Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor

Abstract

The aryl hydrocarbon receptor (AhR) has become increasingly recognized for its role in the differentiation and activity of immune cell subsets; however, its role in regulating the activity of natural killer (NK) cells has not been described. Here, we show that AhR expression is induced in murine NK cells upon cytokine stimulation. We show that in the absence of AhR, NK cells have reduced cytolytic activity and reduced capacity to control RMA-S tumor formation in vivo, despite having normal development and maturation markers. Although AhR was first identified to bind the xenobiotic compound dioxin, AhR is now known to bind a variety of natural exogenous (e.g., dietary) and endogenous ligands. We show that activation of AhR with an endogenous tryptophan derivative, 6-formylindolo[3,2-b]carbazole, potentiates NK cell IFN-γ production and cytolytic activity. Further, administration of 6-formylindolo[3,2-b]carbazole in vivo enhances NK cell control of tumors in an NK cell-and AhR-dependent manner. Finally, similar effects on NK cell potency occur with AhR dietary ligands, potentially explaining the numerous associations that have been observed in the past between diet and NK cell function. Our studies introduce AhR as another regulator of NK cell activity in vivo.FICZ | kynurenine, 3,3′-diindolylmethane (DIM) | indole-3-carbinol (I3C)

Control of lymphocyte homeostasis and effector function by the aryl hydrocarbon receptor

“…NK cells develop normally in AhR-deficient mice [51,52]. The activation of NK cells by IL-2, IL-15 and IL-12 is associated with the increased expression of AhR [52,53].…”

“…The activation of NK cells by IL-2, IL-15 and IL-12 is associated with the increased expression of AhR [52,53]. Ahr −/− NK cells showed a reduced cytotoxicity compared to wildtype NK cells whereas various dietary AhR agonistic ligands, such as kynurenine, DIM and 13C enhanced the production IFNγ in NK cells [52].…”

“…The activation of NK cells by IL-2, IL-15 and IL-12 is associated with the increased expression of AhR [52,53]. Ahr −/− NK cells showed a reduced cytotoxicity compared to wildtype NK cells whereas various dietary AhR agonistic ligands, such as kynurenine, DIM and 13C enhanced the production IFNγ in NK cells [52]. The defective production of IL-10 from NK cells was also observed when treated with the AhR antagonist CH-223191 in vitro or in Ahr −/− mice infected with Toxoplasma gondii [53].…”

Transcriptional Control of NK Cells

“…Another transcription factor that is not required for peripheral NK cell numbers or maturation, but induced by cytokine stimulation, is the aryl hydrocarbon receptor (AhR) (Shin et al 2013;Wagage et al 2014). In the absence of AhR, NK cells have reduced cytolytic activity and capacity to control tumors in vivo (Shin et al 2013).…”

“…In the absence of AhR, NK cells have reduced cytolytic activity and capacity to control tumors in vivo (Shin et al 2013). A recent study implicated AHR (and the AHR nuclear translocator) in optimal production of IL-10 during pathogen infection, with AhR-deficient mice being resistance to infection (Wagage et al 2014).…”