Spatial separation of the processing and MHC class I loading compartments for cross-presentation of the tumor-associated antigen HER2/neu by human dendritic cells

Cross-presentation is the process by which professional antigen presenting cells (APCs) (B cells, dendritic cells (DCs) and macrophages) present endocytosed antigens (Ags) via MHC-I to CD8 + T cells. This process is crucial for induction of adaptive immune responses against tumors and infected cells...

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Bibliographic Details
Published in:Oncoimmunology 2015-11, Vol.4 (11), p.e1047585-e1047585
Main Authors: Baleeiro, Renato B, Rietscher, René, Diedrich, Andrea, Czaplewska, Justyna A, Lehr, Claus-Michael, Scherließ, Regina, Hanefeld, Andrea, Gottschaldt, Michael, Walden, Peter
Format: Article
Language:English
Subjects:
cancer
cross-presentation
dendritic cells
HER2/neu
nanoparticles
Original Research
tumor-associated antigens
vaccine
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Summary:Cross-presentation is the process by which professional antigen presenting cells (APCs) (B cells, dendritic cells (DCs) and macrophages) present endocytosed antigens (Ags) via MHC-I to CD8 + T cells. This process is crucial for induction of adaptive immune responses against tumors and infected cells. The pathways and cellular compartments involved in cross-presentation are unresolved and controversial. Among the cells with cross-presenting capacity, DCs are the most efficient, which was proposed to depend on prevention of endosomal acidification to block degradation of the epitopes. Contrary to this view, we show in this report that some cargoes induce strong endosomal acidification following uptake by human DCs, while others not. Moreover, processing of the tumor-associated antigen HER2/neu delivered in nanoparticles (NP) for cross-presentation of the epitope HER2/neu 369-377 on HLA-A2 depended on endosomal acidification and cathepsin activity as well as proteasomes, and newly synthesized HLA class I. However, the HLA-A#0201/HER2/neu 369-377 complexes were not found in the endoplasmic reticulum (ER) nor in endolysosomes but in hitherto not described vesicles. The data thus indicate spatial separation of antigen processing and loading of MHC-I for cross-presentation: antigen processing occurs in the uptake compartment and the cytosol whereas MHC-I loading with peptide takes place in a distinct subcellular compartment. The findings further elucidate the cellular pathways involved in the cross-presentation of a full-length, clinically relevant tumor-associated antigen by human DCs, and the impact of the vaccine formulation on antigen processing and CD8 + T cell induction.
ISSN:2162-4011
2162-402X
2162-402X
DOI:10.1080/2162402X.2015.1047585