title: Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice.
abstract: BACKGROUND
  The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response.
  
  
  OBJECTIVE
  We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras.
  
  
  METHODS
  PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines.
  
  
  RESULTS
  PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired.
  
  
  CONCLUSIONS
  PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice.
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill; Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago, Chicago, Ill; Department of Pediatrics, Section of Pediatric Critical Care, University of Chicago, Chicago, Ill.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Verhoef
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Constantinides
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: McDonald
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, Md.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill; Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago, Chicago, Ill.
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, Ill; Department of Pathology, University of Chicago, Chicago, Ill. Electronic address: abendela@bsd.uchicago.edu.
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006373:Helminthiasis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006376:Helminths / Q000276:immunology; D006967:Hypersensitivity / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics*; D016130:Immunophenotyping; D000067596:Interleukin-33 / Q000008:administration & dosage / Q000494:pharmacology; D007378:Interleukins / Q000008:administration & dosage / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics*; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010206:Papain / Q000008:administration & dosage / Q000494:pharmacology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D000954:Antigens, Surface; D015415:Biomarkers; D016207:Cytokines; D000067596:Interleukin-33; D007378:Interleukins; D051741:Kruppel-Like Transcription Factors; C442281:Mydgf protein, mouse; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse; D010047:Ovalbumin; D010206:Papain
keywords: Allergic mechanisms; innate lymphoid cells; mouse models