Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation.
In this study, we elucidate the Fc epsilon RI-mediated Ag uptake and presentation mechanisms of dendritic cells (DC). We found that Fc epsilon RI-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 Ii 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/Fc epsilon RI-mediated Ag presentation by DC. Thus, multimeric ligands of Fc epsilon RI, instead of being delivered into a recycling MHC class H pathway, are channeled efficiently into MIIC (MHC class II compartment)-like organelles of DC, in which Cat S-dependent Ii processing and peptide loading of newly synthesized MHC class II molecules occur. This IgE/Fc epsilon RI-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.
Maurer
D
D
Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, Austria. Dieter.Maurer@akh-wien.ac.at
Fiebiger
E
E
Reininger
B
B
Ebner
C
C
Petzelbauer
P
P
Shi
G P
GP
Chapman
H A
HA
Stingl
G
G
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D002403:Cathepsins / Q000096:biosynthesis / Q000502:physiology*; D002451:Cell Compartmentation / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000378:metabolism; D008024:Ligands; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007132:Immunoglobulin Isotypes; D008024:Ligands; D017455:Receptors, IgE; C045084:invariant chain; D007073:Immunoglobulin E; D002403:Cathepsins; C028217:cathepsin S