scholarly journals Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ceri A Fielding ◽  
Michael P Weekes ◽  
Luis V Nobre ◽  
Eva Ruckova ◽  
Gavin S Wilkie ◽  
...  
Keyword(s):  
Cell Surface ◽  
Natural Killer ◽  
Immune Regulation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Gene Expansion ◽  
Proteomics Approach

The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation.

scholarly journals Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1309-1317 ◽  
Author(s):  
Jumei Shi ◽  
Guido J. Tricot ◽  
Tarun K. Garg ◽  
Priyangi A. Malaviarachchi ◽  
Susann M. Szmania ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Significant Activity

AbstractHuman leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell–mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell–mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m2 bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell–mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell–sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

Impact of β2 integrin deficiency on mouse natural killer cell development and function

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2874-2882 ◽  
Author(s):  
Karine Crozat ◽  
Céline Eidenschenk ◽  
Baptiste N. Jaeger ◽  
Philippe Krebs ◽  
Sophie Guia ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Maturation ◽  
Cell Surface Expression ◽  
Mcmv Infection ◽  
Β2 Integrin

Abstract Natural killer (NK) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A → T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that β2 integrin–deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit+ cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, β2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses.

scholarly journals Cytomegalovirus m154 Hinders CD48 Cell-Surface Expression and Promotes Viral Escape from Host Natural Killer Cell Control

2014 ◽  
Vol 10 (3) ◽  
pp. e1004000 ◽  
Author(s):  
Angela Zarama ◽  
Natàlia Pérez-Carmona ◽  
Domènec Farré ◽  
Adriana Tomic ◽  
Eva Maria Borst ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Cell Surface ◽  
Natural Killer ◽  
Killer Cell ◽  
Surface Expression ◽  
Viral Escape ◽  
Cell Surface Expression ◽  
Cell Control

scholarly journals Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112

2010 ◽  
Vol 91 (8) ◽  
pp. 2034-2039 ◽  
Author(s):  
Virginie Prod'homme ◽  
Daniel M. Sugrue ◽  
Richard J. Stanton ◽  
Akio Nomoto ◽  
James Davies ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Cell Surface ◽  
Natural Killer ◽  
Human Cytomegalovirus ◽  
Killer Cell ◽  
Surface Expression ◽  
Productive Infection ◽  
Cell Surface Expression ◽  
Poliovirus Receptor ◽  
Activating Receptor

Human cytomegalovirus (HCMV) UL141 induces protection against natural killer cell-mediated cytolysis by downregulating cell surface expression of CD155 (nectin-like molecule 5; poliovirus receptor), a ligand for the activating receptor DNAM-1 (CD226). However, DNAM-1 is also recognized to bind a second ligand, CD112 (nectin-2). We now show that HCMV targets CD112 for proteasome-mediated degradation by 48 h post-infection, thus removing both activating ligands for DNAM-1 from the cell surface during productive infection. Significantly, cell surface expression of both CD112 and CD155 was restored when UL141 was deleted from the HCMV genome. While gpUL141 alone is sufficient to mediate retention of CD155 in the endoplasmic reticulum, UL141 requires assistance from additional HCMV-encoded functions to suppress expression of CD112.

Natural killer cell evasion by an E3 ubiquitin ligase from Kaposi's sarcoma-associated herpesvirus

2008 ◽  
Vol 36 (3) ◽  
pp. 459-463 ◽  
Author(s):  
Mair Thomas ◽  
Mark Wills ◽  
Paul J. Lehner
Keyword(s):  
Cell Surface ◽  
Natural Killer ◽  
Kaposi's Sarcoma ◽  
Nk Cell ◽  
Cytoplasmic Tail ◽  
Kaposi’S Sarcoma ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Lysine Residues ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Viruses exploit the ubiquitin system by targeting cell-surface receptors recognized by immune cells for internalization, thereby evading recognition. We have characterized the KSHV (Kaposi's sarcoma-associated herpesvirus)-encoded E3 ubiquitin ligases, K3 and K5. We find their activities not only prevent recognition by cytotoxic T-lymphocytes, but also promote evasion of NK (natural killer) cells. NK cells recognize and lyse virus-infected cells expressing ligands for activatory receptors such as NKG2D (NK group 2D). K5 down-regulates cell-surface expression of the NKG2D ligands MICA/B (MHC class I-related chains A and B) by ubiquitination of MIC cytoplasmic tail lysine residues. Ubiquitination results in redistribution of MICA from the plasma membrane to an intracellular compartment, but does not result in an increased rate of degradation. Furthermore, K5 down-regulates cell-surface expression of another NK cell activatory receptor ligand, AICL (activation-induced C-type lectin). This activity requires the K5 RING (really interesting new gene)-CH domain and AICL cytoplasmic tail lysine residues. MICA and AICL down-regulation by K5 reduces NK cell-mediated cytotoxicity towards target cells, thus providing KSHV with an NK cell evasion mechanism.

scholarly journals NKG2A Complexed with CD94 Defines a Novel Inhibitory Natural Killer Cell Receptor

1997 ◽  
Vol 185 (4) ◽  
pp. 795-800 ◽  
Author(s):  
Andrew G. Brooks ◽  
Phillip E. Posch ◽  
Christopher J. Scorzelli ◽  
Francisco Borrego ◽  
John E. Coligan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Protein S ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Cell Clones

CD94 is a C-type lectin expressed by natural killer (NK) cells and a subset of T cells. Blocking studies using anti-CD94 mAbs have suggested that it is a receptor for human leukocyte antigen class I molecules. CD94 has recently been shown to be a 26-kD protein covalently associated with an unidentified 43-kD protein(s). This report shows that NKG2A, a 43-kD protein, is covalently associated with CD94 on the surface of NK cells. Cell surface expression of NKG2A is dependent on the association with CD94 as glycosylation patterns characteristic of mature proteins are found only in NKG2A that is associated with CD94. Analysis of NK cell clones showed that NKG2A was expressed in all NK cell clones whose CD16-dependent killing was inhibited by cross-linking CD94. The induction of an inhibitory signal is consistent with the presence of two immunoreceptor tyrosine-based inhibitory motifs (V/LXYXXL) on the cytoplasmic domain of NKG2A. Similar motifs are found on Ly49 and killer cell inhibitory receptors, which also transmit negative signals to NK cells.

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