Efficient MHC class I presentation by controlled intracellular trafficking of antigens in octaarginine-modified liposomes.
Recently, much attention has been paid to cell-penetrating peptides (CPPs) as an antigen-delivery tool for presentation through the major histocompatibility complex class I (MHC-I) pathway. However, escape of CPPs from the endosome is inefficient and therefore a bottleneck for antigen delivery. Previously, we showed the importance of topological control of octaarginine (R8) peptides on the liposome surface for regulating cellular uptake as well as intracellular trafficking, especially endosomal escape. In this study, we hypothesized that efficient MHC-I presentation could be achieved by controlled intracellular trafficking of antigen encapsulated in R8-modified liposomes (R8-Lip). The mechanism of uptake of both R8-Lip and cationic liposomes was shown to be by macropinocytosis in dendritic cells. However, confocal laser scanning microscopy (CLSM) revealed that R8-Lip are able to release significantly more antigen to the cytosol than are cationic liposomes. Processing of the antigens delivered by R8-Lip was shown to be proteasome-dependent, which is consistent with selective antigen presentation by R8-Lip via MHC-I. According to antigen-presentation analysis, R8-Lip can induce significantly higher MHC-I presentation at lower doses than either soluble ovalbumin (OVA) or OVA in pH-sensitive or cationic liposomes. Moreover, R8-Lip showed an efficient antitumor effect in vivo. Therefore, R8-Lip is a promising new carrier for MHC-I-specific antigen presentation.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Takashi
T
Nakamura
Rumiko
R
Moriguchi
Kentaro
K
Kogure
Nilabh
N
Shastri
Hideyoshi
H
Harashima
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology*; D042541:Intracellular Space / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D015739:Nocodazole / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D008081:Liposomes; D009842:Oligopeptides; C448619:octaarginine; C067713:lactacystin; D000584:Amiloride; D015739:Nocodazole; D000111:Acetylcysteine