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Journal of Virology, December 2008, p. 11637-11650, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01510-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation{triangledown}

Verena Böhm, Christian O. Simon, Jürgen Podlech, Christof K. Seckert, Dorothea Gendig, Petra Deegen, Dorothea Gillert-Marien, Niels A. W. Lemmermann, Rafaela Holtappels, and Matthias J. Reddehase*

Institute for Virology, Johannes Gutenberg University, Mainz, Germany

Received 18 July 2008/ Accepted 12 September 2008

Cytomegaloviruses express glycoproteins that interfere with antigen presentation to CD8 T cells. Although the molecular modes of action of these "immunoevasins" differ between cytomegalovirus species, the convergent biological outcome is an inhibition of the recognition of infected cells. In murine cytomegalovirus, m152/gp40 retains peptide-loaded major histocompatibility complex class I molecules in a cis-Golgi compartment, m06/gp48 mediates their vesicular sorting for lysosomal degradation, and m04/gp34, although not an immunoevasin in its own right, appears to assist in the concerted action of all three molecules. Using the Ld-restricted IE1 epitope YPHFMPTNL in the BALB/c mouse model as a paradigm, we provide here an explanation for the paradox that immunoevasins enhance CD8 T-cell priming although they inhibit peptide presentation in infected cells. Adaptive immune responses are initiated in the regional lymph node (RLN) draining the site of pathogen exposure. In particular for antigens that are not virion components, the magnitude of viral gene expression providing the antigens is likely a critical parameter in priming efficacy. We have therefore focused on the events in the RLN and have related priming to intranodal viral gene expression. We show that immunoevasins enhance priming by downmodulating an early CD8 T-cell-mediated "negative feedback" control of the infection in the cortical region of the RLN, thus supporting the model that immunoevasins improve antigen supply for indirect priming by uninfected antigen-presenting cells. As an important consequence, these findings predict that deletion of immunoevasin genes in a replicative vaccine virus is not a favorable option but may, rather, be counterproductive.

* Corresponding author. Mailing address: Institute for Virology, Johannes Gutenberg University, Hochhaus am Augustusplatz, 55101 Mainz, Germany. Phone: 49 6131 39 33650. Fax: 49 6131 39 35604. E-mail: Matthias.Reddehase{at}uni-mainz.de

{triangledown} Published ahead of print on 24 September 2008.

Journal of Virology, December 2008, p. 11637-11650, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01510-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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