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.
Institute of Experimental Immunology, Department of Pathology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland. stefan.freigang@gmx.net
Stefan
S
Freigang
Bruno
B
Eschli
Nicola
N
Harris
Markus
M
Geuking
Katharina
K
Quirin
Sabrina
S
Schrempf
Raphael
R
Zellweger
Jacqueline
J
Weber
Hans
H
Hengartner
Rolf M
RM
Zinkernagel
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D014764:Viral Proteins / Q000276:immunology*
D006023:Glycoproteins; D014764:Viral Proteins