Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator

Broeck, Tina Van Den; Stevenaert, Frederick; Taveirne, Sylvie; Debacker, Veronique; Vangestel, Christel; Vandekerckhove, Bart; Taghon, Tom; Matthys, Patrick; Plum, Jean; Held, Werner; Dewerchin, Mieke; Yokoyama, Wayne M.; Leclercq, Georges

doi:10.1182/blood-2008-06-164350

Cited by 19 publications

(29 citation statements)

References 29 publications

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“…Similarly, the finding that Ly49E bgeo/bgeo and WT LAK cells showed essentially identical killing of YAC or J774 tumor targets indicates that these cells also lack Ly49E ligands or that Ly49E receptors expressed on WT cells fail to deliver measurable signals under the assay conditions used. J774 is of particular relevance because it was recently reported to express a ligand, identified as uPA, that can deliver inhibitory signals via Ly49E (18). We attempted to determine whether Ly49E bgeo/bgeo fetal NK cells would be resistant to uPA-mediated inhibition of anti-NK1.1-induced IFN-g production, as reported for WT fetal NK cells (18).…”

Section: Discussionmentioning

confidence: 95%

“…Brooks, unpublished observations) and is also present on a substantial proportion of adult thymic NKT cells (defined in this article as NK1.1 + CD3 + cells) (14). Fifth, all attempts to demonstrate interaction with MHC class I molecules have failed (15)(16)(17), and recently it has been suggested that its ligand is a serum protease, urokinase plasminogen activator (uPA) (18).…”

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confidence: 94%

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Mice Lacking Ly49E Show Normal NK Cell Development and Provide Evidence for Probabilistic Expression of Ly49E in NK Cells and T Cells

Aust

Gays

Hussain

et al. 2011

The Journal of Immunology

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Ly49E is an unusual member of the Ly49 family that is expressed on fetal NK cells, epithelial T cells, and NKT cells, but not on resting adult NK cells. Ly49Ebgeo/bgeo mice in which the Ly49E gene was disrupted by inserting a β-geo transgene were healthy, fertile, and had normal numbers of NK and T cells in all organs examined. Their NK cells displayed normal expression of Ly49 and other NK cell receptors, killed tumor and MHC class I-deficient cells efficiently, and produced normal levels of IFN-γ. In heterozygous Ly49E+/bgeo mice, the proportion of epidermal T cells, NKT cells, and IL-2–activated NK cells that expressed Ly49E was about half that found in wild-type mice. Surprisingly, although splenic T cells rarely expressed Ly49E, IL-2–activated splenic T cells from Ly49Ebgeo/bgeo mice were as resistant to growth in G418 as NK cells and expressed similar levels of β-geo transcripts, suggesting that disruption of the Ly49E locus had increased its expression in these cells to the same level as that in NK cells. Importantly, however, the proportion of G418-resistant heterozygous Ly49E+/bgeo cells that expressed Ly49E from the wild-type allele was similar to that observed in control cells. Collectively, these findings demonstrate that Ly49E is not required for the development or homeostasis of NK and T cell populations or for the acquisition of functional competence in NK cells and provide compelling evidence that Ly49E is expressed in a probabilistic manner in adult NK cells and T cells.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 94%

Mice Lacking Ly49E Show Normal NK Cell Development and Provide Evidence for Probabilistic Expression of Ly49E in NK Cells and T Cells

Aust

Gays

Hussain

et al. 2011

The Journal of Immunology

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“…This hypothesis adds to the list of unique characteristics of Ly49E within the Ly49 family: Ly49E 1) contains both inhibitory and activating motifs in its cytoplasmic and transmembrane region, 2) is highly conserved between different mouse strains, 3) is the only Ly49 member expressed by fetal and neonatal NK cells and by fetal thymic DETC precursors and adult skin DETCs, 4) is triggered by the non-MHC class I protein uPA, and finally 5) as we showed in the current study for intraepithelial gd T cells and as was already shown for NK cells (19), can be upregulated in several innate lymphocytic subpopulations. Combined with our previous observation that Ly49E exerts inhibitory functions through the stress-induced uPA in Ly49E pos IL-2-activated NK cell lines (20), we hypothesize that Ly49E upregulation might be a general feature of several lymphocytic populations to temper their immune response after initial activation and hence to prevent autoimmunity. Although LTb 2/2 and LTbR 2/2 mice display an impaired basal Pro2-driven Ly49E expression, these mice cannot be used to investigate the role of Ly49E upon TCRmediated activation because their Pro3-driven Ly49E expression is not impaired.…”

Section: Discussionmentioning

confidence: 99%

“…4A). The NK cell line KY, which was obtained upon long-term IL-2 culture (31) and uniformly expresses Ly49E at high levels (20), was used to validate both primer pairs. No Pro1 transcripts could be detected in either of the sorted skin-and gutresiding TCRgd + subpopulations (data not shown).…”

Section: De Novomentioning

confidence: 99%

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DifferentialLy49eExpression Pathways in Resting versus TCR-Activated Intraepithelial γδ T Cells

Broeck

Ammel

Delforche

et al. 2013

The Journal of Immunology

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The Ly49 NK receptor family in mice is composed of several members that recognize MHC class I (MHC-I) or MHC-I–related molecules. We and others have shown before that Ly49E is a unique member, with a different expression pattern on NK cells and being triggered by the non–MHC-I–related protein urokinase plasminogen activator. Among the entire Ly49 receptor family, Ly49E is the only Ly49 member expressed by epidermal-localized γδ T cells and their fetal thymic TCRγδ precursors, and it is the most abundantly expressed member on intestinal intraepithelial γδ T cell lymphocytes. In this study, we provide mechanistic insights into the regulation of Ly49e expression in γδ T cells. First, we demonstrate that TCR-mediated activation of intraepithelial γδ T cells significantly increases Ly49E expression. This results from de novo Ly49E expression and is highly selective, because no other Ly49 family members are induced. TCR-mediated Ly49E induction is a conserved feature of skin- and gut-residing intraepithelial-localized γδ T cell subsets, whereas it is not observed in spleen γδ T cells. By investigating Ly49e promoter activities and lymphotoxin (LT) αβ dependency in resting versus TCR-activated intraepithelial γδ T cells, we reveal two separate regulatory pathways for Ly49E expression, as follows: a LTαβ-dependent pathway leading to basal Ly49E expression in resting cells that is induced by Pro2-mediated Ly49e transcription, and a LTαβ-independent pathway leading to elevated, Pro3-driven Ly49E expression in TCR-stimulated cells.

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Inhibitory Ly49 Receptors on Mouse Natural Killer Cells

Orr

Lanier

2010

Current Topics in Microbiology and Immunology

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The Ly49 receptors, which are expressed in a stochastic manner on subsets of murine natural killer (NK) cells, T cells, and other cells, are encoded by the Klra gene family and include receptors with either inhibitory or activating function. All of the inhibitory Ly49 receptors are characterized by an immunoreceptor tyrosine-based inhibitory motif in their cytoplasmic domain, which upon phosphorylation recruits tyrosine or lipid phosphatases to dampen signals transmitted through other activating receptors. Most of the inhibitory Ly49 receptors recognize polymorphic epitopes on major histocompatibility complex (MHC) class I proteins as ligands. Here, we review the polymorphism, ligand specificity, and signaling capacity of the inhibitory Ly49 receptors and discuss how these molecules regulate NK cell development and function.

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Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator

Cited by 19 publications

References 29 publications

Mice Lacking Ly49E Show Normal NK Cell Development and Provide Evidence for Probabilistic Expression of Ly49E in NK Cells and T Cells

Mice Lacking Ly49E Show Normal NK Cell Development and Provide Evidence for Probabilistic Expression of Ly49E in NK Cells and T Cells

DifferentialLy49eExpression Pathways in Resting versus TCR-Activated Intraepithelial γδ T Cells

Inhibitory Ly49 Receptors on Mouse Natural Killer Cells

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