IRFE-mediated regulation of mCMV m152 expression

Abstract

Cytomegaloviruses (CMVs) have evolved genes dedicated to subvert literally all components of the host´s immune system. The host in turn has evolved mechanisms to attenuate viral immune evasion to control the virus. The model of murine CMV (mCMV) has been pivotal to the discovery of CMV immune evasion genes and made it feasible to study their roles in vivo. Two of these genes are strong MHC class-I (MHC-I) regulators, named m06 and m152. Whereas m06 is the strongest downmodulator of total cell surface MHC-I, m152 preferentially blocks trafficking of recently-loaded peptide-MHC-I complexes to the cell surface. Here we present a previous unknown host modulation of m152 by type-I interferons (IFNs). We recognized a consensus IFN regulatory factor element (IRFE) in the promoter region of the m152 gene. Conspicuously, this m152-IRFE is one of only three IRFE sequences present in the mCMV genome, and the only one that is located in a promoter region. Moreover, the m152-IRFE is conserved among a panel of sequenced mCMV genomes and showed functional properties under type-I IFN signaling. A loss-of-function motif mutation of the m152-IRFE is associated with reduced m152 transcripts and protein expression in infected cells. Analysis by flow cytometry revealed that the IRFE-mediated regulation of m152 transcription affects MHC-I cell surface expression. In addition, we could confirm the requirement of type-I IFN signaling for antiviral CD8 T cell control in C57BL/6 IFNAR-/-mice. While mCMV wildtype virus is not controlled by adoptively transferred CD8 T cells in the absence of IFNAR signaling, an mCMV recombinant lacking m152 is again controlled. These findings suggest that type-I IFN signaling is regulating m152 expression and therefore works as a direct host counter-measure to dampen viral immune evasion.