The Dendritic Cell Major Histocompatibility Complex II (MHC II) Peptidome Derives from a Variety of Processing Pathways and Includes Peptides with a Broad Spectrum of HLA-DM Sensitivity

Cristina C Clement, Aniuska Becerra, Liusong Yin, Valerio Zolla, Liling Huang, Simone MERLIN, Antonia FOLLENZI, Scott A Shaffer, Lawrence J Stern, Laura Santambrogio

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

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 originaleInglese
pagine (da-a)5576-5595
Numero di pagine20
RivistaJournal of Biological Chemistry
Volume291
Numero di pubblicazione11
DOI
Stato di pubblicazionePubblicato - 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

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