Natural Aryl Hydrocarbon Receptor Ligands Control Organogenesis of Intestinal

Innate lymphoid cells (ILC) expressing the transcription factor RORgt induce the postnatal formation of intestinal lymphoid follicles and regulate intestinal homeostasis. RORgt+ 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 RORgt+ ILC and the formation of intestinal lymphoid follicles. AhR activity within RORgt+ 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. Adaptation to environmental cues in mul-ticellular organisms requires a complexcomposition of the transcriptional output of responding cells. At gut mucosal surfaces, constant integration of microbial and dietary sig-nals is required for the maintenance of intestinal homeostasis (1–3). Disturbances lead to suscep-tibility to intestinal infections, inflammatory bow-el diseases, and inflammation-induced cancer (4). The intestinal lamina propria harbors nu-merous lymphoid follicles that in mice develop during the first weeks after birth. Their genesis is a multistep process initiated by the formation of cryptopatch (CP) clusters containing RORgt+ ILC that have lymphoid tissue–inducing (LTi) function (5–7). B cells are attracted to CP, leading to the formation of isolated lymphoid follicles (ILF), a process under the control of cues from the indigenous microbiota (8, 9). Besides their LTi function, RORgt+ ILC constitutively produce interleukin (IL)–22 (10–14), required for the pro-tection against intestinal attaching and effacing (A/E) infections that cause disease in mice and humans such as those with enterohemorrhag-ic Escherichia coli (15–17). The AhR control