The Distal-less (Dlx) homeobox transcription factors (TFs) play a prominent role in regulating multiple facets of vertebrate biology. Though widely studied as mediators of tissue development, recent work has uncovered a role for this TF family in modulating the vertebrate hematopoietic compartment. Pertinent to our study, murine Dlx1-3 are expressed in an innate lymphocyte population known as natural killer (NK) cells, and they are implicated to assume a functional role in the NK cell maturation pathway. However, Dlx target genes are poorly understood. In Drosophila, the invertebrate Dlx ortholog Distal-less (Dll) regulates another transcription factor called Spineless (ss), which is critical for specifying distal antennal segments. Importantly, the vertebrate ortholog of ss is the aryl hydrocarbon receptor (AhR), a transcription factor recently shown to be important in the regulation of a number of immune cell subsets, including NK cells. Given these findings, we investigated whether Dlx TF family members might analogously regulate AhR in an NK cell context. Our results demonstrate that Dlx3 is constitutively co-expressed with AhR in murine and human CD127(+) NK cells. Critically, we show that Dlx3 induces AhR promoter activity by binding to a regulatory region that resides ~5.5 kb upstream of the transcriptional start site. This mechanism is functionally relevant, as Dlx3 expression in human NK cells significantly enhances TF activity at AhR DNA-binding elements (Xenobiotic Responsive Elements, XREs). Thus, our study defines Dlx3 as a positive regulator of the aryl hydrocarbon receptor.
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