Intracellular Retention of the MHC Class I-Related Chain B Ligand of NKG2D by the Human Cytomegalovirus UL16 Glycoprotein

Wu, Jennifer D.; Chalupny, N. Jan; Manley, Thomas; Riddell, Stanley R.; Cosman, David; Spies, Thomas A.

doi:10.4049/jimmunol.170.8.4196

Cited by 125 publications

(93 citation statements)

References 20 publications

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“…tivity of NKG2D ligand recognition is important in several biological settings, such as immune evasion by viral pathogens and tumor cells. Immune responses mediated by NK cells and CD8 T cells are important in the control of cytomegalovirus (CMV), and human and murine CMV encode viral proteins (UL16 for human CMV and gp40 for murine CMV) that retain NKG2D ligands in intracellular compartments and thus impair antiviral NK cell and CD8 T cell responses (35)(36)(37)(38). Recognition of tumor cells that express NKG2D ligands can be impaired by tumor-derived soluble MICA, which reduces NKG2D surface expression on tumor-infiltrating and circulating T cells (19,39).…”

Section: Discussionmentioning

confidence: 99%

The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure

Garrity

Call

Feng

et al. 2005

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

175

152

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The activating NKG2D receptor plays a critical role in innate and adaptive immune responses by natural killer cells and subpopulations of T cells. The human receptor assembles with the DAP10 signaling dimer, and it is thought that one NKG2D homodimer pairs with a single DAP10 dimer by formation of two salt bridges between charged transmembrane (TM) residues. However, direct stoichiometry measurements demonstrated that one NKG2D homodimer assembles with four DAP10 chains. Selective mutation of one of the basic TM residues of NKG2D resulted in loss of two DAP10 chains, indicating that each TM arginine serves as an interaction site for a DAP10 dimer. Assembly of the hexameric structure was cooperative because this mutation also significantly reduced NKG2D dimerization. A monomeric NKG2D TM peptide was sufficient for assembly with a DAP10 dimer, indicating that the interaction between these proteins occurs in the membrane environment. Formation of a three-helix interface among the TM domains involved ionizable residues from all three chains, the TM arginine of NKG2D and both TM aspartic acids of the DAP10 dimer. The organization of the TM domains thus shows similarities to the T cell antigen receptor-CD3 complex, in particular to the six-chain assembly intermediate between T cell antigen receptor and the CD3␦ and CD3␥ dimers. Binding of a single ligand can thus result in phosphorylation of four DAP10 chains, which may be relevant for the sensitivity of NKG2D receptor signaling, in particular in situations of low ligand density.natural killer cells ͉ stoichiometry ͉ membrane biochemistry T he NKG2D receptor recognizes a group of ligands that represent distant relatives of MHC class I molecules, and expression of these ligands is induced or up-regulated by infected and transformed cells (1)(2)(3)(4)(5)(6)(7)(8). In innate immune responses mediated by natural killer (NK) cells, NKG2D serves as a primary activating receptor and ligand binding triggers cytotoxicity and cytokine production. The receptor is also expressed by CD8 T cells and ␥␦ T cells and provides important costimulatory signals in T cell-mediated adaptive immune responses by amplifying T cell cytokine production and proliferation (2, 3, 9, 10). The human NKG2D ligands MICA and MICB have a domain organization similar to MHC class I molecules (␣1, ␣2, and ␣3 domains) but do not associate with ␤ 2 -microglobulin or peptide (1). The NKG2D homodimer binds in a diagonal orientation across the surface of the ␣1 and ␣2 domains, and each receptor monomer contacts one of the long ␣-helices of the ␣1-␣2 platform, reminiscent of the binding of T cell antigen receptor (TCR) ␣␤ heterodimers to MHC͞peptide complexes (11). The human NKG2D ligands UL binding proteins 1, 2, 3, and 4 and the murine ligands RAE-1␣-, H60, and murine UL binding protein-like transcript 1 lack the membrane-proximal ␣3 domain and are quite dissimilar in sequence (4, 5, 12), but NKG2D nevertheless binds in a similar diagonal orientation to the ␣1-␣2 domains of these proteins (13, 14).The NKG2D rec...

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Section: Discussionmentioning

confidence: 99%

The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure

Garrity

Call

Feng

et al. 2005

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

175

152

View full text Add to dashboard Cite

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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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181

169

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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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“…Down-regulation of NKG2DL on Ma-Mel-86b cells was dependent on the concentration of IFN-g, as shown in Figure 2c, with 20 U/ml being already sufficient to induce a clearly detectable reduction in MICA and ULBP2 expression levels. We speculated that upon IFN-g treatment NKG2DL might be sequestered to distinct cellular compartments as observed during infections [30][31][32] or retained intracellular as reported for tumors, including melanoma. 18,33 However, Western blot analysis revealed that in the presence of IFN-g, MICA and ULBP2 molecules were not retained within Ma-Mel-86b cells rather the specific cellular protein levels were decreased strongly after 48 hr of cytokine treatment (Fig.…”

Section: Nkg2dl Surface Expression On Melanoma Cells Is Decreased In mentioning

confidence: 99%

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Schwinn

Vokhminova

Sucker

et al. 2009

Intl Journal of Cancer

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NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of ab CD81 T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-c (IFN-c) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-c treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-c treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-c-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-c, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. ' 2008 Wiley-Liss, Inc.Key words: melanoma; MHC class I loss; natural killer cell; NKG2D; interferon-c Malignant melanoma is well characterized for its recognition by cytotoxic ab CD8 1 T lymphocytes (CTLs) that respond to tumorassociated peptide antigens presented in the complex with classical MHC class I surface molecules.1 Indeed, CTLs can eliminate metastatic tumors in melanoma patients, as demonstrated in different clinical trials of adoptive T cell transfer.2 The efficiency of tumor cell killing is determined by the strength of the antigen signal and co-stimulatory signals sensed by different activating receptors. Very recently, it was demonstrated that triggering of the co-stimulatory receptor NKG2D on CTLs strongly enhanced the T cells capacity to kill melanoma cells. 3Besides the importance of antigen-specific CTLs in immune surveillance of melanoma, one can assume that early detection and elimination of premalignant and malignant cutaneous melanocytes might be a major task of skin-resident innate NK cells and innate-like Vd1 gd T lymphocytes. 4 Both effectors are capable of preventing and inhibiting the growth of autologous human melanoma grafted into the skin of severe combined immunodeficient (SCID) mice.5 Interestingly, the receptor NKG2D is constitutively expressed on Vd1 gd T cells present in normal human sk...

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Intracellular Retention of the MHC Class I-Related Chain B Ligand of NKG2D by the Human Cytomegalovirus UL16 Glycoprotein

Cited by 125 publications

References 20 publications

The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure

The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure

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

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

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