Faculty Opinions recommendation of Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control.

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.

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

Blood ◽

10.1182/blood-2007-03-078535 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1309-1317 ◽

Cited By ~ 104

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.

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Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Blood ◽

10.1182/blood-2013-01-481705 ◽

2013 ◽

Vol 122 (3) ◽

pp. 394-404 ◽

Cited By ~ 84

Author(s):

Jessica Matta ◽

Myriam Baratin ◽

Laurent Chiche ◽

Jean-Marie Forel ◽

Céline Cognet ◽

...

Keyword(s):

Natural Killer Cell ◽

Cell Surface ◽

Killer Cell ◽

Surface Expression ◽

Cell Surface Expression ◽

Inflammatory Conditions ◽

Key Points ◽

Activating Receptor

Key Points B7-H6 transcripts, B7-H6 cell-surface expression, and sB7-H6 can be induced in inflammatory conditions in vitro and in vivo. B7-H6 is expressed on proinflammatory CD14+CD16+ monocytes in sepsis conditions and is linked to an increased mortality.

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

eLife ◽

10.7554/elife.22206 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 29

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.

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

Blood ◽

10.1182/blood-2010-10-315457 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2874-2882 ◽

Cited By ~ 18

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.

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Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells

Nature Medicine ◽

10.1038/4779 ◽

1999 ◽

Vol 5 (1) ◽

pp. 90-96 ◽

Cited By ~ 259

Author(s):

G. Bossi ◽

G.M. Griffiths

Keyword(s):

T Cells ◽

Natural Killer Cells ◽

Cell Surface ◽

Natural Killer ◽

Fas Ligand ◽

Surface Expression ◽

Cell Surface Expression ◽

Killer Cells

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Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype.

Journal of Experimental Medicine ◽

10.1084/jem.183.4.1817 ◽

1996 ◽

Vol 183 (4) ◽

pp. 1817-1827 ◽

Cited By ~ 116

Author(s):

J E Gumperz ◽

N M Valiante ◽

P Parham ◽

L L Lanier ◽

D Tyan

Keyword(s):

T Cells ◽

Cell Surface ◽

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Peripheral Blood Lymphocytes ◽

Class I ◽

Cell Surface Expression ◽

Target Cells ◽

Hla Type

Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population of NKB1+ cells, but some had two populations expressing different cell surface levels of NKB1, and others had no detectable NKB1+ cells. Among the donors expressing NKB1, both the relative abundance of NKB1+ NK cells and their level of cell surface expression varied substantially. The percentage of NKB1+ NK cells ranged from 0 to >75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage of T cells expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4+ HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogeneous, but not correlated with HLA type.

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