The Transcription Factor AHR Prevents the Differentiation of a Stage 3 Innate Lymphoid Cell Subset to Natural Killer Cells

• Main Authors: Tiffany Hughes, Edward L. Briercheck, Aharon G. Freud, Rossana Trotta, Susan McClory, Steven D. Scoville, Karen Keller, Youcai Deng, Jordan Cole, Nicholas Harrison, Charlene Mao, Jianying Zhang, Don M. Benson, Jianhua Yu, Michael A. Caligiuri
• Format: Article
• Language: English
• Published: Elsevier 2014-07-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124714004367

Accumulating evidence indicates that human natural killer (NK) cells develop in secondary lymphoid tissue (SLT) through a so-called “stage 3” developmental intermediate minimally characterized by a CD34−CD117+CD94− immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC) types that include interleukin-1 receptor (IL-1R1)-positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here, we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes the differentiation of tonsillar IL-22-producing IL-1R1hi human ILC3s to CD56brightCD94+ interferon (IFN)-γ-producing cytolytic mature NK cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, we demonstrate the lineage plasticity of human ILCs by identifying AHR as a transcription factor that prevents IL-1R1hi ILC3s from differentiating into NK cells.