A lymphocytic choriomeningitis virus glycoprotein variant that is retained in the endoplasmic reticulum efficiently cross-primes CD8(+) T cell responses
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.
Keywords: Animals ; Blotting, Western ; CD8-Positive T-Lymphocytes/*immunology ; Endoplasmic Reticulum/*metabolism ; Flow Cytometry ; Glycoproteins/*immunology ; Hela Cells ; Humans ; Lymphocytic choriomeningitis virus/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Viral Proteins/*immunology
Freigang, Stefan Eschli, Bruno Harris, Nicola Geuking, Markus Quirin, Katharina Schrempf, Sabrina Zellweger, Raphael Weber, Jacqueline Hengartner, Hans Zinkernagel, Rolf M Research Support, Non-U.S. Gov't United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13426-31. Epub 2007 Aug 8.
Record created on 2010-01-06, modified on 2016-08-08