RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity

Cao, Wei; Xi, Xueyan; Zhang, Hao; Li, Wenjing; Kong, Yan; Cui, Lianxian; Ma, Chi; Ba, Denian; Wang, He

doi:10.1074/jbc.m702504200

Cited by 68 publications

(53 citation statements)

References 41 publications

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“…In gastrointestinal tumors, but not always in breast and lung cancers, NKG2D-L levels are systematically increased compared with adjacent normal tissues (31). We showed that NKG2D-L is involved in most tumor cell lines killing, but we and others also showed that soluble MICA/B is a major mechanism inhibiting NK cells activation against tumor cells (32,33). sMICA expression is even considered as a poor prognosis factor in breast cancer (34).…”

Section: Discussionmentioning

confidence: 99%

Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition

et al. 2011

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Breast cancer is the leading cause of death for women between the ages of 35 to 65. This is mostly due to intertumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced antitumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibilities to natural killer (NK) cells' antitumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK cell ligand expression. We found that despite heterogeneous levels of inhibitory HLA members, NKG2D ligands and DNAM ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK cell functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study shows that breast cancer cells, independent of the subtype, have developed different mechanisms to escape from NK cells' antitumor immunity. These results emphasize the role of NK cells in breast tumor clearance and underlie the importance of devising future therapy aiming at enhancing NK cell-mediated recognition in parallel with the prevention of the tumor-editing process.

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Section: Discussionmentioning

confidence: 99%

Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition

et al. 2011

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“…Furthermore, soluble forms of ULBP2 and ULBP4 (also named as RAET1E2 or LETAL (lymphocyte effector cell toxicity activating ligand)) have been described (Salih et al, 2006;Waldhauer and Steinle, 2006;Cao et al, 2007). However, engagement of the NKG2D receptor by soluble ligands does not necessarily lead to the downregulation of cell surface expression of NKG2D .…”

Section: Nkg2d In Antitumor Responsesmentioning

confidence: 99%

NKG2D ligands in tumor immunity

2008

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The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, cd þ and CD8 þ T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed.

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“…UL-16 binding protein (ULBP) is a novel ligand for NKG2D receptor in humans (15). We found that RAET1E2, a soluble isoform of the UL16-binding protein RAET1E produced by tumor cells, inhibits NKG2D-mediated NK cytotoxicity (16). Because of the sequence and structure similarity of the extracellular domains between MICA and ULBPs, ULBPs are also considered as antigens for V␦1 ␥␦T cells (17).…”

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confidence: 99%

Identification of Human T Cell Receptor γδ-recognized Epitopes/Proteins via CDR3δ Peptide-based Immunobiochemical Strategy

Chen¹,

He²,

Wang

et al. 2008

Journal of Biological Chemistry

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Human T lymphocytes, bearing T cell receptor (TCR) ␥␦, play an important role in anti-tumor/microbe immune responses. However, few tumor antigens recognized by TCR␥␦ have been defined so far. To investigate antigenic epitopes/proteins recognized by ␥␦T cells, we have established a new immunobiochemical strategy that uses complementarity-determining region 3 of TCR ␦ chain (CDR3␦) peptide-mediated epitope/protein-binding assays. CDR3␦ peptides synthesized using the CDR3 region in TCR V␦2 chain were validated for their binding specificity to target cells or tissues. These CDR3␦ peptides were then employed as probes to pan putative epitopes in a 12-mer random peptide phage-displayed library and to identify putative protein ligands within tumor protein extracts by affinity chromatography and liquid chromatography/electrospray ionizationtandem mass spectrometry analysis. As a result, we have identified nine peptides and two proteins for TCR␥␦, including human mutS homolog 2 (hMSH2) and heat shock protein (HSP) 60. All nine tested epitope peptides not only bind to ␥␦T cells but also functionally activate ␥␦T cells in vitro. Identification of HSP60 confirms the validity of this method as HSP60 is an identified ligand for TCR␥␦. We show that hMSH2 is expressed on the surface of SKOV3 tumor cells, and cytotoxicity of V␦2 ␥␦T cells to SKOV3 cells was blocked by anti-hMSH2 antibody, suggesting that hMSH2 may be a new ligand for TCR␥␦. Taken together, our findings provide a novel immunobiochemical strategy to identify epitopes/proteins recognized by ␥␦T cells. T lymphocytes are classified structurally into two types according to different T cell receptors (TCR)3 ␣␤ or ␥␦. TCR␣␤ specifically recognize antigenic peptides (epitopes) presented by MHC I/II molecules. Although many peptide ligands have been identified for TCR␣␤ (1), only a few ligands have been identified for TCR␥␦ so far (2, 3).Human ␥␦T cells account for ϳ5% of CD3 ϩ T cells in the peripheral blood, but constitute a major T cell subset in other anatomic locations, such as the intestine. In the peripheral blood of healthy individuals, TCR V␦2 chain pairing with one particular V␥9 chain is expressed on 50 -90% of the ␥␦T cells, whereas intestinal intraepithelial ␥␦T cells frequently express the V␦1 gene, which can associate with different V␥ elements (4). The antigen-binding site of TCR␥␦ is formed primarily from three complementarity-determining regions (CDRs) contributed by each V␥ and V␦ domain. CDR1 and CDR2 fragments are encoded by germ line V genes, whereas the CDR3 is formed by somatic rearrangement of V(D) and J fragments. Sequence diversity in antigen receptors is not evenly distributed among all six CDRs but is highly concentrated in one or two CDR3. It had been proposed that the principal antigen specificity of an immunoglobulin or TCR is derived from its most diverse CDR3 fragments (5).In addition to TCR diversity, structures of the TCR-CD3 complex, and tissue distribution, the pattern of antigenic recognition is another key difference between ␥␦T cel...

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RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity

Cited by 68 publications

References 41 publications

Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition

Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition

NKG2D ligands in tumor immunity

Identification of Human T Cell Receptor γδ-recognized Epitopes/Proteins via CDR3δ Peptide-based Immunobiochemical Strategy

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