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Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins¹

Robert J. Binder^2,*, John B. Kelly, III, Ralph E. Vatner and Pramod K. Srivastava

^* Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030

The peptide-binding property of MHC is central to adaptive immunological functions. A similar property of heat shock proteins (HSPs) hsp70 and hsp90 has been implicated in Ag presentation by MHC and in cross-priming. The peptide-binding pocket of hsp70 has been characterized structurally and functionally and a peptide-binding site in gp96 (of hsp90 family) has been defined. Nonetheless, questions persist whether the specific immunogenicity of HSP preparations derives from the peptides chaperoned by the HSPs or by proteins contaminating the HSP preparations. Because absolute purity of a protein preparation is a metaphysical concept, other approaches are necessary to address the question. In this study, we demonstrate that the specific immunogenicity of gp96 preparations isolated from cells expressing β-galactosidase derives from the MHC I epitope precursors associated with the gp96 and not from contaminating β-galactosidase protein nor unassociated fragments derived from it. Although the observations here are limited to a single HSP and antigenic peptides chaperoned by it, they can be extended broadly.

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 by National Institutes of Health Grant CA84479-07 and a sponsored research agreement with Antigenics Incorporated.

² Address correspondence and reprint requests to Dr. Robert J. Binder, BSTWR E1051, 200 Lothrop Street, University of Pittsburgh, Pittsburgh, PA 15261. E-mail address: rjb42{at}pitt.edu

³ Abbreviations used in this paper: HSP, heat shock protein; β-gal, β-galactosidase; X-GAL, 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside; fg, femtogram; MHC I, MHC class I.

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