The Experts below are selected from a list of 783 Experts worldwide ranked by ideXlab platform
David Cosman - One of the best experts on this subject based on the ideXlab platform.
-
leukemias maturation of normal myelomonocytic cells but are low in acute myeloid Ligands for natural killer cell activating receptors are expressed upon
2020Co-Authors: Lucia Mori, David Cosman, Pegah Nowbakht, Mihai-constantin S. Ionescu, Andreas Rohner, Christian P. Kalberer, Gennaro De Libero, Aleksandra Wodnar-filipowicz, Emmanuel RossyAbstract:Abstract Natural killer (NK) cell-mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as yet unknown cell surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44 and NKp46 as staining reagents binding the putative cognate ligands. Analysis of ULBP1, ULBP2 and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44 and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow-derived CD34 + progenitor cells and the acquisition of cell surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from about 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors together with interferon- upregulated cell surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell-mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest upon malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.
-
NK cells lyse T regulatory cells that expand in response to an intracellular pathogen.
Journal of Immunology, 2008Co-Authors: Peter F. Barnes, David Cosman, Ankita Garg, Shiping Wu, Ramakrishna VankayalapatiAbstract:We evaluated the capacity of NK cells to influence expansion of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in response to microbial Ags, using Mycobacterium tuberculosis as a model. We previously found that Tregs expand when CD4+ cells and monocytes are exposed to M. tuberculosis. Addition of NK cells that were activated by monokines (IL-12, IL-15, and IL-18) or by exposure to M. tuberculosis-stimulated monocytes reduced Treg expansion in response to M. tuberculosis. NK cell inhibition of Treg expansion was not mediated through IFN-γ. Activated NK cells lysed expanded, but not freshly isolated Tregs. Although monokines increased NK cell expression of the activating receptors NKp46, NKG2D, 2B4, CD16, and DNAM-1, only anti-NKG2D and anti-NKp46 inhibited NK cell lysis of expanded Tregs. Of five NKG2D ligands, only UL16-binding protein 1 (ULBP1) was up-regulated on M. tuberculosis-expanded Tregs, and anti-ULBP1 inhibited NK cell lysis of expanded Tregs. M. tuberculosis-stimulated monocytes activated NK cells to lyse expanded Tregs, and this was also inhibited by anti-NKG2D and anti-ULBP1, confirming the physiological relevance of this effect. Our study identifies a potential new role for NK cells in maintaining the delicate balance between the regulatory and effector arms of the immune response.
-
down regulation of the nkg2d ligand mica by the human cytomegalovirus glycoprotein ul142
Biochemical and Biophysical Research Communications, 2006Co-Authors: Jan N Chalupny, Annie Reinweston, Stephanie Dosch, David CosmanAbstract:Abstract Human cytomegalovirus (HCMV) employs a variety of strategies to modify or evade the host immune response, and natural killer (NK) cells play a crucial role in controlling cytomegalovirus infections in mice and humans. Activation of NK cells through the receptor NKG2D/DAP10 leads to killing of NKG2D ligand-expressing cells. We have previously shown that HCMV is able to down-regulate the surface expression of some NKG2D ligands, ULBP1, ULBP2, and MICB via the viral glycoprotein UL16. Here, we show that the viral gene product UL142 is able to down-regulate another NKG2D ligand, MICA, leading to protection from NK cytotoxicity. UL142 is not able to affect surface expression of all MICA alleles, however, which may reflect selective pressure on the host to thwart viral immune evasion, further supporting an important role for the MICA–NKG2D interaction in immune surveillance.
-
Role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with an intracellular bacterium
Journal of Immunology, 2005Co-Authors: Ramakrishna Vankayalapati, David Cosman, Ankita Garg, Angel Porgador, David E. Griffith, Peter Klucar, Hassan Safi, William M. Girard, Thomas Spies, Peter F. BarnesAbstract:We studied the role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Expression of the activating receptors NKp30, NKp46, and NKG2D were enhanced on NK cells by exposure to M. tuberculosis-infected monocytes, whereas expression of DNAX accessory molecule-1 and 2B4 was not. Anti-NKG2D and anti-NKp46 inhibited NK cell lysis of M. tuberculosis-infected monocytes, but Abs to NKp30, DNAX accessory molecule-1, and 2B4 had no effect. Infection of monocytes up-regulated expression of the NKG2D ligand, UL-16 binding protein (ULBP)1, but not expression of ULBP2, ULBP3, or MHC class I-related chain A or chain B. Up-regulation of ULBP1 on infected monocytes was dependent on TLR2, and anti-ULBP1 abrogated NK cell lysis of infected monocytes. The dominant roles of NKp46, NKG2D, and ULBP1 were confirmed for NK cell lysis of M. tuberculosis-infected alveolar macrophages. We conclude that NKp46 and NKG2D are the principal receptors involved in lysis of M. tuberculosis-infected mononuclear phagocytes, and that ULBP1 on infected cells is the major ligand for NKG2D. Furthermore, TLR2 contributes to up-regulation of ULBP1 expression.
-
Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias.
Blood, 2005Co-Authors: Pegah Nowbakht, David Cosman, Mihai-constantin S. Ionescu, Andreas Rohner, Christian P. Kalberer, Emmanuel Rossy, Lucia Mori, Gennaro De Libero, Aleksandra Wodnar-filipowiczAbstract:Natural killer (NK) cell–mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow–derived CD34+ progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-γ, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell–mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.
Jan N Chalupny - One of the best experts on this subject based on the ideXlab platform.
-
proteasome regulation of ULBP1 transcription
Journal of Immunology, 2009Co-Authors: James E Butler, Jan N Chalupny, Mikel B Moore, Steven R Presnell, Hueiwei Chan, Charles T LutzAbstract:Killer lymphocytes recognize stress-activated NKG2D ligands on tumors. We examined NKG2D ligand expression in head and neck squamous cell carcinoma (HNSCC) cells and other cell lines. HNSCC cells typically expressed MHC class I chain-related gene A (MICA), MICB, UL16-binding protein (ULBP)2, and ULBP3, but they were uniformly negative for cell surface ULBP1 and ULBP4. We then studied how cancer treatments affected NKG2D ligand expression. NKG2D ligand expression was not changed by most cancer-relevant treatments. However, bortezomib and other proteasome inhibitor drugs with distinct mechanisms of action dramatically and specifically up-regulated HNSCC ULBP1 mRNA and cell surface protein. Proteasome inhibition also increased RNA for ULBP1 and other NKG2D ligands in nontransformed human keratinocytes. Proteasome inhibitor drugs increased ULBP1 transcription by acting at a site in the 522-bp ULBP1 promoter. Although the DNA damage response pathways mediated by ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) signaling had been reported to up-regulate NKG2D ligand expression, we found that ULBP1 up-regulation was not inhibited by caffeine and wortmannin, inhibitors of ATM/ATR signaling. ULBP1 expression in HNSCC cells was not increased by several ATM/ATR activating treatments, including bleomycin, cisplatin, aphidicolin, and hydroxyurea. Ionizing radiation caused ATM activation in HNSCC cells, but high-level ULBP1 expression was not induced by gamma radiation or UV radiation. Thus, ATM/ATR signaling was neither necessary nor sufficient for high-level ULBP1 expression in human HNSCC cell lines and could not account for the proteasome effect. The selective induction of ULBP1 expression by proteasome inhibitor drugs, along with variable NKG2D ligand expression by human tumor cells, indicates that NKG2D ligand genes are independently regulated.
-
down regulation of the nkg2d ligand mica by the human cytomegalovirus glycoprotein ul142
Biochemical and Biophysical Research Communications, 2006Co-Authors: Jan N Chalupny, Annie Reinweston, Stephanie Dosch, David CosmanAbstract:Abstract Human cytomegalovirus (HCMV) employs a variety of strategies to modify or evade the host immune response, and natural killer (NK) cells play a crucial role in controlling cytomegalovirus infections in mice and humans. Activation of NK cells through the receptor NKG2D/DAP10 leads to killing of NKG2D ligand-expressing cells. We have previously shown that HCMV is able to down-regulate the surface expression of some NKG2D ligands, ULBP1, ULBP2, and MICB via the viral glycoprotein UL16. Here, we show that the viral gene product UL142 is able to down-regulate another NKG2D ligand, MICA, leading to protection from NK cytotoxicity. UL142 is not able to affect surface expression of all MICA alleles, however, which may reflect selective pressure on the host to thwart viral immune evasion, further supporting an important role for the MICA–NKG2D interaction in immune surveillance.
-
ULBP1 2 3 novel mhc class i related molecules that bind to human cytomegalovirus glycoprotein ul16 activate nk cells
European Journal of Immunology, 2001Co-Authors: Marek Kubin, Jan N Chalupny, David Cosman, Jurgen Mullberg, Wilson Chin, William C Fanslow, Linda Cassiano, Annemarie C Rousseau, D Ulrich, Richard J ArmitageAbstract:New members of the extended MHC class I-like family were identified based on their ability to bind human cytomegalovirus glycoprotein UL16 and/or their mutual homology. Soluble UL16 binding prteins (ULBP) competed with each other for binding to NK cells. Treatment of human and mouse NK cells with ULBP led to increased production of cytokines/chemokines, proliferation, cytotoxic activity and up-regulation of activation-associated surface molecules. The presence of ULBP during the stimulation phase of the CTL assay caused increased cytotoxic activity. Addition of soluble recombinant UL16 protein inhibited the biological activities mediated by ULBP, suggesting the existence of a novel mechanism utilized by CMV to evade elimination by the host immune system.
-
ulbps novel mhc class i related molecules bind to cmv glycoprotein ul16 and stimulate nk cytotoxicity through the nkg2d receptor
Immunity, 2001Co-Authors: David Cosman, Claire L. Sutherland, Jurgen Mullberg, Wilson Chin, Richard J Armitage, William C Fanslow, Marek Kubin, Jan N ChalupnyAbstract:Abstract The human cytomegalovirus glycoprotein, UL16, binds to two members of a novel family of molecules, the ULBPs, and to the MHC class I homolog, MICB. The ULBPs are GPI-linked glycoproteins belonging to the extended MHC class I family but are only distantly related to MICB. The ULBP and MICB molecules are ligands for the activating receptor, NKG2D/DAP10, and this interaction is blocked by a soluble form of UL16. The ULBPs stimulate cytokine and chemokine production from NK cells, and expression of ULBPs in NK cell–resistant target cells confers susceptibility to NK cell cytotoxicity. Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus–infected cells might evade attack by the immune system.
Salem Chouaib - One of the best experts on this subject based on the ideXlab platform.
-
c myc regulates expression of nkg2d ligands ULBP1 2 3 in aml and modulates their susceptibility to nk mediated lysis
Blood, 2014Co-Authors: Arash Nanbakhsh, Cecile Pochon, Aude Mallavialle, Sophie Amsellem, Jean Bourhis, Salem ChouaibAbstract:Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of patients diagnosed with acute myeloid leukemia (AML). Despite its efficiency against AML cells, the emergence of drug resistance due to prolonged chemotherapy in most patients is still a major obstacle. Several studies have shown that drug resistance mechanisms alter the sensitivity of leukemia cells to immune system effector cells. To investigate this phenomenon, parental acute myeloid cell lines, HL-60 and KG-1, were continuously exposed to increasing doses of cytarabine in order to establish equivalent resistant cell lines, HL-60(R) and KG-1(R). Our data indicate that cytarabine-resistant cells are more susceptible to natural killer (NK)-mediated cell lysis as compared with parental cytarabine-sensitive cells. The increased susceptibility correlates with the induction of UL-16 binding proteins (ULBP) 1/2/3 and NK group 2, member D (NKG2D) ligands on target cells by a mechanism involving c-Myc induction. More importantly, chromatin immunoprecipitation assay revealed that ULBP1/3 are direct targets of c-Myc. Using drug-resistant primary AML blasts as target cells, inhibition of c-Myc resulted in decreased expression of NKG2D ligands and the subsequent impairment of NK cell lysis. This study provides for the first time, the c-Myc dependent regulation of NKG2D ligands in AML.
-
c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis.
Blood, 2014Co-Authors: Arash Nanbakhsh, Cecile Pochon, Aude Mallavialle, Sophie Amsellem, Jean Bourhis, Salem ChouaibAbstract:Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of patients diagnosed with acute myeloid leukemia (AML). Despite its efficiency against AML cells, the emergence of drug resistance due to prolonged chemotherapy in most patients is still a major obstacle. Several studies have shown that drug resistance mechanisms alter the sensitivity of leukemia cells to immune system effector cells. To investigate this phenomenon, parental acute myeloid cell lines, HL-60 and KG-1, were continuously exposed to increasing doses of cytarabine in order to establish equivalent resistant cell lines, HL-60(R) and KG-1(R). Our data indicate that cytarabine-resistant cells are more susceptible to natural killer (NK)-mediated cell lysis as compared with parental cytarabine-sensitive cells. The increased susceptibility correlates with the induction of UL-16 binding proteins (ULBP) 1/2/3 and NK group 2, member D (NKG2D) ligands on target cells by a mechanism involving c-Myc induction. More importantly, chromatin immunoprecipitation assay revealed that ULBP1/3 are direct targets of c-Myc. Using drug-resistant primary AML blasts as target cells, inhibition of c-Myc resulted in decreased expression of NKG2D ligands and the subsequent impairment of NK cell lysis. This study provides for the first time, the c-Myc dependent regulation of NKG2D ligands in AML.
Marek Kubin - One of the best experts on this subject based on the ideXlab platform.
-
major histocompatibility complex class i related chain a and ul16 binding protein expression on tumor cell lines of different histotypes analysis of tumor susceptibility to nkg2d dependent natural killer cell cytotoxicity
Cancer Research, 2002Co-Authors: Daniela Pende, David Cosman, Marek Kubin, Paola Rivera, Stefania Marcenaro, Chienchung Chang, Roberto Biassoni, Romana Conte, Soldano Ferrone, Lorenzo MorettaAbstract:NKG2D, together with NKp46 and NKp30, represents a major triggering receptor involved in the induction of cytotoxicity by both resting and activated human natural killer cells. In this study, we analyzed the expression and the functional relevance of MHC class I-related chain A (MICA) and UL16 binding protein (ULBP), the major cellular ligands for human NKG2D, in human tumor cell lines of different histological origin. We show that MICA and ULBP are frequently coexpressed by carcinoma cell lines, whereas MICA is expressed more frequently than ULBP by melanoma cell lines. Interestingly, the MICA − ULBP + phenotype was detected in most T cell leukemia cell lines, whereas the MICA − ULBP − phenotype characterized all acute myeloid leukemia and most B-cell lymphoma cell lines analyzed. These results, together with functional experiments, based on monoclonal antibody-mediated blocking of either NKG2D or its ligands, showed that killing of certain MICA − cell tumors is at least in part NKG2D dependent. Indeed, leukemic T cells as well as certain B-cell lymphomas were killed in a NKG2D-dependent fashion upon recognition of ULBP molecules. Moreover, ULBP could induce NKG2D-mediated NK cell triggering also in tumors coexpressing MICA. Our data suggest that the involvement of NKG2D in natural killer cell-mediated cytotoxicity strictly correlates with the expression and the surface density of MICA and ULBP on target cell tumors of different histotypes.
-
ULBP1 2 3 novel mhc class i related molecules that bind to human cytomegalovirus glycoprotein ul16 activate nk cells
European Journal of Immunology, 2001Co-Authors: Marek Kubin, Jan N Chalupny, David Cosman, Jurgen Mullberg, Wilson Chin, William C Fanslow, Linda Cassiano, Annemarie C Rousseau, D Ulrich, Richard J ArmitageAbstract:New members of the extended MHC class I-like family were identified based on their ability to bind human cytomegalovirus glycoprotein UL16 and/or their mutual homology. Soluble UL16 binding prteins (ULBP) competed with each other for binding to NK cells. Treatment of human and mouse NK cells with ULBP led to increased production of cytokines/chemokines, proliferation, cytotoxic activity and up-regulation of activation-associated surface molecules. The presence of ULBP during the stimulation phase of the CTL assay caused increased cytotoxic activity. Addition of soluble recombinant UL16 protein inhibited the biological activities mediated by ULBP, suggesting the existence of a novel mechanism utilized by CMV to evade elimination by the host immune system.
-
ulbps novel mhc class i related molecules bind to cmv glycoprotein ul16 and stimulate nk cytotoxicity through the nkg2d receptor
Immunity, 2001Co-Authors: David Cosman, Claire L. Sutherland, Jurgen Mullberg, Wilson Chin, Richard J Armitage, William C Fanslow, Marek Kubin, Jan N ChalupnyAbstract:Abstract The human cytomegalovirus glycoprotein, UL16, binds to two members of a novel family of molecules, the ULBPs, and to the MHC class I homolog, MICB. The ULBPs are GPI-linked glycoproteins belonging to the extended MHC class I family but are only distantly related to MICB. The ULBP and MICB molecules are ligands for the activating receptor, NKG2D/DAP10, and this interaction is blocked by a soluble form of UL16. The ULBPs stimulate cytokine and chemokine production from NK cells, and expression of ULBPs in NK cell–resistant target cells confers susceptibility to NK cell cytotoxicity. Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus–infected cells might evade attack by the immune system.
Jean Bourhis - One of the best experts on this subject based on the ideXlab platform.
-
c myc regulates expression of nkg2d ligands ULBP1 2 3 in aml and modulates their susceptibility to nk mediated lysis
Blood, 2014Co-Authors: Arash Nanbakhsh, Cecile Pochon, Aude Mallavialle, Sophie Amsellem, Jean Bourhis, Salem ChouaibAbstract:Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of patients diagnosed with acute myeloid leukemia (AML). Despite its efficiency against AML cells, the emergence of drug resistance due to prolonged chemotherapy in most patients is still a major obstacle. Several studies have shown that drug resistance mechanisms alter the sensitivity of leukemia cells to immune system effector cells. To investigate this phenomenon, parental acute myeloid cell lines, HL-60 and KG-1, were continuously exposed to increasing doses of cytarabine in order to establish equivalent resistant cell lines, HL-60(R) and KG-1(R). Our data indicate that cytarabine-resistant cells are more susceptible to natural killer (NK)-mediated cell lysis as compared with parental cytarabine-sensitive cells. The increased susceptibility correlates with the induction of UL-16 binding proteins (ULBP) 1/2/3 and NK group 2, member D (NKG2D) ligands on target cells by a mechanism involving c-Myc induction. More importantly, chromatin immunoprecipitation assay revealed that ULBP1/3 are direct targets of c-Myc. Using drug-resistant primary AML blasts as target cells, inhibition of c-Myc resulted in decreased expression of NKG2D ligands and the subsequent impairment of NK cell lysis. This study provides for the first time, the c-Myc dependent regulation of NKG2D ligands in AML.
-
c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis.
Blood, 2014Co-Authors: Arash Nanbakhsh, Cecile Pochon, Aude Mallavialle, Sophie Amsellem, Jean Bourhis, Salem ChouaibAbstract:Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of patients diagnosed with acute myeloid leukemia (AML). Despite its efficiency against AML cells, the emergence of drug resistance due to prolonged chemotherapy in most patients is still a major obstacle. Several studies have shown that drug resistance mechanisms alter the sensitivity of leukemia cells to immune system effector cells. To investigate this phenomenon, parental acute myeloid cell lines, HL-60 and KG-1, were continuously exposed to increasing doses of cytarabine in order to establish equivalent resistant cell lines, HL-60(R) and KG-1(R). Our data indicate that cytarabine-resistant cells are more susceptible to natural killer (NK)-mediated cell lysis as compared with parental cytarabine-sensitive cells. The increased susceptibility correlates with the induction of UL-16 binding proteins (ULBP) 1/2/3 and NK group 2, member D (NKG2D) ligands on target cells by a mechanism involving c-Myc induction. More importantly, chromatin immunoprecipitation assay revealed that ULBP1/3 are direct targets of c-Myc. Using drug-resistant primary AML blasts as target cells, inhibition of c-Myc resulted in decreased expression of NKG2D ligands and the subsequent impairment of NK cell lysis. This study provides for the first time, the c-Myc dependent regulation of NKG2D ligands in AML.
