title: Octaarginine-modified liposomes enhance cross-presentation by promoting the C-terminal trimming of antigen peptide.
abstract: Exogenous antigen proteolysis by proteasomes and amino peptidases is essential for the production of mature major histocompatibility complex class I (MHC-I) peptides to induce cross-presentation. We report here that when liposomes are modified with octaarginine (R8-Lip), a type of cell-penetrating peptide, the production of the mature MHC-I peptide is enhanced by promoting the C-terminal trimming of the antigen peptide. The efficiency of cross-presentation of ovalbumin (OVA) using the R8-Lip was dramatically higher than that by octalysine modified liposomes (K8-Lip) in mouse bone-marrow derived dendritic cells (BMDCs), although the physical characters of both liposomes were comparable. In this study, we investigated the mechanism responsible for the enhancement in cross-presentation by R8-Lip. Although the efficiencies of cellular uptake, endosomal escape, proteolysis of OVA and DC maturation between the two systems were essentially the same, an analysis of peptide trimming to SIINFEKL (mature MHC-I peptide of OVA) by using R8-Lip and K8-Lip encapsulating peptides of various length clearly indicates that the use of R8-Lip enhances the efficiency of the C-terminal cleavage of antigen-derived peptides. This finding provides a new strategy for achieving efficient cross-presentation by using R8 peptide and arginine-rich peptides. Moreover, this result may contribute to the development of a new paradigm regarding the machinery associated with antigen peptide production.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Sapporo 060-0812, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kouhei
authors.initials: K
authors.lastname: Ono
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Rumiko
authors.initials: R
authors.lastname: Moriguchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kogure
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D002738:Chloroquine / Q000737:chemistry; D045142:Cross-Priming; D003713:Dendritic Cells / Q000166:cytology; D011992:Endosomes / Q000378:metabolism; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009842:Oligopeptides / Q000737:chemistry*; D010047:Ovalbumin / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D017434:Protein Structure, Tertiary
chemical_list: D000941:Antigens; D057846:Cell-Penetrating Peptides; D015395:Histocompatibility Antigens Class I; D008081:Liposomes; D009842:Oligopeptides; C448619:octaarginine; D002738:Chloroquine; D010047:Ovalbumin; D001120:Arginine; D046988:Proteasome Endopeptidase Complex