Enhanced major histocompatibility complex class I-dependent presentation of antigens modified with cationic and fusogenic peptides.
Soluble extracellular protein antigens are notoriously poor stimulators of CD8+ cytotoxic T-lymphocyte (CTL) responses, largely because these antigens have inefficient access to an endogenous cytosolic pathway of the major histocompatibility complex (MHC) class I-dependent antigen presentation. Here, we present a strategy that facilitates antigen penetration into the cytosol of antigen-presenting cells (APC) by addition to the antigen of charge-modifying peptide sequences. As a result of this intervention, the charge modification enhances antigen uptake into APC by counteracting the repulsive cell surface charge, and then endosomal membranes are disrupted with a subsequent release of antigen into the cytosol. This technology significantly improves MHC class I-dependent antigen presentation to CTL, enabling a more efficient generation of specific CTL immunity in vivo. The strategy described here has potential for use in developing efficient vaccines for antigen-specific immunotherapy of human malignancies.
Laus
R
R
Dendreon Corporation, Seattle, WA 98121, USA.
Graddis
T J
TJ
Hakim
I
I
Vidovic
D
D
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006388:Hemagglutinins / Q000737:chemistry; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000941:Antigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006388:Hemagglutinins; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D010455:Peptides; C411888:influenza virus hemagglutinin peptide 2 (1-25); D010047:Ovalbumin