Cross-Presentation of Glycoprotein 96-associated Antigens on Major Histocompatibility Complex Class I Molecules Requires Receptor-mediated Endocytosis

doi:10.1084/jem.191.11.1965

Published online 6 June 1999.

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© The Rockefeller University Press, 0022-1007/2000/6/1965/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 11, June 5, 2000 1965-1974

Original Article

Cross-Presentation of Glycoprotein 96–associated Antigens on Major Histocompatibility Complex Class I Molecules Requires Receptor-mediated Endocytosis

Harpreet Singh-Jasuja^a, René E.M. Toes^b, Pieter Spee^c, Christian Münz^d, Norbert Hilf^a, Stephen P. Schoenberger^b, Paola Ricciardi-Castagnoli^e, Jacques Neefjes^c, Hans-Georg Rammensee^a, Danièle Arnold-Schild^a, and Hansjörg Schild^a
^a Institute for Cell Biology, Department of Immunology, University of Tübingen, D-72076 Tübingen, Germany
^b Department of Immunohematology and Transfusion Bank, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
^c Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
^d Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021
^e Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milan, Italy

Correspondence to: Hansjörg Schild, Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, D-72076 Tübingen, Germany. Tel:49-7071-2980992 Fax:49-7071-295653 E-mail:hansjoerg.schild{at}uni-tuebingen.de.

Heat shock proteins (HSPs) like glycoprotein (gp)96 (glucose-regulatedprotein 94 [grp94]) are able to induce specific cytotoxic Tlymphocyte (CTL) responses against cells from which they originate.Here, we demonstrate that for CTL activation by gp96-chaperonedpeptides, specific receptor-mediated uptake of gp96 by antigen-presentingcells (APCs) is required. Moreover, we show that in both humansand mice, only professional APCs like dendritic cells (DCs),macrophages, and B cells, but not T cells, are able to bindgp96. The binding is saturable and can be inhibited using unlabeledgp96 molecules. Receptor binding by APCs leads to a rapid internalizationof gp96, which colocalizes with endocytosed major histocompatibilitycomplex (MHC) class I and class II molecules in endosomal compartments.Incubation of gp96 molecules isolated from cells expressingan adenovirus type 5 E1B epitope with the DC line D1 resultsin the activation of E1B-specific CTLs. This CTL activationcan be specifically inhibited by the addition of irrelevantgp96 molecules not associated with E1B peptides. Our resultsdemonstrate that only receptor-mediated endocytosis of gp96molecules leads to MHC class I–restricted re-presentationof gp96-associated peptides and CTL activation; non–receptor-mediated,nonspecific endocytosis is not able to do so. Thus, we provideevidence on the mechanisms by which gp96 is participating inthe cross-presentation of antigens from cellular origin.

Key Words: heat shock protein–peptide complex, cross-priming, receptor-mediatedendocytosis, cytotoxic T lymphocyte activation, dendritic cell

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