Abstract
The repertoire of peptides displayed in vivo by MHC II molecules derives from a wide spectrum of proteins produced by different cell types. Although intracellular endosomal processing in dendritic cells and B cells has been characterized for a few antigens, the overall range of processing pathways responsible for generating the MHC II peptidome are currently unclear. To determine the contribution of non-endosomal processing pathways, we eluted and sequenced over 3000 HLA-DR1-bound peptides presented in vivo by dendritic cells. The processing enzymes were identified by reference to a database of experimentally determined cleavage sites and experimentally validated for four epitopes derived from complement 3, collagen II, thymosin β4, and gelsolin. We determined that self-antigens processed by tissue-specific proteases, including complement, matrix metalloproteases, caspases, and granzymes, and carried by lymph, contribute significantly to the MHC II self-peptidome presented by conventional dendritic cells in vivo. Additionally, the presented peptides exhibited a wide spectrum of binding affinity and HLA-DM susceptibility. The results indicate that the HLA-DR1-restricted self-peptidome presented under physiological conditions derives from a variety of processing pathways. Non-endosomal processing enzymes add to the number of epitopes cleaved by cathepsins, altogether generating a wider peptide repertoire. Taken together with HLA-DM-dependent and-independent loading pathways, this ensures that a broad self-peptidome is presented by dendritic cells. This work brings attention to the role of "self-recognition" as a dynamic interaction between dendritic cells and the metabolic/catabolic activities ongoing in every parenchymal organ as part of tissue growth, remodeling, and physiological apoptosis.
Lingua originale | Inglese |
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pagine (da-a) | 5576-5595 |
Numero di pagine | 20 |
Rivista | Journal of Biological Chemistry |
Volume | 291 |
Numero di pubblicazione | 11 |
DOI | |
Stato di pubblicazione | Pubblicato - 2016 |
Keywords
- Amino Acid Sequence
- Animals
- Cells, Cultured
- Collagen Type II
- Complement C3
- Dendritic Cells
- Gelsolin
- HLA-DR1 Antigen
- Humans
- Lymph
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Molecular Sequence Data
- Peptides
- Protein Binding
- Proteome
- Proteomics
- Signal Transduction
- Thymosin
- antigen presentation
- antigen processing
- dendritic cell
- immunological tolerance
- lymph
- major histocompatibility complex (MHC)
- proteomics
- tolerance