title: Differential processing of autoantigens in lysosomes from human monocyte-derived and peripheral blood dendritic cells.
abstract: Dendritic cells (DC) initiate immunity and maintain tolerance. Although in vitro-generated DC, usually derived from peripheral blood monocytes (MO-DC), serve as prototype DC to analyze the biology and biochemistry of DC, phenotypically distinct primary types of DC, including CD1c-DC, are present in peripheral blood (PB-DC). The composition of lysosomal proteases in PB-DC and the way their MHC class II-associated Ag-processing machinery handles a clinically relevant Ag are unknown. We show that CD1c-DC lack significant amounts of active cathepsins (Cat) S, L, and B as well as the asparagine-specific endopeptidase, the major enzymes believed to mediate MHC class II-associated Ag processing. However, at a functional level, lysosomal extracts from CD1c-DC processed the multiple sclerosis-associated autoantigens myelin basic protein and myelin oligodendrocyte glycoprotein in vitro more effectively than MO-DC. Although processing was dominated by CatS, CatD, and asparagine-specific endopeptidase in MO-DC, it was dominated by CatG in CD1c-DC. Thus, human MO-DC and PB-DC significantly differ with respect to their repertoire of active endocytic proteases, so that both proteolytic machineries process a given autoantigen via different proteolytic pathways.
authors.affiliation: Department of Medicine II, University of Tübingen, Tübingen, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Burster
authors.forename: Alexander
authors.initials: A
authors.lastname: Beck
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.forename: Petra
authors.initials: P
authors.lastname: Schnorrer
authors.forename: Robert
authors.initials: R
authors.lastname: Weissert
authors.forename: Michael
authors.initials: M
authors.lastname: Reich
authors.forename: Marianne
authors.initials: M
authors.lastname: Kraus
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Herman
authors.initials: H
authors.lastname: Overkleeft
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
mesh_terms: D017951:Antigen Presentation; D018949:Antigens, CD1 / Q000032:analysis; D001324:Autoantigens / Q000378:metabolism*; D002403:Cathepsins / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism*; D004705:Endocytosis; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D018949:Antigens, CD1; D001324:Autoantigens; C437944:CD1C protein, human; D006023:Glycoproteins; C571326:MOG protein, human; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D002403:Cathepsins