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Journal of Virology, August 2006, p. 7613-7624, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00723-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cytomegalovirus Encodes a Positive Regulator of Antigen Presentation

Rafaela Holtappels,^1, Dorothea Gillert-Marien,^1, Doris Thomas,¹ Jürgen Podlech,¹ Petra Deegen,¹ Sylvia Herter,² Silke A. Oehrlein-Karpi,¹ Dennis Strand,³ Markus Wagner,^4, and Matthias J. Reddehase^1*

Institutes for Virology,¹ Immunology, Johannes Gutenberg-University, Mainz, Germany,² Medical Clinic I and Imaging Core Facility of the Immunology Cluster of Excellence "Immunointervention," Medical Centre Mainz, Mainz, Germany,³ Max von Pettenkofer Institute, Department for Virology and Gene Center of the Ludwig Maximilians-University, Munich, Germany⁴

Received 10 April 2006/ Accepted 15 May 2006

Murine cytomegalovirus encodes three regulators of antigen presentation to antiviral CD8 T cells. According to current paradigms, all three regulators are committed to the inhibition of the presentation of antigenic peptides. Whereas m152/gp40 catalyzes the retention of peptide-loaded major histocompatibility complex (MHC) class I molecules in a cis-Golgi compartment, m06/gp48 binds stably to class I molecules and directs them into the cellular cargo-sorting pathway of lysosomal degradation. Regulator m04/gp34 also binds stably to class I molecules, but unlike m152 and m06, it does not downmodulate MHC class I cell surface expression. It has entered the literature as a direct inhibitor of T-cell recognition of the MHC-peptide complex at the cell surface. In this work, we have studied the presentation of antigenic viral peptides in cells infected with a comprehensive set of mutant viruses expressing the three regulators separately as well as in all possible combinations. The results redefine m04 as a positive regulator dedicated to the facilitation of antigen presentation. When expressed alone, it did not inhibit T-cell recognition, and when expressed in the presence of m152, it restored antigen presentation by antagonizing the inhibitory function of m152. Its intrinsic positive function, however, was antagonized and even slightly overcompensated for by the negative regulator m06. In an adoptive cell transfer model, the opposing forces of the three regulators were found to govern immune surveillance in the infected host. While negative regulators, also known as immunoevasins, are common, the existence of a positive regulator is without precedent and indicates an intriguing genetic potential of this virus to influence antigen presentation.

Present address: Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.

R.H. and D.G.-M. contributed equally to this work.

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