Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells

Falco, Michela; Marcenaro, Emanuela; Romeo, Elisa; Bellora, Francesca; Marras, Daniele; Vély, Frederic; Ferracci, Géraldine; Moretta, Lorenzo; Bottino, Cristina

doi:10.1002/eji.200424886

Cited by 92 publications

(77 citation statements)

References 35 publications

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“…These Ly108-positive NK cells were lost when cells were propagated and activated in vitro with IL-2. The absence of Ly108 on most mouse NK cells was surprising given that human NK cells uniformly express high levels of NTB-A, the human Ly108 equivalent (11)(12)(13)(14). Ly108 was present on all liver NK-T cells, in keeping with a recent report (27) (Fig.…”

Section: Mouse Ly108 Is Expressed On T Cells and B Cells But Not Onsupporting

confidence: 85%

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Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Zhong

Veillette

2008

Journal of Biological Chemistry

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The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice.

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Section: Mouse Ly108 Is Expressed On T Cells and B Cells But Not Onsupporting

confidence: 85%

“…Early studies showed that engagement of Ly108 was able to promote SAPdependent natural cytotoxicity by human NK cells (11)(12)(13)(14). Subsequently, it was shown that stimulation of human CD4 ϩ T cells by an anti-Ly108 monoclonal antibody (mAb) enhanced T helper 1 (T H 1) cytokine release (15).…”

mentioning

confidence: 99%

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Zhong

Veillette

2008

Journal of Biological Chemistry

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“…These cDNAs were cloned from either existing MGC clones or amplified from mixed-tissue human cDNA essentially as described (Collins et al 2004). Within this set of proteins are published negative interactions (Martin et al 2001;Kumaresan et al 2002;Falco et al 2004;Flaig et al 2004;Romero et al 2005), outlined with black circles in Figure 1D.…”

Section: Avexis Validationmentioning

confidence: 99%

Large-scale screening for novel low-affinity extracellular protein interactions

Söllner²,

et al. 2008

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Extracellular protein-protein interactions are essential for both intercellular communication and cohesion within multicellular organisms. Approximately a fifth of human genes encode membrane-tethered or secreted proteins, but they are largely absent from recent large-scale protein interaction datasets, making current interaction networks biased and incomplete. This discrepancy is due to the unsuitability of popular high-throughput methods to detect extracellular interactions because of the biochemical intractability of membrane proteins and their interactions. For example, cell surface proteins contain insoluble hydrophobic transmembrane regions, and their extracellular interactions are often highly transient, having half-lives of less than a second. To detect transient extracellular interactions on a large scale, we developed AVEXIS (avidity-based extracellular interaction screen), a high-throughput assay that overcomes these technical issues and can detect very transient interactions (halflives Յ 0.1 sec) with a low false-positive rate. We used it to systematically screen for receptor-ligand pairs within the zebrafish immunoglobulin superfamily and identified novel ligands for both well-known and orphan receptors. Genes encoding receptor-ligand pairs were often clustered phylogenetically and expressed in the same or adjacent tissues, immediately implying their involvement in similar biological processes. Using AVEXIS, we have determined the first systematic low-affinity extracellular protein interaction network, supported by independent biological data. This technique will now allow large-scale extracellular protein interaction mapping in a broad range of experimental contexts.

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“…NTB-A, another member of the SRR family, is homophilic [30,31]. The presence of NTB-A on Baf3 cells effectively induces NTB-A-mediated NK cell cytotoxicity [27,32].…”

Section: Activation-induced Down-modulation Of 2b4 Surface Expressionmentioning

confidence: 99%

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

2006

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Natural killer (NK) cell activity can be stimulated by different surface receptors. 2B4 is a member of the signaling lymphocyte activation molecule (SLAM)-related receptor family and is important for stimulating human NK cell cytotoxicity and cytokine production. Here we show that stimulation of human NK cells by antibody-mediated 2B4 cross-linking or incubation with target cells expressing the 2B4 ligand CD48 results in a strong down-modulation of 2B4 surface expression. This down-modulation is observed in NK cell lines, purified human NK cells and NK cell clones, and is accompanied by an internalization of 2B4. The modulation of 2B4 is dependent on the activity of Src-family kinases, but independent of PI3 K activity or actin polymerization. Inhibitory receptors can interfere with 2B4-mediated signals and NK cell activation. However, co-engagement of inhibitory killer cell Ig-like receptors has no influence on the down-modulation of 2B4. This suggests that the modulation of 2B4 expression is independent of inhibitory receptors. The lower surface expression of 2B4 after ligandinduced down-modulation results in reduced 2B4-mediated NK cell activation and cytotoxicity. The modulation of activating surface receptors may therefore be another mechanism for the fine-tuning of NK cell activity and may lead to the adaptation of NK cell cytotoxicity in tissues with high ligand expression. IntroductionNatural killer (NK) cells have the ability to immediately kill infected or transformed cells and are important for the control of acute viral infections [1,2]. By modulating dendritic cell functions, NK cells also play an important role in the development of protective T cell responses against intracellular pathogens and tumors [3,4]. The activity of NK cells is regulated by a balance of positive and negative signals, mediated by different surface receptors [5,6]. Human NK cell inhibitory receptors include members of the killer cell Ig-like receptors (KIR), and the CD94/NKG2A heterodimer, which recognize MHC class I molecules on target cells [7]. NK cell activation can be mediated by a variety of different receptors, which include the natural cytotoxicity receptors (NCR) NKp30, NKp44, NKp46, the activating receptors NKG2D and DNAM-1, and members of the signaling lymphocyte activation molecule (SLAM)-related receptors (SRR) 2B4 (CD244), NTB-A and CRACC (CS1, CD319) [6,8,9].Under physiological conditions the positive and negative signals are balanced, ensuring that NK cells do not attack normal cells [10]. Loss of MHC class I expression on infected or transformed cells can reduce the negative signal mediated by inhibitory NK cell receptors, thereby tilting the balance toward activation, resulting in NK cell-mediated lysis. Alternatively, upregulation of ligands for the activating NKG2D receptor can enhance the positive signal, resulting in the lysis of target cells with normal MHC class I expression [11]. The activity of NK cells is not only dictated by the expression of stimulating or inhibiting ligands on target cells. The ...

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Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells

Cited by 92 publications

References 35 publications

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Large-scale screening for novel low-affinity extracellular protein interactions

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

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