Cutting Edge: The Human Cytomegalovirus<i>UL40</i>Gene Product Contains a Ligand for HLA-E and Prevents NK Cell-Mediated Lysis

Ulbrecht, Matthias; Martinozzi, Silvia; Grzeschik, Mariola; Hengel, Hartmut; Ellwart, Joachim W.; Pla, Marika; Weiß, Elisabeth H.

doi:10.4049/jimmunol.164.10.5019

Cited by 274 publications

(229 citation statements)

References 23 publications

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“…Similar results were obtained by co-transfection of UL40 and HLA-E in K562 cells. 24 More interestingly, Cerboni et al 25 have extended these results by showing how IFN-g can increase the inhibitory effect of UL40, through the upregulation of HLA-E. These findings may have important biological implications and support the hypothesis that IFN-g released during an antiviral or antitumoral response may lead to enhanced inhibitory signaling to effector cells carrying the CD94/NKG2A receptors and thereby turn off their effector functions.…”

Section: Discussionsupporting

confidence: 57%

HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT

Nguyen

Béziat

Dhédin

et al. 2008

Bone Marrow Transplant

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Natural killer (NK) cells generated after haploidentical hematopoietic SCT in patients with AML are characterized by specific phenotypic features and impaired functioning that may affect transplantation outcome. We show that IFN-c produced by immature CD56 bright NK cells upregulates cell surface expression of HLA-E on AML blasts and that this upregulation protects leukemic cells from NK-mediated cell lysis through the mediation of CD94/NKG2A, an inhibitory receptor overexpressed on NK cells after haploidentical SCT. Two years after transplantation, however, maturing NK cells were functionally active, as evidenced by high cytotoxicity and poor IFN-c production. This implies that maturation of NK cells is the key to improved immune responses and transplantation outcome.

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Section: Discussionsupporting

confidence: 57%

HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT

Nguyen

Béziat

Dhédin

et al. 2008

Bone Marrow Transplant

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“…However, an HLA-E-binding peptide is contained within the leader sequence of HCMV gpUL40. We recently demonstrated that adenoviral expression of UL40 in cell lines induced TAPindependent up-regulation of HLA-E cell-surface expression (21) and elicited protection against lysis by NK cells (21,22). Recent data has suggested that this effect may be enhanced by IFN␥ (23), but no studies to date have investigated UL40 in the context of an active HCMV infection.…”

Section: Nk Cells ͉ Inhibitionmentioning

confidence: 99%

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Wang

McSharry

Retière

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

153

126

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Human cytomegalovirus (HCMV) exploits a range of strategies to evade and modulate the immune response. Its capacity to downregulate MHC I expression was anticipated to render infected cells vulnerable to natural killer (NK) attack. Kinetic analysis revealed that during productive infection, HCMV strain AD169 first enhanced and then inhibited lysis of primary skin fibroblasts by a CD94͞NKG2A ؉ NKG2D ؉ ILT2 ؉ NK line. The inhibition of cytotoxicity against strain AD169-infected fibroblasts was abolished by prior treatment of targets or effectors with anti-MHC I and anti-CD94 monoclonal antibodies, respectively, implying a CD94͞HLA-Edependent mechanism. An HCMV strain AD169, UL40 deletion mutant could not inhibit CD94͞NKG2A ؉ NK killing against skin fibroblasts. The contribution of UL40 to evasion of primary NK cells then was tested in a system where targets and effectors were MHC-matched. Primary NK cells activated with IFN␣ as well as cultured primary NK cell lines showed increased killing against ⌬UL40-infected fibroblasts compared with AD169-infected targets. This effect was abrogated by depletion of CD94 ؉ cells. These findings demonstrate that HCMV encodes a mechanism of evasion specifically targeted against a proportion of CD94 ؉ NK cells and show that this system functions during a productive infection. NK cells ͉ inhibitionH uman cytomegalovirus (HCMV) is the prototypical ␤-herpesvirus and an important pathogen, being the major viral cause of congenital malformation and associated with severe morbidity in immunocompromised individuals. Primary infection is followed by lifelong persistence. The cellular immune response is crucial in controlling infection and providing resistance to disease (1). HCMV encodes an impressive arsenal of genes that act to counter MHC I-restricted cytotoxic T lymphocyte recognition by down-regulation of MHC I at various stages of the replicative cycle (reviewed in ref.2).Although down-regulation of MHC I expression is associated with protection against antigen-specific cytotoxic T lymphocytes, it also may enhance natural killer (NK) recognition of HCMVinfected cells. The importance of NK cells for control of CMV has been shown in vivo: in mice, an NK resistance locus, cmv1, has been identified (3) and mapped to the gene for Ly-49H, an NK-activating receptor (4, 5); in humans, an absence of NK cells increases susceptibility to several herpesvirus infections including HCMV (6). A number of human NK-activating and -inhibitory receptors have now been identified (reviewed in refs. 7-9). Members of the killer inhibitory receptor (KIR) family and the leukocyte Ig-like receptors (LIR-1͞ILT-2 and LIR-2͞ILT-4) bind HLA class I molecules. The HCMV MHC I homolog gpUL18 exhibits high affinity for LIR-1͞ILT-2 (10, 11); however, the function of gpUL18 during virus infection is yet to be resolved. A surface C-type lectin receptor CD94͞NKG2A͞B also has been shown to interact specifically with the nonclassical MHC I molecule, HLA-E, to deliver an inhibitory signal to NK cells (12)(13)(14). HLA-E ex...

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“…[122][123][124] In other cases, viral proteins that block NK cell activity interact with MHC-like molecules. The HCMV-specific UL16 protein interferes with the recognition of activating NKG2D receptors on NK cells by binding to MHC class I-related molecules such as MIC and ULBP, which serve as ligands for these activating receptors.…”

Section: Control Of Viral Immune Responses: Paralysis By Different Mementioning

confidence: 99%

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

Seliger

Ritz

Ferrone

2005

Intl Journal of Cancer

113

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In humans as in other animal species, CD81 cytotoxic T lymphocytes (CTLs) play an important if not the major role in controlling virus-infected and malignant cell growth. The interactions between CD81 T cells and target cells are mediated by human leukocyte antigen (HLA) class I antigens loaded with viral and tumor antigen-derived peptides along with costimulatory receptor/ligand stimuli. Thus, to escape from CD8 1 T-cell recognition and destruction, viruses and tumor cells have developed strategies to inhibit the expression and/or function of HLA class I antigens. In contrast, cells with downregulated MHC class I surface expression can be recognized by NK cells, although NK cell-mediated lysis could be abrogated by the expression of inhibiting NK cell receptors. This review discusses the molecular mechanisms utilized by viruses to inhibit the formation, transport and/or expression of HLA class I antigen/peptide complexes on the cell surface. The knowledge about viral interference with MHC class I antigen presentation is not only crucial to understand the pathogenesis of viral diseases, but contributes also to the design of novel strategies to counteract the escape mechanisms utilized by viruses. These investigations may eventually lead to the development of effective immunotherapies to control viral infections and virus-associated malignant diseases. ' 2005 Wiley-Liss, Inc.

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Cutting Edge: The Human CytomegalovirusUL40Gene Product Contains a Ligand for HLA-E and Prevents NK Cell-Mediated Lysis

Cited by 274 publications

References 23 publications

HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT

HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

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