NTB-A, a New Activating Receptor in T Cells That Regulates Autoimmune Disease

Valdez, Patricia; Wang, Hua; Seshasayee, Dhaya; Campagne, Menno van Lookeren; Gurney, Austin; Lee, Wyne P.; Grewal, Iqbal S.

doi:10.1074/jbc.m312313200

Cited by 63 publications

(68 citation statements)

References 39 publications

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“…The cytoplasmic tail of NTB-A contains three tyrosines, two of which are embedded within an ITSM (18,19). Upon phosphorylation, NTB-A is able to associate with SAP, EAT-2, SHP-1, and SHP-2 (18,19,23). The importance of SAP for NTB-A function is supported by the finding that NK cells from XLP patients cannot be activated via NTB-A and that NTB-A might even become inhibitory in the absence of SAP (18).…”

supporting

confidence: 55%

“…Previous reports that found an association of NTB-A with SAP, EAT-2, SHP-1, and SHP-2 used the yeast two-hybrid system, pervanadate treatment of NK cells, or Ab-mediated cross-linking of NTB-A on T cells (18,19,23). To investigate the receptor-proximal signaling of NTB-A in human NK cells, we first used a mAb to cross-link NTB-A on IL-2-activated human NK cells (Fig.…”

Section: Ntb-a Associates With Sap and Eat-2 Upon Phosphorylationmentioning

confidence: 99%

“…Similar to other SRR members, NTB-A represents its own ligand through homophilic binding (21)(22)(23). Engagement of NTB-A on human T cells can substitute the CD28 costimulatory pathway and induces polarization toward a Th1 phenotype (23).…”

mentioning

confidence: 99%

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Molecular Analysis of NTB-A Signaling: A Role for EAT-2 in NTB-A-Mediated Activation of Human NK Cells

Eissmann

Watzl

2006

The Journal of Immunology

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Engagement of NTB-A on human NK cells by homophilic interaction with NTB-A-expressing target cells can trigger NK cell cytotoxicity, cytokine production, and proliferation. To better understand how NTB-A can activate NK cells, we analyzed the molecular mechanisms of NTB-A signaling. We show that NTB-A is tyrosine phosphorylated in unstimulated human NK cells and associates with SLAM-associated protein (SAP) and EAT-2. This phosphorylation of NTB-A is mediated by Src family kinases and is most likely a result of the homophilic interaction of NTB-A among neighboring NK cells. Stimulation of NK cells by NTB-A-positive targets results in increased NTB-A phosphorylation. The cytoplasmic tail of NTB-A contains three tyrosines, two of which are embedded within an immunoreceptor tyrosine-based switch motif. We generated a NTB-A-negative NK cell line, in which we expressed different mutants of NTB-A. Functional studies showed that the second tyrosine is sufficient and essential for NTB-A-mediated cytotoxicity. EAT-2, but not SAP, is recruited to this second tyrosine, indicating that SAP may be dispensable for this NTB-A function. To further investigate this, we silenced SAP expression in NK cell lines. Functional analysis of these cells showed that NTB-A can mediate NK cell cytotoxicity in the absence of SAP, probably via EAT-2. In contrast, NTB-A-mediated IFN-γ production was greatly reduced in the absence of SAP, demonstrating that cytokine production and cytotoxicity are differentially dependent on SAP and possibly EAT-2.

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supporting

confidence: 55%

Section: Ntb-a Associates With Sap and Eat-2 Upon Phosphorylationmentioning

confidence: 99%

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Molecular Analysis of NTB-A Signaling: A Role for EAT-2 in NTB-A-Mediated Activation of Human NK Cells

Eissmann

Watzl

2006

The Journal of Immunology

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“…21 In accordance with these results, we observed expression of CD229 on a variety of myeloma cell lines. Members of the SLAM family of molecules other than CD229 have previously been suggested to be expressed on normal B cells [25][26][27][28][29][30][31] and SLAM family member CS-1 has also been detected on malignant plasma cells. 32 However, our findings indicate that CD229 is the SLAM family member with the highest potential for the development of myeloma-targeting therapies because: (i) CD229 showed the broadest expression of all SLAM members on myeloma cell lines and (ii) CD229 seems to have the most tumor-restricted expression of all SLAM members.…”

Section: Discussionmentioning

confidence: 99%

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

Atanackovic¹,

Panse²,

Hildebrandt³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundTo date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myelomaspecific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. Design and MethodsPotential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential. ResultsOur screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement-and cell-mediated lysis of myeloma cells. ConclusionsOur results demonstrate that the immunoreceptor CD229 is specifically over-expressed on myeloma cells including their clonogenic precursors and contributes to their malignant phenotype. Monoclonal antibodies against this protein may represent a promising diagnostic and immunotherapeutic instrument in this disease. Haematologica 2011;96(10):1512-1520. doi:10.3324/haematol.2010 Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

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“…24 Stimulation of Ly108 with an anti-Ly108 mAb has been shown to enhance Th1 cytokine release in human T cells. 25 Thus, the increased proliferation and IFNg secretion by B6.NZBc1(96-100) T cells observed following anti-CD3 cross-linking could arise from this polymorphism.…”

Section: Discussionmentioning

confidence: 99%

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Landolt-Marticorena

Lajoie

et al. 2011

Genes Immun

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Lupus susceptibility loci on chromosome 1 have an important role in the development of autoimmunity in the New Zealand Black (NZB) mouse. We have previously shown that C57BL/6 congenic mice with an introgressed homozygous NZB chromosome 1 interval extending from B35 to 106 cM develop anti-nuclear antibodies and mild glomerulonephritis. In this study, we produced subcongenic mouse strains to localize the susceptibility loci in this interval and investigate how they promote autoimmunity. Our results indicate at least four susceptibility alleles and a suppressor allele. One allele is located in the 96-100 cM region and is sufficient to breach tolerance to chromatin. Addition of a second locus in the 88-96 cM interval enhances anti-dsDNA antibody production and promotes renal disease, which together with a third susceptibility allele in the 70-88 interval results in significant mortality. We further demonstrate the presence of a suppressor locus in the 35-70 or 100-102 cM interval that abrogates these phenotypes and an additional susceptibility allele in the 102-106 cM interval that restores a milder autoimmune phenotype. Several of these loci alter T-cell function. Thus, there is substantial genetic complexity in the NZB 35-106 cM interval, with disease reflecting a balance between susceptibility and suppressor loci.

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NTB-A, a New Activating Receptor in T Cells That Regulates Autoimmune Disease

Cited by 63 publications

References 39 publications

Molecular Analysis of NTB-A Signaling: A Role for EAT-2 in NTB-A-Mediated Activation of Human NK Cells

Molecular Analysis of NTB-A Signaling: A Role for EAT-2 in NTB-A-Mediated Activation of Human NK Cells

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

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