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Nkg2d ligand

Maulik Vyas, Ann-Charlott Schneider, Olga Shatnyeva, Katrin S Reiners, Samir Tawadros, Stephan Kloess, Ulrike Köhl, Michael Hallek, Hinrich P Hansen, Elke Pogge von Strandmann
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8(+) T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts...
2016: Oncoimmunology
Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Andrew R Osterburg, Rebecca L Nelson, Benyamin Z Yaniv, Rachel Foot, Walter R F Donica, Madison A Nashu, Huan Liu, Kathryn A Wikenheiser-Brokamp, Joel Moss, Nishant Gupta, Francis X McCormack, Michael T Borchers
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules...
October 6, 2016: JCI Insight
Benedetta Pignoloni, Cinzia Fionda, Valentina Dell'Oste, Anna Luganini, Marco Cippitelli, Alessandra Zingoni, Santo Landolfo, Giorgio Gribaudo, Angela Santoni, Cristina Cerboni
Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I-related chain (MIC) A/B and UL16-binding proteins (ULBP)1-6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell-mediated lysis of infected cells...
October 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Joseph G Pressey, Julia Adams, Lualhati Harkins, David Kelly, Zhiying You, Lawrence S Lamb
INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB...
September 2016: Medicine (Baltimore)
Sheila López-Cobo, Carmen Campos-Silva, Mar Valés-Gómez
Communication within the immune system depends on the release of factors that can travel and transmit information at points distant from the cell that produced them. In general, immune cells use two key strategies that can occur either at the plasma membrane or in intracellular compartments to produce such factors, vesicle release and proteolytic cleavage. Release of soluble factors in exosomes, a subset of vesicles that originate from intracellular compartments, depends generally on biochemical and lipid environment features...
2016: Frontiers in Cell and Developmental Biology
Cheol-Hun Son, Hong-Rae Lee, Eun-Kyoung Koh, Dong-Yeok Shin, Jae-Ho Bae, Kwangmo Yang, You-Soo Park
Decitabine has been found to have anti-metabolic and anti-tumor activities in various tumor cells. Recently, the use of decitabine in combination with other conventional therapies reportedly resulted in improved anti-tumor activity against various tumors. Ionizing radiation (IR) is widely used as a cancer treatment. Decitabine and IR improve immunogenicity and susceptibility of tumor cells to immune cells by up-regulating the expression of various molecules such as major histocompatibility complex (MHC) class I; natural-killer group 2, member D (NKG2D) ligands; and co-stimulatory molecules...
September 27, 2016: Scientific Reports
Rosa Molfetta, Linda Quatrini, Beatrice Zitti, Cristina Capuano, Ricciarda Galandrini, Angela Santoni, Rossella Paolini
NKG2D is an activating receptor that can bind to a large number of stress-induced ligands that are expressed in the context of cancer or viral infection. This receptor is expressed on many cytotoxic lymphocytes, and plays a crucial role in antitumor and antiviral immune responses. However, exposure to NKG2D ligand-expressing target cells promotes receptor endocytosis, ultimately leading to lysosomal receptor degradation and impairment of NKG2D-mediated functions. Interestingly, before being degraded, internalized receptors can signal from the endosomal compartment, leading to the appropriate activation of cellular functional programs...
September 22, 2016: Trends in Immunology
Yun Luan, Junli Liu, Xiaoli Liu, Xia Xue, Feng Kong, Chao Sun, Jue Wang, Ling Liu, Hongying Jia
Tetramethypyrazine (TMP), one of the active compounds extracted from the traditional Chinese medicinal herb (Chuanxiong), has been verified as an anticancer compound against several types of cancer. However, understanding of the molecular mechanisms have not been fully elucidated. In the present study, the anticancer efficacy of TMP was investigated in human clear cell renal cell carcinoma (ccRCC) cells. We showed that TMP significantly inhibited ccRCC cell viability, proliferation, apoptosis, invasion and migration through the methods of MTT, flow cytometry, wound healing and transwell assays...
October 2016: International Journal of Oncology
Takahisa Kouwaki, Yoshimi Fukushima, Takuji Daito, Takahiro Sanada, Naoki Yamamoto, Edin J Mifsud, Chean Ring Leong, Kyoko Tsukiyama-Kohara, Michinori Kohara, Misako Matsumoto, Tsukasa Seya, Hiroyuki Oshiumi
UNLABELLED: The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV infection induced hepatic interferon (IFN)-γ expression during early infection. Our in vitro study demonstrated that hepatic NK cells produced IFN-γ in response to HBV only in the presence of hepatic F4/80(+) cells...
2016: Frontiers in Immunology
Xiansheng Lin, Mei Huang, Fang Xie, Hangcheng Zhou, Ji Yang, Qiang Huang
Due to early onset of local invasion and distant metastasis, pancreatic cancer is the most lethal human malignant tumor, with a 5 year survival rate of less than 5%. As a effective chemotherapy drug for pancreatic cancer patients, gemcitabine is reported to inhibit cell proliferation as a nucleotide analog. In this study, we investigated the role of gemcitabine in immune regulation of pancreatic cancer. Our data showed that the level of soluble ULBP2 (sULBP2), a ligand of NKG2D receptor, decreased in the supernatants of pancreatic cancer cell lines when gemcitabine was added, and sULBP2 level correlated with NK92 cells cytotoxicity to pancreatic cancer cell lines...
September 1, 2016: Oncotarget
Elizabeth R Sturgill, Daniel Malouli, Scott G Hansen, Benjamin J Burwitz, Seongkyung Seo, Christine L Schneider, Jennie L Womack, Marieke C Verweij, Abigail B Ventura, Amruta Bhusari, Krystal M Jeffries, Alfred W Legasse, Michael K Axthelm, Amy W Hudson, Jonah B Sacha, Louis J Picker, Klaus Früh
The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression...
August 2016: PLoS Pathogens
Huaijian Guo, Stacey A Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E Mahl, Ning Wu, Dominique Davidson, Stephen N Waggoner, André Veillette
Signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) can mediate either activating or inhibitory effects during natural killer cell (NK cell) activation. In this study, we addressed the global role, regulation, and mechanism of action of the SLAM family in NK cells by analyzing a mouse lacking the entire ∼400-kilobase Slam locus, which encodes all six SFRs and CD48, the ligand of SFR 2B4. This mouse displayed enhanced NK cell activation responses toward hematopoietic target cells. Analyses of mice lacking individual SFRs showed that the inhibitory function of the Slam locus was due solely to 2B4 and was not influenced positively or negatively by other SFRs...
September 19, 2016: Journal of Experimental Medicine
Ana Montalban-Arques, Philipp Wurm, Slave Trajanoski, Silvia Schauer, Sabine Kienesberger, Bettina Halwachs, Christoph Högenauer, Cord Langner, Gregor Gorkiewicz
Corpus-dominant lymphocytic gastritis (LyG) is characterized by CD8(+) T-cell infiltration of the stomach epithelium by a so far uncharacterized mechanism. Although Helicobacter pylori is typically undetectable in LyG, patients respond to H. pylori antibiotic eradication therapy, suggesting a non-H. pylori microbial trigger for the disease. Comparative microbiota analysis of specimens from LyG, H. pylori gastritis and healthy controls precluded involvement of H. pylori in LyG but identified Propionibacterium acnes as a possible disease trigger...
August 19, 2016: Journal of Pathology
Dominik Schmiedel, Julie Tai, Francesca Levi-Schaffer, Sarah Dovrat, Ofer Mandelboim
: The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the less-studied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications...
November 1, 2016: Journal of Virology
Yun Guan, Weiqun Li, Zhaohua Hou, Qiuju Han, Peixiang Lan, Jian Zhang, Zhigang Tian, Cai Zhang
Decreased expression of NKG2D ligands on HBV-infected human hepatoma cells impairs NK cells lysis. However, which components of HBV exert this effect and the precise mechanisms need to be further investigated. In the present study, we observed that the HBx and HBc genes significantly down-regulated MICA expression. Through analysis with the chromatin immunoprecipitation assay, we found that HBV infection promotes the expression of transcription factors GATA-2 and GATA-3, which specifically suppressed MICA/B expression by directly binding to the promoter region of MICA/B...
August 12, 2016: Oncotarget
Qiuxia Fu, Shaoduo Yan, Licui Wang, Xiangguo Duan, Lei Wang, Yue Wang, Tao Wu, Xiaohui Wang, Jie An, Yulong Zhang, Qianqian Zhou, Linsheng Zhan
The role of hepatic NK cells in the pathogenesis of HCV-associated hepatic failure is incompletely understood. In this study, we investigated the effect of HCV on ConA-induced immunological hepatic injury and the influence of HCV on hepatic NK cell activation in the liver after ConA administration. An immunocompetent HCV mouse model that encodes the entire viral polyprotein in a liver-specific manner based on hydrodynamic injection and φC31o integrase was used to study the role of hepatic NK cells. Interestingly, the frequency of hepatic NK cells was reduced in HCV mice, whereas the levels of other intrahepatic lymphocytes remained unaltered...
August 4, 2016: Oncotarget
Xiulong Xu, Geetha Rao, Yi Li
MICA/B (the major histocompatibility antigen-related chain A and B) and Rae I are stress-inducible ligands for the immune-receptor NKG2D. Mechanisms by which genotoxic stress and DNA damage induce the expression of NKG2D ligands remain incompletely understood. Here, we report that inhibition of xanthine oxidoreductase (XOR) activity by allopurinol or inhibition of XOR expression by gene knockdown abrogated genotoxic stress-induced expression of MICA/B and Rae I in three tumor cell lines. XOR knockdown also blocked gemcitabine-mediated antitumor activity in an orthotopic syngeneic mouse model of breast cancer...
August 3, 2016: Oncotarget
Matthew S Parsons, Jonathan Richard, Wen Shi Lee, Hillary Vanderven, Michael D Grant, Andrés Finzi, Stephen J Kent
The utility of antibody-dependent cellular cytotoxicity (ADCC) for eliminating HIV-1-infected cells is of much interest for the design of both prophylactic vaccines for HIV-1 prevention and therapeutics to eliminate latently infected cells following reactivation. Significant research has been conducted to understand the antibody specificities involved in anti-HIV-1 ADCC responses. Perhaps equally important as the identity of the antibodies mediating these responses are factors regulating the ability of ADCC effector cells, in particular, natural killer (NK) cells, to respond to antibody-coated target cells...
October 2016: AIDS Research and Human Retroviruses
M Sauer, M Schuldner, N Hoffmann, A Cetintas, K S Reiners, O Shatnyeva, M Hallek, H P Hansen, S Gasser, E P von Strandmann
Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells...
August 1, 2016: Oncogene
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