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International Immunology Advance Access published online on December 16, 2005
International Immunology, doi:10.1093/intimm/dxh362
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received March 23, 2005
Accepted October 28, 2005

Article

Subtle sequence variation among MHC class I locus products greatly influences sensitivity to HCMV US2- and US11-mediated degradation

Martine T. Barel 1, Nathalie Pizzato 2, Philippe Le Bouteiller 2, Emmanuel J. H. J. Wiertz 1, and Francoise Lenfant 3 *

1 Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
2 INSERM U563, CPTP, Bat A, Hôpital Purpan, BP 3028, 31024 Toulouse cedex 3, France
3 INSERM U563, CPTP, Bat A, Hôpital Purpan, BP 3028, 31024 Toulouse cedex 3, France; Present address: INSERM U 589, Institut L. Bugnard, Hôpital Rangueil, BP 84225, 31 432 Toulouse cedex 4, France

* To whom correspondence should be addressed.
Francoise Lenfant, E-mail: lenfant{at}toulouse.inserm.fr


  Abstract

Human cytomegalovirus (HCMV) interferes with cellular immune responses by modulating surface expression of MHC class I molecules. Here, we focused on HCMV-encoded unique short (US) 2 and US11, which bind newly synthesized MHC class I heavy chains (HCs) and support their dislocation into the cytosol for subsequent degradation by proteasomes. Not all MHC class I locus products are equally sensitive to this down-modulation. The aim of this study was to identify which domains, and ultimately which residues, are responsible for the resistance or sensitivity of MHC class I molecules to US2- and US11-mediated down-regulation. We show that, besides endoplasmic reticulum-lumenal regions, the C-terminus of class I molecules represents an important determinant for allele specificity in US11-mediated degradation. HLA-E becomes sensitive to US11-mediated down-regulation when its cytoplasmic tail is extended. Interestingly, this only requires two additional residues, lysine and valine, at its C-terminus. For US2, the MHC class I allele specificity is largely determined by a small region at the junction of the {alpha}2/{alpha}3 domain of the HC. It is quite remarkable that minor changes, in only four residues, can completely revert the sensitivity of naturally US2-resistant HLA-E molecules. With this study we provide better insights into the features underlying the selectivity in MHC class I down-regulation by US2 and US11.

Keywords: cytomegalovirus; HLA-E; immune evasion; US.
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