Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 30, Pages 12391-12396Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1302856110
Keywords
FICZ; kynurenine; 3,3 '-diindolylmethane (DIM); indole-3-carbinol (I3C)
Categories
Funding
- National Institutes of Health [R01CA158516]
- Stanford Cancer Center Developmental Cancer Research Award Grant
- National Science Foundation Graduate Research Fellowship
- Tobacco Related Diseases Research Program
- Cancer Research Institute, National Institutes of Health [K08CA128893, R01CA157885]
- American Cancer Society [ACS-IRG 70-002]
- Cancer Research Coordinating Committee [6-34384]
- Concern Foundation
- Hartwell Foundation
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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-gamma 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.
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