title: C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma.
abstract: The pathways underlying dendritic cell (DC) activation in allergic asthma are incompletely understood. Here we demonstrate that adoptive transfer of ovalbumin-pulsed wild-type (wt) but not of C5a receptor-deficient (C5aR⁻/⁻) bone marrow (BM)-derived DCs (BMDCs) induced mixed T helper type 2 (Th2)/Th17 maladaptive immunity, associated with severe airway hyperresponsiveness, mucus production, and mixed eosinophilic/neutrophilic inflammation. Mechanistically, antigen uptake, processing, and CD11b expression were reduced in C5aR⁻/⁻ BMDCs. Further, interleukin (IL)-1β, -6, and -23 production were impaired resulting in reduced Th17 cell differentiation, associated with accelerated activated T-cell death in vitro and in vivo. Surprisingly, we found an increased frequency of CD11b(hi)CD11c(int)Gr1⁺F4/80⁺ cells, expressing arginase and nitric oxide synthase in C5aR⁻/⁻ BM preparations. Intratracheal administration of ovalbumin-pulsed wt DCs and sorted CD11b(hi)CD11c(int)Gr1⁺F4/80⁺ C5aR⁻/⁻ cells reduced Th2 immune responses in vivo. Together, we uncover novel roles for C5aR in Th17 differentiation, T-cell survival, and differentiation of a DC-suppressor population controlling Th2 immunity in experimental allergic asthma.
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schmudde
authors.forename: H A
authors.initials: HA
authors.lastname: Ströver
authors.forename: T
authors.initials: T
authors.lastname: Vollbrandt
authors.forename: P
authors.initials: P
authors.lastname: König
authors.forename: C M
authors.initials: CM
authors.lastname: Karsten
authors.forename: Y
authors.initials: Y
authors.lastname: Laumonnier
authors.forename: J
authors.initials: J
authors.lastname: Köhl
mesh_terms: D000485:Allergens / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D000485:Allergens; D000954:Antigens, Surface; D039481:CD11b Antigen; D016207:Cytokines; D044087:Receptor, Anaphylatoxin C5a