Natural Aryl Hydrocarbon Receptor Ligands Control Organogenesis of Intestinal Lymphoid Follicles

Abstract

Innate lymphoid cells (ILC) expressing the transcription factor RORγt induce the postnatal formation of intestinal lymphoid follicles and regulate intestinal homeostasis. RORγt(+) ILC express the aryl hydrocarbon receptor (AhR), a highly conserved, ligand-inducible transcription factor believed to control adaptation of multicellular organisms to environmental challenges. We show that AhR is required for the postnatal expansion of intestinal RORγt(+) ILC and the formation of intestinal lymphoid follicles. AhR activity within RORγt(+) ILC could be induced by dietary ligands such as those contained in vegetables of the family Brassicaceae. AhR-deficient mice were highly susceptible to infection with Citrobacter rodentium, a mouse model for attaching and effacing infections. Our results establish a molecular link between nutrients and the formation of immune system components required to maintain intestinal homeostasis and resistance to infections.

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Vitamin A deprivation results in a loss of intestinal ILC3 in adult mice, which can be reversed upon supplementation of diet with the vitamin A‐derived metabolite retinoic acid 44, 45. Similarly, Ahr acts to sense soluble aromatic hydrocarbons – present in the diet and produced by commensal bacteria – and is essential for the development of both LTi‐like and NKp46 + ILC3, as well as IL‐22 production 14, 27, 28, 46, 47, 48, 49, 50, 51. Together these signals tune ILC3 numbers and responses and establish bidirectional interactions between ILC3 and the commensal microbiota during the initial colonization of barrier tissue sites.…”

Regulation of innate and adaptive immunity by Notch

“…On activation and ligand binding, AHR translocates from the cytoplasm to the nucleus and binds to promoter regions containing so-called xeno biotic response elements in order to induce target gene expression. 52,53 , suggesting that the development and/or expansion of NKp46 + ILCs in certain microenvironments is mediated by AHR-induced Notch signalling 54 . Another RORγt-dependent but NKp46-negative subset of ILCs is mostly found in the colon of mice during inflammation.…”

Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus‐infected macaques

“…Here, we examined the expression of conventional NK cell markers and cytokine production in intestinal ILC3 cells in healthy macaques. The AhR is a sensor of plant-derived dietary antigens and/or microflora in the gut, which is believed to promote receptor-related orphan receptor g-positive ILC3 function, particularly in the initial formation of lymphoid follicles in neonates (anlagen) and maintenance of intestinal immunity in adults (36)(37)(38)(39). Here, we examined the expression of AhR by confocal microscopy and show that it is expressed intracellularly in ILC3 but not CD20 + B cells, as indicated by coexpression of c-Kit and AhR in lymph nodes of uninfected macaques ( Fig.…”