Human Cytomegalovirus Glycoprotein UL16 Causes Intracellular Sequestration of NKG2D Ligands, Protecting Against Natural Killer Cell Cytotoxicity

Dunn, Claire; Chalupny, N. Jan; Sutherland, Claire L.; Dosch, Stephanie; Sivakumar, Pallavur V.; Johnson, David C.; Cosman, David

doi:10.1084/jem.20022059

Cited by 250 publications

(180 citation statements)

References 58 publications

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“…58 To draw a conclusion, a large scale and time-course analysis of blood cells of patients with PNH is needed. With regard to the discrete features of ULBP3, 61 our inhibition assays with antibodies indicate that ULBP3 was not engaged in the killing of K562 cells in contrast with ULBPs 1 and 2.…”

Section: Discussionmentioning

confidence: 99%

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Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder of clonal nature characterized by intravascular hemolysis, venous thrombosis, bone marrow (BM) dysfunction, and infrequent development of leukemia. [1][2][3][4] In the last 2 decades, virtually the entire mechanism leading to PNH hemolysis has been elucidated. [5][6][7][8] PNH stem cells acquire PIGA mutations and do not generate glycosylphosphatidylinositol (GPI), resulting in a deficiency of a series of GPI-linked membrane proteins, including complement regulatory molecules such as decay-accelerating factor (DAF) and CD59. PNH cells are then vulnerable to autologous complement. For example, PNH erythrocytes undergo complement-mediated hemolysis. Soon after, the molecular events leading to clinically serious hemolytic precipitation induced by infection were clarified. 9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases. 1,12 Indeed, immunosuppressive therapy ameliorates their marrow failure. 1,12,14,15 Of interest, combination therapy with antithymocyte globulin and cyclosporine A, these immunosuppressants having individual target spectra, 16,17 gives better results than therapy with each 1 of the 2 immunosuppressants. 12,18 In general, both cytotoxic T lymphocytes (CTLs) of adaptive immunity and natural killer (NK) cells of innate immunity operate in combination rather than independently. [19][20][21][22] It is then conceivable that both cytotoxic cells exert critical roles in BM injury, 12,[23][24][25][26] although real features of the autoimmunity have not been delineated.The marked progress in understanding of PNH pathophysiology evokes the next concern about the etiology of PNH, and the mechanisms of both selective expansion of PNH clones 27 and development of leukemia. 28 Above all, we have focused on the expansion of affected cells to mani...

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Section: Discussionmentioning

confidence: 99%

“…Proportions of PNH granulocytes in lanes 4 to 7 were 35%, 15%, 1%, and 100%, respectively. Both lack of membrane ULBPs and up-regulation of ULBP2 mRNA in lanes 5 and 7 may be explained by inhibition of their display on the membrane (so-called masking) 58 and the absence of GPI ϩ granulocytes (patient no. 6 in Table 1), respectively.…”

mentioning

confidence: 99%

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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“…The endogenous ligands for human NKG2D are MHC class I chain-related proteins (MIC)A and MICB and another family of class I-related molecules, the UL16-binding proteins (ULBP)1-3. Some NKG2D ligands are up-regulated in cells infected with CMV (47,48), but the signals regulating the expression of MIC and ULBP in the context of other viral infections have yet to be defined.…”

Section: Nkp46 and Nkg2d Recognition Of Infected Dendritic Cells Is Nmentioning

confidence: 99%

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Draghi

Pashine

Sanjanwala

et al. 2007

The Journal of Immunology

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At an early phase of viral infection, contact and cooperation between dendritic cells (DCs) and NK cells activates innate immunity, and also influences recruitment, when needed, of adaptive immunity. Influenza, an adaptable fast-evolving virus, annually causes acute, widespread infections that challenge the innate and adaptive immunity of humanity. In this study, we dissect and define the molecular mechanisms by which influenza-infected, human DCs activate resting, autologous NK cells. Three events in NK cell activation showed different requirements for soluble mediators made by infected DCs and for signals arising from contact with infected DCs. IFN-α was mainly responsible for enhanced NK cytolysis and also important for CD69 up-regulation, whereas IL-12 was necessary for enhancing IFN-γ production. Increased CD69 expression and IFN-γ production, but not increased cytolysis, required recognition of influenza-infected DCs by two NK cell receptors: NKG2D and NKp46. Abs specific for these receptors or their known ligands (UL16-binding proteins 1–3 class I-like molecules for NKG2D and influenza hemagglutinin for NKp46) inhibited CD69 expression and IFN-γ production. Activation of NK cells by influenza-infected DCs and polyinosinic:polycytidylic acid (poly(I:C))-treated DCs was distinguished. Poly(I:C)-treated DCs did not express the UL16-binding protein 3 ligand for NKG2D, and in the absence of the influenza hemagglutinin there was no involvement of NKp46.

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“…Blocking this interaction would therefore be of obvious benefit to the virus as emphasized by the demonstration that deletion of miR-UL112-1 led to an increased susceptibility to NK killing. Interestingly, HCMV also encodes a protein, UL16, which was previously shown to inhibit MICB signaling by intracellular sequestration, suggesting a level of redundancy in targeting of MICB (Dunn et al, 2003).…”

Section: Functional Role Of Hcmv Mirnasmentioning

confidence: 99%

Identification and function of human cytomegalovirus microRNAs

Grey¹,

Nelson²

2008

Journal of Clinical Virology

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AbstractmicroRNAs are an extensive class of non-coding genes that regulate gene expression through posttranscriptional repression. These small RNAs are evolutionarily conserved and are likely to be a basic mechanism of gene regulation present within most eukaryotic organisms. Over 100 viral miRNAs have been identified to date through a combination of bioinformatics and cloning studies. In this review we discuss the use of bioinformatics for the identification of HCMV miRNAs and also for the discovery of potential target transcripts. Such studies will enable us to define the functional role of viral miRNAs and gain a better understanding of viral gene regulation.

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Human Cytomegalovirus Glycoprotein UL16 Causes Intracellular Sequestration of NKG2D Ligands, Protecting Against Natural Killer Cell Cytotoxicity

Cited by 250 publications

References 58 publications

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Identification and function of human cytomegalovirus microRNAs

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