]. T cell receptor interaction with MHCII expressed on intestinal ILC3s is thought to promote tolerance due to the lack of co-stimulation. When commensal bacteria-specific T cells encounter antigen presented by MHCII molecules on CCR6+ ILC3s, T cell apoptosis is induced [112]. AHR expression in ILC3s controls adaptive Th17 cell responses [95,113]. AHR deficiency in vivo leads to upregulated Th17 cell responses, correlating with the aberrant outgrowth of Th17-inducing commensal SFB in Ahr−/− mice [95]. Lack of innate expression of IL-22 by ILC3s in Ahr–/– mice at least in part accounts for the upregulation of SFB proliferation and Th17 cell responses [95,114]. It remains to be determined if AHR regulates MHCII expression in ILC3s. The role of AHR in innate T cells, such as γδT cells, has been reviewed elsewhere [115]. Although γδT cells do express a unique T cell receptor (TCR), engagement of this TCR with MHC–antigen complexes is not a prerequisite for their activation. Unlike conventional αβT cells, cytokine stimulation alone is sufficient for IL-17-secreting γδT cell activation, rendering these cells rapid and potent innate mediators of inflammation [116]. Although expressed in all γδT cell subsets [7,25,117–119], including the systemic Vγ1 and Vγ2, epidermal Vγ3, reproductive tract/lung/oral mucosal Vγ4, and intestinal Vγ5, AHR expression is higher in γδT cells in mucosal tissues (e.g., the skin, intestine, or lung) [11]. IL-22 production by some of systemic Vγ2 γδT cells is dependent on AHR [119]. The survival of epidermal Vγ3 and intestinal Vγ5 γδT cells requires the expression of AHR, whereas Vγ4 γδT cells that express high levels of AHR in the lung are, surprisingly, present despite the absence of AHR [11,25].
Mouse AHR versus Human AHR Phylogenetic analysis shows that functional orthologs of the Ahr gene are present in mammals, amphibians, reptiles, and birds [120]. Although rodent studies can yield invaluable insights into the function of AHR, particularly in the human immune system, it needs to be kept in mind that there are several differences between the mouse and human AHR pathways that may complicate the interpretation of results. First, a decrease in stability of the human AHR/HSP90 interaction compared to mouse AHR [121] has been reported. Second, although N-terminal half of the protein (∼85% sequence homology) is well conserved, mouse and human AHR differ significantly in the C-terminal half of the receptor that interacts with coactivators for transactivation [122]. Studies using primary hepatocytes from humans, mice, and humanized mice have revealed that human and mouse AHR differentially regulate gene expression in hepatocytes [123–125]. It is conceivable that similar differences in gene regulation caused by AHR might also be present in mouse and human immune cells. Third, the sensitivity and affinity to ligand activation is different between the mouse and human AHR. For example, the mouse AHR binds to TCDD with a 10-fold higher affinity than the human AHR as a result of a single amino acid residue difference in the ligand-binding PAS-B domain [126]. By contrast, human AHR binds endogenous indole derivatives such as indirubin and indoxyl sulfate with much higher affinity than the mouse AHR [127,128]. Finally, considering the importance of gut microbes in generating and metabolizing the ligands of AHR, the differences between the mice and human gut microbiome will inevitably affect the function of AHR in vivo. Furthermore, unlike most studies carried out with mice in a controlled environment (e.g., using defined diet and commensal conditions), the variations in dietary components and commensal communities among each individual will potentially impact on the AHR pathway in humans.