title: Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.
abstract: The innate signaling pathways for Th2 immunity activated by inhaled antigens are not well defined. We previously identified Dectin-2 as a receptor for glycans in allergen extracts from the house dust mite Dermatophagoides farinae (Df) that mediates cysteinyl leukotriene (cys-LT) generation from pulmonary CD11c+ cells and from GM-CSF-cultured bone marrow cells (BMCs(GM-CSF)). Using lentiviral knockdown of Dectin-2 in BMCs(GM-CSF) and adoptive transfer of Df-pulsed BMCs(GM-CSF) to sensitize naive mice, we now report that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Sensitization with Df-pulsed BMCs(GM-CSF) from LTC(4) synthase (LTC(4)S)-deficient mice or type 1 cys-LT receptor (CysLT1R)-deficient mice demonstrated that both proteins were required for Df-elicited eosinophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Direct sensitization and challenge of Ltc4s-/- and Cysltr1-/- mice confirmed that cys-LTs mediate these parameters of Df-elicited Th2 pulmonary inflammation. Thus, the Dectin-2-cys-LT pathway is critical for the induction of Th2 immunity to a major allergen, in part through CysLT1R. These findings identify a previously unrecognized link between a myeloid C-type lectin receptor and Th2 immunity.
authors.affiliation: Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Barrett
authors.forename: Opu M
authors.initials: OM
authors.lastname: Rahman
authors.forename: James M
authors.initials: JM
authors.lastname: Fernandez
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Parsons
authors.forename: Wei
authors.initials: W
authors.lastname: Xing
authors.forename: K Frank
authors.initials: KF
authors.lastname: Austen
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000502:physiology; D003545:Cysteine / Q000096:biosynthesis / Q000502:physiology*; D004804:Eosinophils / Q000276:immunology / Q000502:physiology; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D053759:Interleukin-23 / Q000096:biosynthesis / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology; D037181:Lectins, C-Type / Q000276:immunology*; D015289:Leukotrienes / Q000096:biosynthesis / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D008198:Lymph Nodes / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018077:Receptors, Leukotriene / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology
chemical_list: D053759:Interleukin-23; D015850:Interleukin-6; D037181:Lectins, C-Type; D015289:Leukotrienes; D018077:Receptors, Leukotriene; D014409:Tumor Necrosis Factor-alpha; C112381:cysteinyl-leukotriene; C445340:dectin-2, mouse; D016753:Interleukin-10; D003545:Cysteine