A lymphocytic choriomeningitis virus glycoprotein variant that is retained in the endoplasmic reticulum efficiently cross-primes CD8+ T cell responses
- Stefan Freigang*,†,
- Bruno Eschli*,
- Nicola Harris*,‡,
- Markus Geuking*,
- Katharina Quirin§,
- Sabrina Schrempf¶,
- Raphael Zellweger*,
- Jacqueline Weber*,
- Hans Hengartner*, and
- Rolf M. Zinkernagel*,‖
- *Institute of Experimental Immunology, Department of Pathology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland;
- ‡Environmental Biomedicine, Eidgenössische Technische Hochschule Zentrum, Wagistrasse 25/27, CH-8952 Schlieren, Switzerland;
- §Institute of Biochemistry, Eidgenössische Technische Hochschule Hönggerberg, Schafmattstrasse 18, CH-8093 Zurich, Switzerland; and
- ¶Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany
-
Contributed by Rolf M. Zinkernagel, June 3, 2007 (received for review April 16, 2007)
Abstract
Recent studies indicate that T cell cross-priming preferentially occurs against long-lived, stable proteins. We have studied cross-priming by using the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), a protein that normally is not MHC class I cross-presented. This study shows that a C-terminally truncated, noncleavable variant of LCMV-GP led to the accumulation of stable, soluble GP trimers in the endoplasmic reticulum (ER) of the antigen donor cell, and thereby converted LCMV-GP into a potent immunogen for cytotoxic T lymphocyte cross-priming. Immunization of mice with tumor cells expressing an ER-retained LCMV-GP variant cross-primed protective antiviral cytotoxic T lymphocyte responses in vivo at least 10,000-fold better than immunization with cells expressing the cross-presentation-“resistant” wild-type LCMV-GP. Thus the ER is a cellular compartment that can provide antigen for cross-presentation, and modifications affecting stability and subcellular localization of the antigen significantly increase its availability for MHC class I cross-presentation. These findings impinge on vaccine strategies.
Footnotes
- †To whom correspondence may be sent at the present address: Department of Immunology-Imm23, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail: stefan.freigang{at}gmx.net
- ‖To whom correspondence may be addressed. E-mail: rolf.zinkernagel{at}usz.ch
-
Author contributions: S.F. and B.E. contributed equally to this work; S.F., B.E., H.H., and R.M.Z. designed research; S.F., B.E., N.H., M.G., K.Q., S.S., R.Z., and J.W. performed research; S.F., B.E., H.H., and R.M.Z. analyzed data; and S.F., B.E., and R.M.Z. wrote the paper.
-
The authors declare no conflict of interest.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0704423104/DC1.
- Abbreviations:
- APC,
- antigen-presenting cell;
- CTL,
- cytotoxic T lymphocyte;
- Endo H,
- endoglycosidase H;
- ER,
- endoplasmic reticulum;
- ERAD,
- ER-associated degradation;
- GP,
- glycoprotein;
- GPc,
- GP precursor;
- GPER,
- ER-retained LCMV-GP;
- LCMV,
- lymphocytic choriomeningitis virus;
- MC-GP,
- murine MC57 fibrosarcoma cells expressing LCMV-GP;
- MC-GPER,
- MC57 cells expressing LCMV-GPER;
- RIP-GP,
- LCMV-GP expressed under control of the rat insulin promoter;
- VV-G2,
- recombinant vaccinia virus expressing LCMV-GP.
- © 2007 by The National Academy of Sciences of the USA
