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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803768v1 183/9/5861    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kutomi, G. Articles by Sato, N. PubMed PubMed Citation Articles by Kutomi, G. Articles by Sato, N.

Targeting to Static Endosome Is Required for Efficient Cross-Presentation of Endoplasmic Reticulum-Resident Oxygen-Regulated Protein 150-Peptide Complexes¹

Goro Kutomi,^* Yasuaki Tamura,^2* Koichi Okuya,^* Takashi Yamamoto,^* Yoshihiko Hirohashi,^* Kenjiro Kamiguchi,^* Jun Oura,^* Keita Saito,^* Toshihiko Torigoe,^* Satoshi Ogawa, Koichi Hirata, and Noriyuki Sato^*

^*Department of Pathology and Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan; and Department of Neuroanatomy, Kanazawa University Medical School, Kanazawa, Ishikawa, Japan

Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit intriguing, efficient CTL responses by cross-presentation via an as yet entirely unknown mechanism. Oxygen-regulated protein 150 (ORP150), also known as grp170, is an endoplasmic reticulum-resident HSP and is up-regulated by hypoxia. It has been demonstrated that ORP150 binds tumor-associated Ag peptides within cancer cells. Immunization with an ORP150-tumor Ag complex has been shown to generate tumor-specific CTLs. Most recently, it has been shown that exogenous ORP150 induces cross-presentation of a chaperoned Ag, thereby stimulating Ag-specific CTLs. However, the mechanism underlying this efficient cross-presentation is still unsolved. In this study, we show that the ORP150-precursor peptide complex can elicit CTL response through cross-presentation as well as the CD4⁺ T cell response by dendritic cells. Furthermore, we observed that the internalized ORP150-peptide complex, but not OVA protein, which was not cross-presented, was sorted to the Rab5⁺, EEA1⁺ static early endosome, followed by translocation to a recycling endosome, where the ORP150-chaperoned peptide was processed and bound to MHC class I molecules. Moreover, we observed that immunization of mice with ORP150-peptide complexes elicited strong peptide-specific CTLs and antitumor effects in vivo. Our data indicate that targeting of the Ag to a "static" early endosme by ORP150 is required for the efficient cross-presentation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Yasuaki Tamura, Department of Pathology, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan. E-mail address: ytamura{at}sapmed.ac.jp

³ Abbreviations used in this paper: HSP, heat shock protein; BMDC, bone marrow-derived dendritic cell; CPRG, chlorophenol red-β-D-galactopyranoside; DC, dendritic cell; ER, endoplasmic reticulum; HPF, high-power field; LAMP-1, lysosome-associated membrane protein 1; ORP150, oxygen-regulated protein 150; SR-A, scavenger receptor type A; SREC-I, scavenger receptor expressed by endothelial cells-I.

⁴ The online version of this article contains supplemental material.