CD58 is an adhesion molecule that is known to play a critical role in costimulation of effector cells and is intrinsic to immune synapse structure. Herein, we describe a virally encoded gene that inhibits CD58 surface expression. Human cytomegalovirus (HCMV) UL148 was necessary and sufficient to promote intracellular retention of CD58 during HCMV infection. Blocking studies with antagonistic anti-CD58 mAb and an HCMV UL148 deletion mutant (HCMV∆UL148) with restored CD58 expression demonstrated that the CD2/CD58 axis was essential for the recognition of HCMV-infected targets by CD8+ HCMV-specific cytotoxic T lymphocytes (CTLs). Further, challenge of peripheral blood mononuclear cells ex vivo with HCMV∆UL148 increased both CTL and natural killer (NK) cell degranulation against HCMV-infected cells, including NK-driven antibody-dependent cellular cytotoxicity, showing that UL148 is a modulator of the function of multiple effector cell subsets. Our data stress the effect of HCMV immune evasion functions on shaping the immune response, highlighting the capacity for their potential use in modulating immunity during the development of anti-HCMV vaccines and HCMV-based vaccine vectors.

• Keywords
• CD58, CTLs, NK cells, human cytomegalovirus, immune modulation,
• MeSH
• Immunity, Cellular * MeSH
• Killer Cells, Natural immunology   pathology   MeSH
• CD8-Positive T-Lymphocytes immunology   pathology   MeSH
• Cytomegalovirus Infections genetics   immunology   pathology   MeSH
• Cytomegalovirus genetics   immunology   MeSH
• Immune Evasion * MeSH
• Humans MeSH
• Viral Fusion Proteins genetics   immunology   MeSH
• Cell Line, Transformed MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Viral Fusion Proteins MeSH
• UL148 protein, human cytomegalovirus MeSH Browser

Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I. Whereas integrin α-chains were selectively degraded, their integrin β1 binding partner accumulated in the ER. Consequently integrin signaling, cell adhesion and migration were strongly suppressed. US2 was necessary and sufficient for degradation of the majority of its substrates, but remarkably, the HCMV NK cell evasion function UL141 requisitioned US2 to enhance downregulation of the NK cell ligand CD112. UL141 retained CD112 in the ER from where US2 promoted its TRC8-dependent retrotranslocation and degradation. These findings redefine US2 as a multifunctional degradation hub which, through recruitment of the cellular E3 ligase TRC8, modulates diverse immune pathways involved in antigen presentation, NK cell activation, migration and coagulation; and highlight US2's impact on HCMV pathogenesis.

• MeSH
• Lymphocyte Activation immunology   MeSH
• Cell Membrane metabolism   MeSH
• Killer Cells, Natural immunology   MeSH
• Cytomegalovirus immunology   MeSH
• Mass Spectrometry MeSH
• Immune Evasion immunology   MeSH
• Immunoblotting MeSH
• Immunoprecipitation MeSH
• Humans MeSH
• RNA, Small Interfering MeSH
• Membrane Glycoproteins metabolism   MeSH
• Membrane Proteins metabolism   MeSH
• Cell Line, Tumor MeSH
• Viral Envelope Proteins metabolism   MeSH
• Proteomics methods   MeSH
• Flow Cytometry MeSH
• Transduction, Genetic MeSH
• Viral Proteins metabolism   MeSH
• Chromatography, High Pressure Liquid MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA, Small Interfering MeSH
• Membrane Glycoproteins MeSH
• Membrane Proteins MeSH
• Viral Envelope Proteins MeSH
• UL141 glycoprotein, human cytomegalovirus MeSH Browser
• US2 protein, Varicellovirus MeSH Browser
• Viral Proteins MeSH