The Aryl Hydrocarbon Receptor (AHR) Promotes Late-Stage Human NK Cell Maturation

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B1027
Abstract ID: 4553

Presenting Author:
Kinda Sara , visiting fellow at Ohio State Univ. Comp. Cancer Ctr.

Abstract:

Prior studies showed that the ligand-activated transcription factor, AHR, inhibits human NK cell development by skewing innate lymphoid cell (ILC) progenitors toward non-NK ILC fates. However, AHR is expressed by committed NK cells; and in mice, AHR deficiency reduces NK cell function. We hypothesized that AHR promotes late-stage human NK cell maturation. To test this, we generated ILCs and NK cells by culturing human adult blood CD34⁺ progenitors on OP9-DL1 stroma for 14 days with Flt3 ligand (FL), c-kit ligand (KL), and interleukin (IL)-3 followed by 14 days of FL, KL, and IL-15 +/- an AHR agonist (FICZ), antagonist (CH-223191), or vehicle control (DMSO). As expected, AHR activation resulted in more ILC3s among total ILCs produced (50+/-5% DMSO, 75+/-5% FICZ*, 42+/- 5% CH, n=28, *p=<0.0001); however, while fewer, the resultant NK cells expressed more markers of terminal maturation, including CD16 and killer immunoglobulin-like receptors (KIRs) (CD16⁺: 18+/-2% DMSO, 30+/-2% FICZ*, 16+/-2% CH; KIR⁺: 20+/-2% DMSO, 30+/-5% FICZ*, 13+/-2% CH; n=28, *p=0.03). We also observed less KIR⁺ NK cells when KIR^- NK cells were purified at culture day 14 and re-cultured for two more weeks with FL, KL, and IL-15 + CH-223191 (23+/-4% DMSO, 7+/-2% CH*, n=9, *p=0.002), suggesting that AHR antagonism intrinsically blocks KIR acquisition in the developing NK cells. These findings reveal a novel role for AHR in human NK cell maturation, and ongoing work seeks to determine the mechanism.