title: Ikaros Inhibits Group 3 Innate Lymphoid Cell Development and Function by Suppressing the Aryl Hydrocarbon Receptor Pathway.
abstract: Group 3 innate lymphoid cells (ILC3s) expressing the transcription factor (TF) RORγt are important for the defense and homeostasis of host intestinal tissues. The zinc finger TF Ikaros, encoded by Ikzf1, is essential for the development of RORγt(+) fetal lymphoid tissue inducer (LTi) cells and lymphoid organogenesis, but its role in postnatal ILC3s is unknown. Here, we show that small-intestinal ILC3s had lower Ikaros expression than ILC precursors and other ILC subsets. Ikaros inhibited ILC3s in a cell-intrinsic manner through zinc-finger-dependent inhibition of transcriptional activity of the aryl hydrocarbon receptor, a key regulator of ILC3 maintenance and function. Ablation of Ikzf1 in RORγt(+) ILC3s resulted in increased expansion and cytokine production of intestinal ILC3s and protection against infection and colitis. Therefore, in contrast to being required for LTi development, Ikaros inhibits postnatal ILC3 development and function to regulate gut immune responses at steady state and in disease.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA.
authors.forename: Shiyang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Heller
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Bostick
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Aileen
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Hilde
authors.initials: H
authors.lastname: Schjerven
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.affiliation: Department of Laboratory Medicine in Geisinger Health System, 100 N. Academy Avenue, MC 19-20, Danville, PA 17822, USA.
authors.forename: Zongming E
authors.initials: ZE
authors.lastname: Chen
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA. Electronic address: liangzhou497@ufl.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016264:Dextran Sulfate; D006706:Homeostasis; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000382:microbiology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018336:Receptors, Aryl Hydrocarbon; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D016264:Dextran Sulfate