title: Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage.
abstract: Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aparicio-Domingo
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Romera-Hernandez
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Julien J
authors.initials: JJ
authors.lastname: Karrich
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Ferry
authors.initials: F
authors.lastname: Cornelissen
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Natalie
authors.initials: N
authors.lastname: Papazian
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Dicky J
authors.initials: DJ
authors.lastname: Lindenbergh-Kortleve
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD, England, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Butler
authors.affiliation: Bioceros, 3584 CM Utrecht, Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD, England, UK.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Coles
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.affiliation: Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands t.cupedo@erasmusmc.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
mesh_terms: D000818:Animals; D007113:Immunity, Innate; D007378:Interleukins / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology*; D008727:Methotrexate / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000502:physiology*; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D008727:Methotrexate; D000097043:Interleukin-22