title: Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity.
abstract: The C-type lectin receptor Dectin-2 can trigger the leukotriene C4 synthase-dependent generation of cysteinyl leukotrienes and the caspase-associated recruitment domain 9- and NF-κB-dependent generation of cytokines, such as IL-23, IL-6, and TNF-α, to promote Th2 and Th17 immunity, respectively. Dectin-2 activation also elicits the type 2 cytokine IL-33, but the mechanism by which Dectin-2 induces these diverse innate mediators is poorly understood. In this study, we identify a common upstream requirement for PI3Kδ activity for the generation of each Dectin-2-dependent mediator elicited by the house dust mite species, Dermatophagoides farinae, using both pharmacologic inhibition and small interfering RNA knockdown of PI3Kδ in bone marrow-derived dendritic cells. PI3Kδ activity depends on spleen tyrosine kinase (Syk) and regulates the activity of protein kinase Cδ, indicating that PI3Kδ is a proximal Syk-dependent signaling intermediate. Inhibition of PI3Kδ also reduces cysteinyl leukotrienes and cytokines elicited by Dectin-2 cross-linking, confirming the importance of this molecule in Dectin-2 signaling. Using an adoptive transfer model, we demonstrate that inhibition of PI3Kδ profoundly reduces the capacity of bone marrow-derived dendritic cells to sensitize recipient mice for Th2 and Th17 pulmonary inflammation in response to D. farinae Furthermore, administration of a PI3Kδ inhibitor during the sensitization of wild-type mice prevents the generation of D. farinae-induced pulmonary inflammation. These results demonstrate that PI3Kδ regulates Dectin-2 signaling and its dendritic cell function.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Eri
authors.identifier: 0000-0003-0194-6845
authors.initials: E
authors.lastname: Yoshimoto
authors.affiliation: Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan;
authors.forename: Shinobu
authors.initials: S
authors.lastname: Saijo
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan; and.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Howard R
authors.initials: HR
authors.lastname: Katz
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; nbarrett@partners.org.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Barrett
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D003713:Dendritic Cells / Q000276:immunology*; D040001:Dermatophagoides farinae / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D037181:Lectins, C-Type; D019869:Phosphatidylinositol 3-Kinases; C445340:dectin-2, mouse; C421683:Pik3cd protein, mouse