Notch and Aryl Hydrocarbon Receptor Regulation of Innate Immune Cell Development
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Date
2019-05
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The Ohio State University
Abstract
Innate lymphoid cells (ILCs) comprise a broad class of lymphocytes that include the
cytotoxic natural killer (NK) cells and three subsets of non-cytotoxic immunoregulatory
“helper ILC” populations (ILC1, ILC2, ILC3). In the innate immune system, NK cells play
an important role in antitumor immunity, and the non-cytotoxic ILCs secrete cytokines to
modulate other immune responses. All ILCs including NK cells are enriched in
secondary lymphoid tissues such as the tonsil and lymph node. A common ILC
precursor cell exists that can develop into each of the ILC and NK cell populations. The
exact mechanisms regulating human ILC development are not fully described, yet
previous studies have identified signal pathways and transcription factors involved in
ILC differentiation. Based on literature precedent and our own previous reports, we
hypothesized that specific signal pathways including Notch and aryl hydrocarbon
receptor (AHR) are involved in regulating ILC development. To test this hypothesis, we
isolated ILC precursor cells from human pediatric tonsils and cultured them with
interleukin-7 and a murine bone marrow-derived stromal cell line (OP9) engineered to
constitutively overexpress the human Notch ligand delta-like-1 (OP9-DL1). Notch and/or
AHR were modulated in vitro via pharmacologic activation or inhibition, and cells were
cultured for 28 days prior to analysis by flow cytometry. Treatment with Notch inhibitor
DAPT resulted in decreased differentiation of both ILC2s and ILC3s, suggesting that
Notch activation supports overall ILC differentiation. Next we tested the effect of AHR
modulation on NK and ILC differentiation. Treatment of ILC precursor cells with an AHR
agonist resulted in decreased NK cell development, and increased ILC3 production. In
contrast, when AHR was inhibited, NK cell production was increased, and ILC3
production was inhibited. From these results we concluded that Notch signaling
supports overall ILC differentiation. Furthermore, activation of AHR promotes ILC3
development and inhibits NK cell maturation. As Notch and AHR may be dysregulated
in certain cancers, these studies elucidate how ILC development can be affected in the
setting of malignancy.