The Multiple Immune-evasion Genes of Murine Cytomegalovirus Are Not Redundant: m4 and m152 Inhibit Antigen Presentation In a Complementary and Cooperative Fashion

doi:10.1084/jem.194.7.967

Published online 1 October 2001. doi:10.1084/jem.194.7.967

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© The Rockefeller University Press, 0022-1007/2001/10/967/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 7, October 1, 2001 967-978

Original Article

The Multiple Immune-evasion Genes of Murine Cytomegalovirus Are Not Redundant: m4 and m152 Inhibit Antigen Presentation In a Complementary and Cooperative Fashion

Daniel G. Kavanagh^a, Marielle C. Gold^a, Markus Wagner^b, Ulrich H. Koszinowski^b, and Ann B. Hill^a
^a Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201
^b Max von Pettenkofer Institut, D-81377 Munich, Germany

Correspondence to: Ann B. Hill, L220, Dept. of Molecular Microbiology and Immunology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201. Tel:503-494-0763 Fax:503-494-6862 E-mail:hillan{at}ohsu.edu.

Both human cytomegaloviruses (HCMVs) and murine cytomegaloviruses(MCMVs) encode multiple genes that interfere with antigen presentationby major histocompatibility complex (MHC) class I, and thusprotect infected targets from lysis by virus-specific cytotoxicT lymphocytes (CTLs). HCMV has been shown to encode four suchgenes and MCMV to encode two. MCMV m152 blocks the export ofclass I from a pre-Golgi compartment, and MCMV m6 directs classI to the lysosome for degradation. A third MCMV gene, m4, encodesa glycoprotein which is expressed at the cell surface in associationwith class I. Here we here show that m4 is a CTL-evasion genewhich, unlike previously described immune-evasion genes, inhibitedCTLs without blocking class I surface expression. m152 was necessaryto block antigen presentation to both K^b- and D^b-restrictedCTL clones, while m4 was necessary to block presentation onlyto K^b-restricted clones. m152 caused complete retention of D^b,but only partial retention of K^b, in a pre-Golgi compartment.Thus, while m152 effectively inhibited D^b-restricted CTLs, m4was required to completely inhibit K^b-restricted CTLs. We proposethat cytomegaloviruses encode multiple immune-evasion genesin order to cope with the diversity of class I molecules inoutbred host populations.

Key Words: murine cytomegalovirus, cytotoxic T lymphocyte, immune evasion,MHC, class I

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