Human Cytomegalovirus Gene Products US3 and US6 Down-Regulate Trophoblast Class I MHC Molecules

Jun, Youngsoo; Kim, Eun‐Ok; Jin, Myung; Sung, Hyun-Chan; Han, Hoon; Geraghty, Daniel E.; Ahn, Kwangseog

doi:10.4049/jimmunol.164.2.805

Cited by 104 publications

(77 citation statements)

References 40 publications

(36 reference statements)

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“…Interestingly, large numbers of NK cells are present within the maternal decidua close to trophoblast cells, and they express HLA-G-specific inhibitory receptors, including LIR-1 [34]. The capacity of HCMV to infect the trophoblast and to down-modulate HLA-G expression may render infected cells susceptible to recognition by NK cells [35,36]. However, in this context, expression of UL18 could provide an important inhibitory signal to NK cells.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

et al. 2006

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Human cytomegalovirus (HCMV) down-regulates cell surface expression of HLA class I molecules (HLA-I). UL18, an HCMV-encoded HLA-I homologue, has been proposed to protect virus-infected cells against NK cell recognition by engaging the inhibitory receptor leukocyte Ig-like receptor (LIR)-1, which also binds a broad spectrum of HLA-I alleles, including HLA-G1. Because genetic and biological differences exist among HCMV strains, we characterized laboratory (AD169) and clinical (4636, 13B, 109B) strain-derived UL18 proteins. Compared to the known AD169-derived UL18, mutations were found in clinical strain-derived UL18. They were clustered in the a3 domain (13B), previously shown to be critical for LIR-1 binding, or in the a1 domain (4636). In cytotoxicity assays, pretreatment of LIR-1 + NKL with soluble 4636-UL18 completely abolished LIR-1-dependent protection from NK lysis, conferred by the expression of HLA-G1 on target cells (721.221-HLA-G1 + ). Similarly, flow cytometry, Biacore and ELISA experiments showed 4636-UL18 and 13B-UL18 to have the strongest binding capacity to LIR-1. Our results suggest the importance of two independent UL18 regions for LIR-1 binding, one localized on the tip of the a3 domain, and another composed of two loops that emerge from the a1 domain. Strain variations in these domains may result in different UL18-mediated effects on LIR-1 + cells during the course of HCMV infection.

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Section: Discussionmentioning

confidence: 99%

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

et al. 2006

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“…Only few maternal CTLs are found at this site, and during HCMV infection T cell recognition of infected trophoblast cells will largely be prohibited due to absence or reduction of surface expression of Ag-presenting MHC class I molecules: HLA-A and -B molecules are lacking in these cells, and surface expression of HLA-G is reduced by US2 (this study), US3 (53), and US6 (54). In addition, HLA-C can be down-regulated by US3, US6 (53), and US11 (Ref. 55 and our own unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus-Encoded US2 Differentially Affects Surface Expression of MHC Class I Locus Products and Targets Membrane-Bound, but Not Soluble HLA-G1 for Degradation

Barel

Ressing

Pizzato

et al. 2003

The Journal of Immunology

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Human CMV (HCMV) can elude CTL as well as NK cells by modulating surface expression of MHC class I molecules. This strategy would be most efficient if the virus would selectively down-regulate viral Ag-presenting alleles, while at the same time preserving other alleles to act as inhibitors of NK cell activation. We focused on the HCMV unique short (US) region encoded protein US2, which binds to newly synthesized MHC class I H chains and supports their dislocation to the cytosol for subsequent degradation by proteasomes. We studied the effect of US2 on surface expression of individual class I locus products using flow cytometry. Our results were combined with crystal structure data of complexed US2/HLA-A2/β2-microglobulin and alignments of 948 HLA class I database sequences of the endoplasmic reticulum lumenal region inplicated in US2 binding. This study suggests that surface expression of all HLA-A and -G and most HLA-B alleles will be affected by US2. Several HLA-B alleles and all HLA-C and -E alleles are likely to be insensitive to US2-mediated degradation. We also found that the MHC class I endoplasmic reticulum-lumenal domain alone is not sufficient for degradation by US2, as illustrated by the stability of soluble HLA-G1 in the presence of US2. Furthermore, we showed that the membrane-bound HLA-G1 isoform, but also tailless HLA-A2, are targeted for degradation. This indicates that the cytoplasmic tail of the MHC class I H chain is not required for its dislocation to the cytosol by US2.

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“…It was previously shown that HCMV evasins differentially modulate detectable levels of MHC I molecules encoded by different loci (25,26,44,45). Products of the HLA-C and HLA-E loci were described to be resistant to US2 and US11 (26) but susceptible to US3 and US6 (45).…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

Ameres

Besold

Plachter

et al. 2014

The Journal of Immunology

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Immunoevasive proteins (“evasins”) of human CMV (HCMV) modulate stability and localization of MHC class I (MHC I) molecules, and their supply of antigenic peptides. However, it is largely unknown to what extent these evasins interfere with recognition by virus-specific CD8 T cells. We analyzed the recognition of HCMV-infected cells by a panel of CD8 T cells restricted through one of nine different MHC I allotypes. We employed a set of HCMV mutants deleted for three or all four of the MHC I modulatory genes US2, US3, US6, and US11. We found that different HCMV evasins exhibited different allotype-specific patterns of interference with CD8 T cell recognition of infected cells. In contrast, recognition of different epitopes presented by the same given MHC I allotype was uniformly reduced. For some allotypes, single evasins largely abolished T cell recognition; for others, a concerted action of evasins was required to abrogate recognition. In infected cells whose Ag presentation efficiency had been enhanced by IFN-γ pretreatment, HCMV evasins cooperatively impared T cell recognition for several different MHC I allotypes. T cell recognition and MHC I surface expression under influence of evasins were only partially congruent, underscoring the necessity to probe HCMV immunomodulation using specific T cells. We conclude that the CD8 T cell evasins of HCMV display MHC I allotype specificity, complementarity, and cooperativity.

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Human Cytomegalovirus Gene Products US3 and US6 Down-Regulate Trophoblast Class I MHC Molecules

Cited by 104 publications

References 40 publications

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

Human Cytomegalovirus-Encoded US2 Differentially Affects Surface Expression of MHC Class I Locus Products and Targets Membrane-Bound, but Not Soluble HLA-G1 for Degradation

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

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