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Differential Processing of Autoantigens in Lysosomes from Human Monocyte-Derived and Peripheral Blood Dendritic Cells¹

Timo Burster^2,*,, Alexander Beck, Eva Tolosa, Petra Schnorrer, Robert Weissert, Michael Reich^*,, Marianne Kraus^*,, Hubert Kalbacher, Hans-Ulrich Häring, Ekkehard Weber^¶, Herman Overkleeft^|| and Christoph Driessen^3,*,

^* Department of Medicine II and Department of Medicine IV, Hertie Institute for Clinical Brain Research and Natural Sciences Research Centre, University of Tübingen, Tübingen, Germany; ^¶ Institute of Physiological Chemistry, University of Halle, Halle, Germany; and ^|| Leiden Institute of Chemistry, University of Leiden, Leiden, The Netherlands

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

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