title: Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells.
abstract: The presentation of an exogenous antigen in a major histocompatibility complex class-I- restricted fashion to CD8(+) T cells is called cross-presentation. Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit efficient CTL responses by cross-presentation through an as-yet entirely unknown mechanism. Hsp90 is the most abundant cytosolic HSP and is known to act as a molecular chaperone. We have shown that a tumor antigen peptide complexed with Hsp90 could be cross-presented by dendritic cells (DCs) through an endosomal pathway in a murine system. However, it has not been determined whether human DCs also cross-present an Hsp90-peptide complex and induce peptide-specific CTLs. In this study, we found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived DCs and induced peptide-specific CTLs. Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5(+), EEA1(+) static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through an endosome-recycling pathway. Our data indicate that targeting of the antigen to a "static" early endosome by Hsp90 is essential for efficient cross-presentation.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Okuya
authors.forename: Goro
authors.initials: G
authors.lastname: Kutomi
authors.forename: Akari
authors.initials: A
authors.lastname: Takaya
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Kajiwara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kanaseki
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D021381:Protein Transport; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: C107489:BIRC5 protein, human; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D000077022:Survivin
keywords: Antigen presentation/processing; T cells; dendritic cells; heat shock protein; tumor immunity