Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity

Nakajima, Hideo; Cella, Marina; Bouchon, Axel; Grierson, Helen L.; Lewis, John L.; Duckett, Colin S.; Cohen, Jeffrey I.; Colonna, Marco

doi:10.1002/1521-4141(200011)30:11<3309::aid-immu3309>3.0.co;2-3

Cited by 155 publications

(113 citation statements)

References 42 publications

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“…These studies suggested a “lack of function” of 2B4 31 32. Further studies should clarify these divergent results and in particular whether they reflect a heterogeneity of the patients phenotype or other yet unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Bottino

Falco

Parolini

et al. 2001

The Journal of Experimental Medicine

290

343

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In humans, natural killer (NK) cell function is regulated by a series of receptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel member of the immunoglobulin superfamily belonging to the CD2 subfamily. NTB-A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyrosine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain–containing protein (SH2D1A) as well as with SH2 domain–containing phosphatases (SHPs). Importantly, analysis of NK cells derived from patients with X-linked lymphoproliferative disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-A can partially revert this inhibitory effect while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneously masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.

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Section: Discussionmentioning

confidence: 99%

“…A dramatically altered function of 2B4 has recently been detected in individuals affected by the X-linked lymphoproliferative disease (XLP [28, 31, 32]). XLP is a severe inherited immune deficiency, characterized by the inability to control EBV infection resulting in fulminant infectious mononucleosis or lymphoma 33 34.…”

Section: Introductionmentioning

confidence: 99%

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Bottino

Falco

Parolini

et al. 2001

The Journal of Experimental Medicine

290

343

View full text Add to dashboard Cite

show abstract

“…Moreover, in NK cells derived from these patients both CD244 and NTBA have been shown transduce abnormal inhibitory signals resulting in sharp inhibition of cytotoxicity against EBV-infected cells [1,[19][20][21]. This may contribute to the pathogenesis and to the progression of the disease since B-EBV-infected cells are characterized by high levels of expression of CD244-and NTBA-specific ligands, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in the absence of SH2D1A molecule, the interaction of CD244 and NTBA with their ligands on EBVinfected cells has been shown to transduce inhibitory signals that render XLP-NK cells unable to kill EBVinfected targets [19][20][21]. While the ligand recognized by CD244, i.e.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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NK-T-B antigen (NTBA) is a CD2 family member that functions as a coreceptor in human NK cell activation. Several receptor/ligand interactions occur between different members of this molecular family. In this study, in order to identify the natural ligand of NTBA, we produced a chimeric protein formed by the NTBA extracellular region fused with the Fc portion of human IgG1 (termed NTBA-Fc*). NTBA-Fc* specifically binds to NTBA cell transfectants but not to cells transfected with other CD2 family members including CD2, CD48, CD84, CD150, CD229, and CD244. Moreover, NTBA-Fc* also binds to NTBA + but not to NTBA -T cell lines. Enzyme-linked immunosorbent assays, plasmon resonance analysis, as well as NTBA-Fc*-mediated down-regulation of NTBA surface expression further confirmed the occurrence of NTBA/NTBA homophilic interaction. Functionally, in NK cells, NTBA-Fc* promoted a strong production of IFN-+ and TNF- § . Moreover, NTBA-transfected targets displayed increased susceptibility to NK-mediated killing as compared to untransfected cells and this effect was specifically inhibited by anti-NTBA mAb. Altogether our data indicate that NTBA is characterized by self recognition.

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“…Ligationinduced phosphorylation of 2B4 recruits intracellular proteins that include PI3K and SLAM-associated protein (SAP) 3 to its cytoplasmic domain, thus initiating a signaling cascade, substantial elements of which are unknown (6, 10 -14). Mutations of SAP, an intracellular adaptor protein containing a single Src homology SH2 domain, are associated with the fatal disorder X-linked lymphoproliferative (XLP) disease (15)(16)(17) and NK cells from XLP patients lack normal function when stimulated through 2B4 (10,12,13,18,19). Although the precise physiologic functions of SAP in NK cells remain unknown, it is thought that this protein competes with SH2 protein tyrosine phosphatases for binding to tyrosinephosphorylated 2B4 thus preventing the delivery of negative signals through 2B4 (16).…”

Section: Role For Glycogen Synthase Kinase-3 In Nk Cellmentioning

confidence: 99%

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

Aoukaty

Tan

2005

The Journal of Immunology

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NK cells from individuals with X-linked lymphoproliferative (XLP) disease exhibit functional defects when stimulated through the NK receptor, 2B4 (CD244). These defects are likely a consequence of aberrant intracellular signaling initiated by mutations of the adaptor molecule SLAM-associated protein. In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation. Lack of GSK-3 phosphorylation prevented the accumulation of the transcriptional coactivator β-catenin in the cytoplasm and its subsequent translocation to the nucleus. Potential signaling pathways leading from 2B4 stimulation to GSK-3 phosphorylation were also investigated. Ligation of 2B4 resulted in the phosphorylation of the guanine nucleotide exchange factor, Vav-1, and subsequent activation of the GTP-binding protein Rac-1 (but not Ras) and the serine-threonine kinase Raf-1 in healthy but not XLP-derived NK cells. In addition, the activity of MEK-2 (but not MEK-1) was up-regulated, and Erk1/2 was phosphorylated in normal NK cells but not those from an individual with XLP suggesting that these proteins relay SLAM-associated protein-dependent signals from 2B4. Finally, inactivation of GSK-3 using a specific inhibitor of GSK-3β increased the cytotoxicity and cytokine secretion of both healthy and XLP NK cells. These data indicate that the signaling of 2B4 in NK cells is mediated by GSK-3 and β-catenin, possibly through a signal transduction pathway that involves Vav-1, Rac-1, Raf-1, MEK-2, and Erk1/2 and that this pathway is aberrant in individuals with XLP.

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Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity

Cited by 155 publications

References 42 publications

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

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

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

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