Differential processing of autoantigens in lysosomes from human monocyte-derived and peripheral blood dendritic cells.
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.
Burster
Timo
T
Department of Medicine II, University of Tübingen, Tübingen, Germany.
Beck
Alexander
A
Tolosa
Eva
E
Schnorrer
Petra
P
Weissert
Robert
R
Reich
Michael
M
Kraus
Marianne
M
Kalbacher
Hubert
H
Häring
Hans-Ulrich
HU
Weber
Ekkehard
E
Overkleeft
Herman
H
Driessen
Christoph
C
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
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