Modification of the amino terminus of a class II epitope confers resistance to degradation by CD13 on dendritic cells and enhances presentation to T cells.
(2000)
Journal - Journal of immunology (Baltimore, Md. : 1950) (UNITED STATES )
Abstract :
Dendritic cells and human B cell lines were compared for ability to present synthetic peptides corresponding to residues 145-159 and 188-203 of human Ig kappa-chains to peptide-specific mouse T cell hybridomas restricted by HLA-DR4Dw4. B cell lines presented both peptides, but dendritic cells could only efficiently present the latter epitope. In this paper, we show that dendritic cells degrade the 145-159 peptide, removing four residues from the amino terminus. Binding of the peptide to the class II restriction element is not required for this process. The degradation product is resistant to further cleavage, accumulates in the culture supernatant, and does not bind to HLA-DR4Dw4 or stimulate T cell reactivity. Cleavage can be blocked with bestatin, but not with other protease inhibitors tested, or by a mAb directed against aminopeptidase N (CD13). Addition of an acetyl group to the amino terminus of peptide 145-159 also blocks degradation, and allows dendritic cells to present the peptide to specific T cells with greatly increased efficiency. These results demonstrate that CD13 on dendritic cells is able to selectively and efficiently degrade exogenously provided peptide Ags, in a process that can be blocked by addition of an acetyl group to the amino terminus of the peptide. Modification of the amino terminus of peptide epitopes susceptible to degradation may prove to be useful as a general strategy for enhancing their immunogenicity.
| ISSN : | 0022-1767 |
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| Mesh Heading : | Acetylation Amino Acid Sequence Animals Antigens, CD13 Cells, Cultured Dendritic Cells Endopeptidases Epitopes, T-Lymphocyte HLA-D Antigens HLA-DR4 Antigen Humans Hybridomas Hydrolysis Immunity, Innate Immunoglobulin kappa-Chains Mice Mice, Transgenic Molecular Sequence Data Peptide Fragments Protein Binding T-Lymphocytes enzymology immunology metabolism immunology biosynthesis genetics biosynthesis genetics metabolism chemical synthesis immunology immunology |
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| Mesh Heading Relevant : | Antigen Presentation physiology metabolism metabolism metabolism metabolism immunology metabolism metabolism |
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Binding and uptake of agalactosyl IgG by mannose receptor on macrophages and dendritic cells.
(1999)
Journal - Journal of immunology (Baltimore, Md. : 1950) (UNITED STATES )
Abstract :
Increased levels of agalactosyl IgG (G0 IgG) are found in several autoimmune diseases, including rheumatoid arthritis, in which they are correlated with severity of the disease. To investigate whether structural alteration of IgG may lead to aberrant processing and presentation of IgG peptides as autoantigens, we have studied uptake of G0 IgG by human dendritic cells and macrophages cultured from PBMC. We found that enzymatic removal of terminal galactose residues, which exposes N-acetylglucosamine residues, increases uptake of soluble IgG mediated by mannose receptor on macrophages and dendritic cells. Efficient uptake appears to require recycling of the receptor, can be blocked by saccharides or Abs reactive with mannose receptor, and is dependent upon the state of maturation of the dendritic cells. No differences between IgG isotypes in ability to be internalized by APC were identified, suggesting that uptake would not be limited to a particular subset of Abs. These results suggest a novel pathway by which Abs or Ag-Ab complexes can be taken into dendritic cells and macrophages, and potentially generate epitopes recognized by T cells. These findings may have particular relevance for autoimmune disorders characterized by high levels of G0 IgG.
| ISSN : | 0022-1767 |
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| Mesh Heading : | Antibodies, Monoclonal Cell Differentiation Cell Line, Transformed Cells, Cultured Dendritic Cells Dose-Response Relationship, Immunologic Endocytosis Humans Immunoglobulin G Immunoglobulin Isotypes Immunophenotyping Macrophages Monosaccharides Neuraminidase Protein Binding Receptors, Cell Surface Time Factors beta-Galactosidase pharmacology immunology drug effects enzymology immunology immunology physiology drug effects enzymology immunology pharmacology metabolism drug effects immunology immunology physiology metabolism |
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| Mesh Heading Relevant : | Lectins, C-Type Mannose-Binding Lectins metabolism metabolism metabolism metabolism |
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