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Receptor I on Dendritic Cells Delivers IgE-Bound Multivalent Antigens into a Cathepsin S-Dependent Pathway of MHC Class II Presentation1
*
Division of Immunology, Allergy and Infectious Diseases,
General Dermatology, Department of Dermatology, and
Institute of General and Experimental Pathology, University of Vienna Medical School, Vienna, Austria; and
§
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
In this study, we elucidate the Fc
RI-mediated Ag uptake and
presentation mechanisms of dendritic cells (DC). We found that
FcRI-bound IgE, after polyvalent but not after monovalent ligation,
is efficiently internalized into acidic, proteolytic compartments,
degraded, and delivered into organelles containing MHC class II,
HLA-DM, and lysosomal proteins. To follow the fate of the fragmented
ligand, we sought to interfere with invariant chain (Ii) degradation, a
process critical for peptide loading of nascent MHC class II molecules.
We found DC to express cathepsin (Cat) S, a cysteine protease involved
in li processing by B cells. Exposure of DC to a specific, active-site
inhibitor of Cat S resulted in the loss of anti-Cat S
immunoreactivity, led to the appearance of an N-terminal Ii remnant,
and decreased the export of newly synthesized MHC class II to the DC
surface. Furthermore, inactivation of Cat S as well as blockade of
protein neosynthesis by cycloheximide strongly reduced
IgE/FcRI-mediated Ag presentation by DC. Thus, multimeric ligands of
FcRI, instead of being delivered into a recycling MHC class II
pathway, are channeled efficiently into MIIC (MHC class II
compartment)-like organelles of DC, in which Cat S-dependent li
processing and peptide loading of newly synthesized MHC class II
molecules occur. This IgE/FcRI-dependent signaling pathway in DC may
be a particularly effective route for immunization and a promising
target for interfering with the early steps of allergen
presentation.
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