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J. Biol. Chem., Vol. 282, Issue 43, 31688-31702, October 26, 2007

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Human Heat Shock Protein 70 Enhances Tumor Antigen Presentation through Complex Formation and Intracellular Antigen Delivery without Innate Immune Signaling^*

Henriette Bendz¹, Sibylle C. Ruhland, Maya J. Pandya^¶2, Otmar Hainzl^¶, Stefan Riegelsberger^||, Christoph Braüchle^||**, Matthias P. Mayer, Johannes Buchner^¶, Rolf D. Issels, and Elfriede Noessner³

From the Institute of Molecular Immunology, GSF-National Research Center for Environment and Health, and the Clinical Cooperation Group of Hyperthermia, Internal Medicine Department III, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 25, 81377 Munich, Germany, ^¶Lehrstuhl Biotechnology IV, Department of Chemistry, Munich Technical University, Lichtenbergstrasse 4, 85747 Garching, Germany, the ^||Department of Chemistry and Biochemistry, Ludwig-Maximilians-University, Butenandtstrasse 11, Haus E, 81377 Munich, Germany, the ^**Center for NanoScience, Ludwig-Maximilians-University, Geschwister-Scholl-Platz 1, 80539 Munich, Germany, and ZMBH, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany

Heat shock proteins (HSPs) have shown promise for the optimization of protein-based vaccines because they can transfer exogenous antigens to dendritic cells and at the same time induce their maturation. Great care must be exercised in interpretating HSP-driven studies, as by-products linked to the recombinant generation of these proteins have been shown to mediate immunological effects. We generated highly purified human recombinant Hsp70 and demonstrated that it strongly enhances the cross-presentation of exogenous antigens resulting in better antigen-specific T cell stimulation. Augmentation of T cell stimulation was a direct function of the degree of complex formation between Hsp70 and peptides and correlated with improved antigen delivery to endosomal compartments. The Hsp70 activity was independent of TAP proteins and was not inhibited by exotoxin A or endosomal acidification. Consequently, Hsp70 enhanced cross-presentation of various antigenic sequences, even when they required different post-uptake processing and trafficking, as exemplified by the tumor antigens tyrosinase and Melan-A/MART-1. Furthermore, Hsp70 enhanced cross-presentation by different antigen-presenting cells (APCs), including dendritic cells and B cells. Importantly, enhanced cross-presentation and antigen-specific T cell activation were observed in the absence of innate signals transmitted by Hsp70. As Hsp70 supports the cross-presentation of different antigens and APCs and is inert to APC function, it may show efficacy in various settings of immune modulation, including induction of antigen-specific immunity or tolerance.

Received for publication, May 18, 2007 , and in revised form, July 23, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB455 (to H. B., R. D. I., E. N., and S. C. R.), SBF486 (to C. B.), SFB594 (to J. B.), and SFB638 (to M. P. M.) and by Fonds der Chemischen Industrie (to J. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods and Fig. 1.

² Present address: Dept. of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.

¹ To whom correspondence may be addressed. Tel.: 49-89-7099-303; Fax: 49-89-7099-300; E-mail: henriette.bendz{at}gsf.de.

³ To whom correspondence may be addressed. Tel.: 49-89-7099-303; Fax: 49-89-7099-300; E-mail: noessner{at}gsf.de.

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