TY - JOUR
T1 - Efficient MHC class I presentation by controlled intracellular trafficking of antigens in octaarginine-modified liposomes
AU - Nakamura, Takashi
AU - Moriguchi, Rumiko
AU - Kogure, Kentaro
AU - Shastri, Nilabh
AU - Harashima, Hideyoshi
N1 - Funding Information:
This work was supported in part by Grants-in-Aid for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by Grants-in-Aid for Scientific Research on Priority Areas from the Japan Society for the Promotion of Science. We thank Shiroh Futaki (Kyoto University, Japan) for providing STR-R8. We also appreciate Daryl Henderson for his helpful advice in writing the English manuscript.
PY - 2008/8
Y1 - 2008/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=48349106432&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48349106432&partnerID=8YFLogxK
U2 - 10.1038/mt.2008.122
DO - 10.1038/mt.2008.122
M3 - Article
C2 - 18560420
AN - SCOPUS:48349106432
SN - 1525-0016
VL - 16
SP - 1507
EP - 1514
JO - Molecular Therapy
JF - Molecular Therapy
IS - 8
ER -