Coordinated Function of Murine Cytomegalovirus Genes Completely Inhibits CTL Lysis

Abstract

Murine CMV (MCMV) encodes three viral genes that interfere with Ag presentation (VIPRs) to CD8 T cells, m04, m06, and m152. Because the functional impact of these genes during normal infection of C57BL/6 mice is surprisingly modest, we wanted to determine whether the VIPRs are equally effective against the entire spectrum of H-2b-restricted CD8 T cell epitopes. We also wanted to understand how the VIPRs interact at a functional level. To address these questions, we used a panel of MCMV mutants lacking each VIPR in all possible combinations, and CTL specific for 15 H-2b-restricted MCMV epitopes. Only expression of all three MCMV VIPRs completely inhibited killing by CTL specific for all 15 epitopes, but removal of any one VIPR enabled lysis by at least some CTL. The dominant interaction between the VIPRs was cooperation: m06 increased the inhibition of lysis achieved by either m152 or m04. However, for 1 of 15 epitopes m04 functionally antagonized m152. There was little differential impact of any of the VIPRs on Kb vs Db, but a surprising degree of differential impact of the three VIPRs for different epitopes. These epitope-specific differences did not correlate with functional avidity, or with timing of VIPR expression in relation to Ag expression in the virus replication cycle. Although questions remain about the molecular mechanism and in vivo role of these genes, we conclude that the coordinated function of MCMV’s three VIPRs results in a powerful inhibition of lysis of infected cells by CD8 T cells.

Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy

“…As shown for cells infected with wild-type mCMV (mCMV-WT), the concerted action of immunoevasins m04/gp34, m06/gp48, and m152/gp40 completely prevents lysis of infected cells by a large array of CTLs differing in MHCrestriction and in the epitopes recognized [6,7], although CTL specific for the D d -restricted m164-epitope represent a reported exception [8]. In principle, these findings also apply to the triggering of a second effector function of CD8 T cells, namely the secretion of interferon (IFN)-c as measured in an ELISpot assay.…”

Batf3 transcription factor‐dependent DC subsets in murine CMV infection: Differential impact on T‐cell priming and memory inflation

“…2F and G). The reduced proliferation in Batf3 À/À mice might be a consequence of impaired antigen presentation or due to an inferior capacity of CD8a À DCs for CD8 1 T-cell priming [10,22]. .…”

“…Cross-presentation may play a fundamental role in the induction of antiviral CD8 1 T-cell responses in situations where viruses encode for proteins that directly interfere with the antigen presentation machinery of infected cells. Murine cytomegalovirus (MCMV) expresses proteins that directly target MHC and costimulatory molecules in infected APCs [8][9][10][11]. Despite such impressive immune evasion, strong CD8 1 T-cell responses are induced upon MCMV infection, suggesting that cross-presentation may play an important role [12].…”

Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

“…For example, CMV evades MHC class I Ag presentation by reducing the stability of class I heavy chains (28) and also by dislocating MHC class I heavy chains from the endoplasmic reticulum (29). The coordinated function of murine CMV genes can completely inhibit CTL lysis (30). Among others, the EBV EBNA1 protein contains an element that interferes with its proteasomal proteolysis, and the HSV ICP47 protein inhibits the TAP complex (31,32).…”