Abstract
Protective MHC class I-dependent immune responses require an overlap between repertoires of proteins directly presented on target cells and cross-presented by professional APC, specifically dendritic cells. How stable proteins that rely on defective ribosomal proteins for direct presentation are captured for cell-to-cell transfer remains enigmatic. In this study, we address this issue using a combination of in vitro (C57BL/6-derived mouse cell lines) and in vivo (C57BL/6 mouse strains) approaches involving stable and unstable versions of OVA model Ags displaying defective ribosomal protein-dependent and -independent Ag presentation, respectively. Apoptosis, but not necrosis, of donor cells was found associated with robust global protein aggregate formation and captured stable proteins permissive for cross-presentation. Potency of aggregates to serve as Ag source was directly demonstrated using polyglutamine-equipped model substrates. Collectively, our data implicate global protein aggregation in apoptotic cells as a mechanism that ensures the overlap between MHC class I epitopes presented directly or cross-presented by APC and demonstrate the unusual ability of dendritic cells to process stable protein aggregates.
Highlights
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These findings suggest that Ova epitopes detected on cells expressing RFP-Ova derive mainly from ribosome-associated quality control (QC) rather than the pool of stable RFP-Ova molecules
These data are consistent with a higher contribution of ribosomeassociated degradation (i.e., defective ribosomal proteins (DRiPs)) as a source of MHC class I (MHC-I) epitopes of stable proteins than less-stable proteins
Summary
The immunodominant Ova MHC-I epitope in C57BL/6 mice (SIINFEKL) was efficiently presented on EL4 cells expressing either RFP-Ova or Ova-RFP, as indicated by Ab surface staining for H-2Kb/SIINFEKL complexes [34] (Fig. 1C). We confirmed that the magnitude of in vitro T cell activation directly correlated with the level of H-2Kb/SIINFEKL complexes presented on cells expressing either RFP-Ova or Ova-RFP (Supplemental Fig. 3).
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