AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch

Abstract

Innate lymphoid cells (ILC)-22 protect the intestinal mucosa from infections by secreting interleukin-22 (IL-22). They include NKp46+ and Lymphoid Tissues inducer (LTi)-like subsets. Both express the aryl-hydrocarbon receptor (AHR), a sensor for environmental, dietary and endogenous aromatic compounds. We show that AHR-/- mice have a marked ILC22 deficit, resulting in diminished IL-22 secretion and inadequate protection against intestinal bacterial infections. AHR-/- mice also lack post-natally-imprinted cryptopatches (CP) and isolated lymphoid follicles (ILF), but not embryonically-imprinted Peyer's Patches (PP). AHR induces Notch, which is required for NKp46+ILC, while LTi-like ILC, CP and ILF are partially dependent on Notch signaling. These results establish that AHR is essential for ILC22 and post-natal intestinal lymphoid tissues and reveal heterogeneity of ILC22 subsets in their developmental requirements and their impact on the generation of intestinal lymphoid tissues.

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

“…Recently, innate lymphoid cells (ILCs) sharing innate functions with gd T cells were identified both in human and mice. RBP-Jk deletion selectively decreased IL-22-producing NKp46 + IL-7Ra + ILCs in the lamina propria but not in the Peyer's patches (45). Epigenetic analysis revealed that IL-7Ra expression in ILC2 cells was directly regulated by TCF1, which was shown to be a direct target of the Notch-RBP-Jk pathway in T cells (46,47).…”

Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5 + and IL-13 + type 2 innate lymphoid cells

“…S5). Among transcriptional activators, transient Notch signaling appears required for ILC2 and ILC3 development from lymphoid progenitors (16)(17)(18). The role for Notch in this process is not understood but could involve transient up-regulation of Gata3 or ROR-γt that are essential for ILC2 and ILC3 generation, respectively.…”

“…The transcriptional regulator inhibitor of differentiation 2 (Id2) has been identified as a common factor required for all ILC subsets (13,14); however, the developmental stages from common lymphoid progenitors (CLPs) to fully mature ILC subsets have not been elucidated. Transient Notch signals appear critical for generation of ILC2s and ILC3s from CLPs (15)(16)(17)(18)(19). Nevertheless, the regulatory factors that orchestrate this process are poorly understood, although recently the transcription factor ROR-α was identified as an essential factor for efficient ILC2 development and in particular for IL-25-mediated expansion of the ILC2 compartment (10,17).…”

Taming the Beast within: Regulation of Innate Lymphoid Cell Homeostasis and Function

“…Similar to LTi cells, these NCR + ILC3s require the transcription factor Rorc for their development. Additionally, the aryl hydrocarbon receptor was shown to be necessary for the optimal expression of IL-22 by distinct ILC3 subsets (30)(31)(32). IL-17A and IL-22 have major effects on epithelial cells of many tissues and are crucial in defense against extracellular pathogens such as Salmonella, Citrobacter, and Klebsiella (26,(33)(34)(35).…”