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

• Published in: Cell reports (Cambridge) Vol. 8; no. 1; pp. 150 - 162
• Main Authors: Hughes, Tiffany, Briercheck, Edward L., Freud, Aharon G., Trotta, Rossana, McClory, Susan, Scoville, Steven D., Keller, Karen, Deng, Youcai, Cole, Jordan, Harrison, Nicholas, Mao, Charlene, Zhang, Jianying, Benson, Don M., Yu, Jianhua, Caligiuri, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2014; Elsevier
• Subjects: Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; CD56 Antigen - genetics; CD56 Antigen - metabolism; Cell Differentiation; Cell Lineage; Cells, Cultured; Humans; Interleukin-22; Interleukins - genetics; Interleukins - metabolism; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Lymphocytes - cytology; Lymphocytes - immunology; Palatine Tonsil - cytology; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Receptors, Interleukin-1 Type I - genetics; Receptors, Interleukin-1 Type I - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.05.042

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. [Display omitted] •IL-1β maintains a human population of IL-22+ IL-1R1hi ILC3s in SLT by regulating AHR•Inhibition of AHR in human IL-1R1hi ILC3s promotes NK cell differentiation in vitro•Expression of AHR prevents human IL-1R1hi ILC3 differentiation to NK cells Natural killer (NK) cells are innate lymphoid cells (ILCs) and critical mediators of antitumor responses. The molecular mechanisms controlling NK cell development are largely unknown, and it is currently unclear whether human group 3 ILCs (ILC3s) are developmentally related to NK cells. In this study, Hughes et al. demonstrate that pharmacologic inhibition and genetic loss of the aryl hydrocarbon receptor promote in vitro differentiation of ILC3s to NK cells. These data provide new evidence for lineage plasticity among human ILCs.