title: 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.
authors.affiliation: Department of Otolaryngology-Head, and Neck Surgery, Stanford Cancer Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: June Ho
authors.initials: JH
authors.lastname: Shin
authors.forename: Luhua
authors.initials: L
authors.lastname: Zhang
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo-Sauca
authors.forename: Junmo
authors.initials: J
authors.lastname: Kim
authors.forename: Holbrook E K
authors.initials: HE
authors.lastname: Kohrt
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
authors.forename: John B
authors.initials: JB
authors.lastname: Sunwoo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004032:Diet; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; D018336:Receptors, Aryl Hydrocarbon
keywords: FICZ; indole-3-carbinol (I3C); kynurenine, 3,3′-diindolylmethane (DIM)