71 results on '"Vincent Pitard"'
Search Results
2. ASS1 Overexpression: A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice
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Margaux Sala, Delphine Gonzales, Thierry Leste‐Lasserre, Nathalie Dugot‐Senant, Valérie Paradis, Sylvaine Di Tommaso, Jean‐William Dupuy, Vincent Pitard, Cyril Dourthe, Amedeo Sciarra, Christine Sempoux, Linda D. Ferrell, Andrew D. Clouston, Gregory Miller, Mathew M. Yeh, Swan Thung, Annette S.H. Gouw, Alberto Quaglia, Jing Han, Ji Huan, Cathy Fan, James Crawford, Yasuni Nakanuma, Kenichi Harada, Brigitte leBail, Claire Castain, Nora Frulio, Hervé Trillaud, Laurent Possenti, Jean‐Frédéric Blanc, Laurence Chiche, Christophe Laurent, Charles Balabaud, Paulette Bioulac‐Sage, Anne Aurélie Raymond, and Frédéric Saltel
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico‐pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis.
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- 2020
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3. Uncovering the Anticancer Potential of Murine Cytomegalovirus against Human Colon Cancer Cells
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Layal Massara, Camille Khairallah, Nathalie Yared, Vincent Pitard, Benoit Rousseau, Julien Izotte, Alban Giese, Pierre Dubus, Xavier Gauthereau, Julie Déchanet-Merville, and Myriam Capone
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Human cytomegalovirus (HCMV) components are often found in tumors, but the precise relationship between HCMV and cancer remains a matter of debate. Pro-tumor functions of HCMV were described in several studies, but an association between HCMV seropositivity and reduced cancer risk was also evidenced, presumably relying on recognition and killing of cancer cells by HCMV-induced lymphocytes. This study aimed at deciphering whether CMV influences cancer development in an immune-independent manner. Using immunodeficient mice, we showed that systemic infection with murine CMV (MCMV) inhibited the growth of murine carcinomas. Surprisingly, MCMV, but not HCMV, also reduced human colon carcinoma development in vivo. In vitro, both viruses infected human cancer cells. Expression of human interferon-β (IFN-β) and nuclear domain (ND10) were induced in MCMV-infected, but not in HCMV-infected human colon cancer cells. These results suggest a decreased capacity of MCMV to counteract intrinsic defenses in the human cellular host. Finally, immunodeficient mice receiving peri-tumoral MCMV therapy showed a reduction of human colon cancer cell growth, albeit no clinical sign of systemic virus dissemination was evidenced. Our study, which describes a selective advantage of MCMV over HCMV to control human colon cancer, could pave the way for the development of CMV-based therapies against cancer. Keywords: mCMV, hCMV, Anti-tumor potential, Decreased host defense, Human Colon cancer, Cross-species, Virotherapy, IFN-B
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- 2020
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4. Performance Evaluation of 5G Use Cases for Smart Factory.
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Mohammed Alfaqawi, Sylvie Baron, Vincent Pitard, Stéphane Davai, and Nathalie Banoun
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- 2022
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5. Supplementary Data from Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies
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Catherine Hoofd, Gregory Driessens, Julie Déchanet-Merville, Mark Cragg, Anne Marie-Cardine, Véronique Baron-Bodo, Mathew J. Carter, Florence Nyawouame, Joäo R. Marchante, Florence Lambolez, Reece Marillier, Margreet Brouwer, Erica Houthuys, Shruthi Prasad, Martine Bagot, Vincent Pitard, Romain Pirson, Anne-Catherine Michaux, Diane Jamart, Sofie Denies, Angela Pappalardo, Noémie Wald, Marjorie Mercier, Lucile Garnero, Virginie Rabolli, Julia Cuende, and Julie Preillon
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Supplementary material (Text)
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- 2023
6. Supp Figures from Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies
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Catherine Hoofd, Gregory Driessens, Julie Déchanet-Merville, Mark Cragg, Anne Marie-Cardine, Véronique Baron-Bodo, Mathew J. Carter, Florence Nyawouame, Joäo R. Marchante, Florence Lambolez, Reece Marillier, Margreet Brouwer, Erica Houthuys, Shruthi Prasad, Martine Bagot, Vincent Pitard, Romain Pirson, Anne-Catherine Michaux, Diane Jamart, Sofie Denies, Angela Pappalardo, Noémie Wald, Marjorie Mercier, Lucile Garnero, Virginie Rabolli, Julia Cuende, and Julie Preillon
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Supplemental figures
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- 2023
7. Supplementary Table S2 from Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
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Abdel-Majid Khatib, Serge Evrard, Geraldine Siegfried, Isabelle Soubeyran, Julie Déchanet-Merville, François Ghiringhelli, Juan Antonio Rosado, Mariane Fonck, Dominique Bechade, Vincent Pitard, Frédéric Delom, Delphine Fessart, Amandine Mouchard, Marielle Dubreuil, Yannick Leger, Jone Olaizola, José Javier López, Fabienne Soulet, Angela Pappalardo, and Mercedes Tomé
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Key resources Table
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- 2023
8. Figures S1-S4 from Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
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Abdel-Majid Khatib, Serge Evrard, Geraldine Siegfried, Isabelle Soubeyran, Julie Déchanet-Merville, François Ghiringhelli, Juan Antonio Rosado, Mariane Fonck, Dominique Bechade, Vincent Pitard, Frédéric Delom, Delphine Fessart, Amandine Mouchard, Marielle Dubreuil, Yannick Leger, Jone Olaizola, José Javier López, Fabienne Soulet, Angela Pappalardo, and Mercedes Tomé
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PCs expression in T cells and effect of PC inhibition on PD-1 expression, T cell signaling, survival and cytotoxicity.
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- 2023
9. Supplementary Materials and Methods from Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
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Abdel-Majid Khatib, Serge Evrard, Geraldine Siegfried, Isabelle Soubeyran, Julie Déchanet-Merville, François Ghiringhelli, Juan Antonio Rosado, Mariane Fonck, Dominique Bechade, Vincent Pitard, Frédéric Delom, Delphine Fessart, Amandine Mouchard, Marielle Dubreuil, Yannick Leger, Jone Olaizola, José Javier López, Fabienne Soulet, Angela Pappalardo, and Mercedes Tomé
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Detailed description of the methodology performed.
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- 2023
10. Data from Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
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Abdel-Majid Khatib, Serge Evrard, Geraldine Siegfried, Isabelle Soubeyran, Julie Déchanet-Merville, François Ghiringhelli, Juan Antonio Rosado, Mariane Fonck, Dominique Bechade, Vincent Pitard, Frédéric Delom, Delphine Fessart, Amandine Mouchard, Marielle Dubreuil, Yannick Leger, Jone Olaizola, José Javier López, Fabienne Soulet, Angela Pappalardo, and Mercedes Tomé
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Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor α1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-κB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy.Significance:Protein convertase enzymatic activity is required for PD-1 expression on T cells, and inhibition of protein convertase improves T-cell targeting of microsatellite instable and stable colorectal cancer.
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- 2023
11. Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies
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Florence Lambolez, Margreet Brouwer, Noémie Wald, Sofie Denies, Virginie Rabolli, Romain Pirson, Florence Nyawouame, Diane Jamart, Anne Marie-Cardine, Mathew J. Carter, Julie Preillon, Mark S. Cragg, Julie Déchanet-Merville, Shruthi Prasad, Erica Houthuys, Catherine Hoofd, Lucile Garnero, Vincent Pitard, Martine Bagot, Julia Cuende, Joao Marchante, Angela Pappalardo, Gregory Driessens, Marjorie Mercier, Reece Marillier, Anne-Catherine Michaux, Véronique Baron-Bodo, Marie-Cardine, Anne, iTeos Therapeutics SA [Charleroi, Belgique], Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Southampton, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
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Cytotoxicity, Immunologic ,0301 basic medicine ,Cancer Research ,Antibodies, Neoplasm ,[SDV]Life Sciences [q-bio] ,T cell ,Population ,T-Lymphocytes, Regulatory ,Lymphocyte Depletion ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,TIGIT ,Antigen ,Antigens, CD ,medicine ,Animals ,Humans ,Receptors, Immunologic ,education ,Antibody-dependent cell-mediated cytotoxicity ,Mice, Inbred BALB C ,education.field_of_study ,biology ,Receptors, IgG ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,Receptors, Antigen, T-Cell, gamma-delta ,Healthy Volunteers ,3. Good health ,[SDV] Life Sciences [q-bio] ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Immunoglobulin G ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Antibody ,CD8 - Abstract
TIGIT is an immune checkpoint inhibitor expressed by effector CD4 þ and CD8 þ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with an anti–PD(L)-1 antibody. In the current work, we demonstrate broader TIGIT expression than previously reported in healthy donors and patients with cancer with expression on gd T cells, particularly in CMV-seropositive donors, and on tumor cells from hematologic malignancies. Quantification of TIGIT density revealed tumor-infiltrating Tregs as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be wider than the previously described anti–PD(L)-1-like restoration of ab T-cell function. CD155 also mediated inhibition of gd T cells, an immune population not previously described to be sensitive to TIGIT inhibition, which could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS-448). In PBMCs from patients with cancer, as well as in tumor-infiltrating lymphocytes from mice, the higher TIGIT expression in Tregs correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, the ADCC/ADCP–enabling format of the anti-TIGIT mAb had superior antitumor activity, which was dependent upon Fcg receptor engagement. In addition, the anti-TIGIT mAb was able to induce direct killing of TIGIT-expressing tumor cells both in human patient material and in animal models, providing strong rationale for therapeutic intervention in hematologic malignancies. These findings reveal multiple therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.
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- 2021
12. Understanding human γδ T cell biology toward a better management of cytomegalovirus infection
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Vincent Pitard, Florent Guerville, Gabriel Marsères, Jean-Jacques Fournié, Julie Déchanet-Merville, Pierre Merville, Anaïs Cosentino, Hannah Kaminski, Lionel Couzi, Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,T cell ,Immunology ,Congenital cytomegalovirus infection ,Biology ,Immunocompromised Host ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,T-Lymphocyte Subsets ,Receptors ,medicine ,Humans ,Immunology and Allergy ,Receptor ,gamma-delta ,Endothelial protein C receptor ,T-cell receptor ,Hematopoietic Stem Cell Transplantation ,Receptors, Antigen, T-Cell, gamma-delta ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,T-Cell ,medicine.disease ,Phenotype ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Antigen ,Cytomegalovirus Infections ,Annexin A2 ,030215 immunology - Abstract
International audience; Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αβ and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients.
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- 2020
13. Characterization of a Unique γδ T-Cell Subset as a Specific Marker of Cytomegalovirus Infection Severity
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Coline Ménard, Pierre Merville, Vincent Pitard, Bouchra El Hayani, Isabelle Garrigue, Maxime Courant, Sonia Burrel, And-Nan Adjibabi, Hannah Kaminski, Lionel Couzi, Gabriel Marsères, Julie Déchanet-Merville, Atika Zouine, Jean-François Moreau, Jonathan Visentin, Immunology from Concept and Experiments to Translation (ImmunoConcept), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
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Male ,0301 basic medicine ,Cytomegalovirus ,Disease ,Lymphocyte Activation ,medicine.disease_cause ,Severity of Illness Index ,Cell Line ,Immunocompromised Host ,Interferon-gamma ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,T-Lymphocyte Subsets ,Receptors ,Humans ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Cause of death ,gamma-delta ,business.industry ,Effector ,virus diseases ,Receptors, Antigen, T-Cell, gamma-delta ,Fibroblasts ,Middle Aged ,T-Cell ,Kidney Transplantation ,In vitro ,3. Good health ,Transplantation ,030104 developmental biology ,Infectious Diseases ,Antigen ,Cytomegalovirus Infections ,Immunology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,business ,Biomarkers ,030215 immunology - Abstract
Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the Vγ9posVδ2pos T cells that respond to phosphoantigens but not to CMV. A third Vγ9negVδ2pos subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these Vγ9negVδ2pos T cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδ T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2pos T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T cells responded specifically to CMV-infected cells in a T-cell receptor–dependent manner and through strong interferon γ production. Finally, Vγ9negVδ2pos T cells were the only γδ T-cell subset in which expansion was tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T cells as an immune marker for CMV disease severity in immunocompromised patients.
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- 2020
14. Synaptomic analysis of dopaminergic inputs reveal hub synapses in the mouse striatum
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Etienne Herzog, Paul Lapios, Vincent Paget-Blanc, Sabrina Lacomme, Maria-Florencia Angelo, Véronique Desmedt-Peyrusse, Stéphane Claverol, Thomas Biederer, Roman Walle, David Perrais, Vincent Pitard, Melina Petrel, Marie Pronot, Fabrice P. Cordelières, Christelle Martin, Marlene E. Pfeffer, Florian Levet, Pierre Trifilieff, Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Interdisciplinary Institute for Neuroscience (IINS), Plateforme Métabolome-Fluxome du Centre de Génomique Fonctionnelle de Bordeaux, Institut National de la Recherche Agronomique (INRA), Université de Bordeaux (UB), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
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0303 health sciences ,[SDV]Life Sciences [q-bio] ,Dopaminergic ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Striatum ,Biology ,Inhibitory postsynaptic potential ,Spine apparatus ,Synapse ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Dopamine ,medicine ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Active zone ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
SUMMARYDopamine is a monoamine involved in reward processing and motor control. Volume transmission is thought to be the mechanism by which monoamines modulate effector systems at glutamate and GABA synapses. Hence, dopamine synapses are scarcely described. We applied fluorescence activated synaptosome sorting to explore the features of the dopaminergic synaptome. We provide the proteome of striatal dopaminergic synapses with 57 proteins specifically enriched. Beyond canonical markers of dopamine neurotransmission (Th, Slc6a3/DAT, Slc18a2/VMAT2), we validated 6 proteins belonging to pre- and postsynaptic sides (Cpne7, Apba1/Mint1, Cadps2, Cadm2/SynCAM 2, Stx4 and Mgll). Moreover, dopaminergic varicosities adhere to both a post-synapse with cognate receptors and glutamatergic, GABAergic or cholinergic synapses in structures we named dopaminergic “hub synapses”. Markers of presynaptic vesicles and active zone, post-synaptic density and spine apparatus, are significantly increased upon association with dopamine inputs in hubs. Thus neuromodulation frequently operates from hub synapses affecting associated synapses and is not solely dependent on volume transmission. Finally, FASS provides a new framework for the exploration of dopaminergic synapses and more generally for discrete synapse populations ex-vivo.HighlightsA first proteome of dopaminergic synapses in the striatumStriatal dopaminergic synaptosomes display post-synaptic cognate receptorsDopaminergic projections build hub synapses with excitatory, inhibitory, and cholinergic projections.Cortico-striatal synaptic scaffolds are strengthened upon association in hub synapses.
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- 2021
15. mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αβ and γδ T cells in Kidney Transplantation
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Isabelle Garrigue, Nathalie Yared, Pierre Merville, Lionel Couzi, Marie-Julie Nokin, Myriam Capone, Maria Mamani, Vincent Pitard, Raúl V. Durán, Roxane Coueron, Benoît Pinson, Xavier Gauthereau, Gabriel Marsères, Julie Déchanet-Merville, Séverine Loizon, Isabelle Pellegrin, Atika Zouine, Hannah Kaminski, Rodolphe Thiébaut, Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Transbiomed : Biologie Fondamentale et Appliquée à la Médecine, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), CHU Bordeaux [Bordeaux], Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-19-CE18-0024,TEPEE,Conjugués polymersomes-cellules T bio-inspirés et biomimétiques: un concept biohybride combinant thérapie cellulaire et vectorisation(2019), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Composantes innées de la réponse immunitaire et différenciation (CIRID), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), TBM-Core [Bordeaux] (UMS3427 - INSERM US005), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie Fondamentale et Pathogénicité (MFP), Université de Bordeaux (UB), Admin, Oskar, Conjugués polymersomes-cellules T bio-inspirés et biomimétiques: un concept biohybride combinant thérapie cellulaire et vectorisation - - TEPEE2019 - ANR-19-CE18-0024 - AAPG2019 - VALID, PINSON, Benoît, and TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005)
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Male ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Programmed Cell Death 1 Receptor ,Congenital cytomegalovirus infection ,Cell Culture Techniques ,Mycophenolic acid ,03 medical and health sciences ,0302 clinical medicine ,Leukocyte Immunoglobulin-like Receptor B1 ,Antigens, CD ,T-Lymphocyte Subsets ,CMV, CMV-specific immunity, kidney transplantation, mTOR inhibitors ,Up Front Matters ,medicine ,Cytotoxic T cell ,Humans ,Kidney transplantation ,030304 developmental biology ,Aged ,0303 health sciences ,business.industry ,TOR Serine-Threonine Kinases ,Immunity ,CMV ,General Medicine ,MTOR Inhibitors ,Middle Aged ,Mycophenolic Acid ,medicine.disease ,Phenotype ,Kidney Transplantation ,In vitro ,3. Good health ,Anti-Bacterial Agents ,[SDV] Life Sciences [q-bio] ,Transplantation ,CMV-specific immunity ,Basic Research ,Nephrology ,Immunology ,Cytomegalovirus Infections ,Biomarker (medicine) ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,business ,030215 immunology ,medicine.drug - Abstract
International audience; Background The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unexplained. Methods The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and in vitro mTORi effects on T-cell phenotype and functions were analyzed. Results In KTRs who were R+ and treated with MPA, both αβ and γδ T cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTRs with severe CMV infection, as compared with the 17 KTRs without or with spontaneously resolving CMV infection. In patients treated with mTORis ( n =27), the proportion of PD-1+ and CD85j+ αβ and γδ T cells decreased, when compared with patients treated with MPA ( n =44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic γδ T cells and IFN γ -producing and cytotoxic αβ T cells. In vitro , mTORis increased proliferation, viability, and CMV-induced IFN γ production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMES low Hobit high profile. In γδ T cells, the mTORi effect was related to increased TCR signaling. Conclusion Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment. Clinical Trial registry name and registration number: Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963
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- 2021
16. Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2
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Emilie Obre, Jean-François Moreau, Rodrigue Rossignol, Christelle Harly, Benoit Viollet, Angela Pappalardo, Vincent Pitard, Isabelle Soubeyran, Charlotte Domblides, Fiyaz Mohammed, Stéphane Claverol, Omar Hawchar, Sonia Netzer, Carla Cano, Layal Massara, Julie Déchanet-Merville, Carrie R. Willcox, Lydia Lartigue, Charlotte Mannat, S.P. Joyce, Benjamin Faustin, Isabelle Mahouche, Thomas Bachelet, Benjamin E. Willcox, Lionel Couzi, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Birmingham [Birmingham], TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Université de Bordeaux (UB), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, ImCheck Therapeutics [Marseille], Laboratoire d'immunologie et d'immunogénétique [CHU Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), Janssen Research & Development, Bernardo, Elizabeth, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Flow Cytometry Facility / TransBioMed Core [Bordeaux] (INSERM US005 - CNRS UMS 3427 - UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
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0301 basic medicine ,T cell ,CD3 ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,AMP-Activated Protein Kinases ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Neoplasms ,medicine ,Ephrin ,Animals ,Humans ,Antigens ,Intraepithelial Lymphocytes ,Tissue homeostasis ,Mice, Knockout ,Receptor, EphA2 ,T-cell receptor ,AMPK ,Antibodies, Monoclonal ,Receptors, Antigen, T-Cell, gamma-delta ,General Medicine ,EPH receptor A2 ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein - Abstract
International audience; Human γδ T cells contribute to tissue homeostasis and participate in epithelial stress surveillance through mechanisms that are not well understood. Here, we identified ephrin type-A receptor 2 (EphA2) as a stress antigen recognized by a human Vγ9Vδ1 TCR. EphA2 is recognized coordinately by ephrin A to enable γδ TCR activation. We identified a putative TCR binding site on the ligand-binding domain of EphA2 that was distinct from the ephrin A binding site. Expression of EphA2 was up-regulated upon AMP-activated protein kinase (AMPK)-dependent metabolic reprogramming of cancer cells, and coexpression of EphA2 and active AMPK in tumors was associated with higher CD3 T cell infiltration in human colorectal cancer tissue. These results highlight the potential of the human γδ TCR to cooperate with a co-receptor to recognize non-MHC-encoded proteins as signals of cellular dysregulation, potentially allowing γδ T cells to sense metabolic energy changes associated with either viral infection or cancer.
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- 2021
17. Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
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Frédéric Delom, Abdel-Majid Khatib, Jone Olaizola, Jose J. Lopez, Marielle Dubreuil, Angela Pappalardo, Amandine Mouchard, Julie Déchanet-Merville, Mariane Fonck, François Ghiringhelli, Yannick Leger, Juan A. Rosado, Serge Evrard, Fabienne Soulet, Geraldine Siegfried, Mercedes Tomé, Delphine Fessart, Isabelle Soubeyran, Vincent Pitard, Dominique Béchade, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'oncologie digestive, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Génétique tumorale - Pathologie, CHU Bordeaux [Bordeaux]-Institut Bergonié [Bordeaux], Hémostase et thrombose, Institut National de la Santé et de la Recherche Médicale (INSERM), Head of Digestive Tumours Unit and Department of Surgery, Université Bordeaux Segalen - Bordeaux 2, Laboratoire de pharmacologie expérimentale et clinique : cibles moléculaires en cancérologie ((U 716)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Colorectal cancer ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Mice, Nude ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Furin ,ComputingMilieux_MISCELLANEOUS ,Mice, Inbred BALB C ,biology ,Chemistry ,NFAT ,Immunotherapy ,medicine.disease ,3. Good health ,CTL ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Heterografts ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Proprotein Convertases ,Colorectal Neoplasms ,T-Lymphocytes, Cytotoxic - Abstract
Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor α1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-κB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy. Significance: Protein convertase enzymatic activity is required for PD-1 expression on T cells, and inhibition of protein convertase improves T-cell targeting of microsatellite instable and stable colorectal cancer.
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- 2019
18. Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the Vγ9Vδ2 TCR and Is Essential for Phosphoantigen Sensing
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Lisa Starick, Mark Jeeves, Anna Nöhren, Carrie R. Willcox, Katie A Berwick, Paul A. Bates, Brigitte Kimmel, Alina Suzann Fichtner, Fiyaz Mohammed, Timothy J. Knowles, Vincent Pitard, Thomas Herrmann, Raphael A. G. Chaleil, Mahboob Salim, Daniel Paletta, Charlotte R Begley, Volker Kunzmann, Julie Déchanet-Merville, Mohindar Murugesh Karunakaran, Benjamin E. Willcox, Angela Noll, and Lutz Walter
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0301 basic medicine ,gamma delta T cell ,butyrophilin ,T cell ,T-Lymphocytes ,Immunology ,ligand ,Germline ,Cofactor ,Article ,03 medical and health sciences ,0302 clinical medicine ,phosphoantigen ,Butyrophilin ,Antigens, CD ,medicine ,Immunology and Allergy ,Humans ,complementarity-determining region ,Surface plasmon resonance ,biology ,Butyrophilins ,Ligand ,T-cell receptor ,Receptors, Antigen, T-Cell, gamma-delta ,3. Good health ,Cell biology ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Vγ9Vδ2 ,biology.protein ,T cell receptor ,Function (biology) - Abstract
Summary Vγ9Vδ2 T cells respond in a TCR-dependent fashion to both microbial and host-derived pyrophosphate compounds (phosphoantigens, or P-Ag). Butyrophilin-3A1 (BTN3A1), a protein structurally related to the B7 family of costimulatory molecules, is necessary but insufficient for this process. We performed radiation hybrid screens to uncover direct TCR ligands and cofactors that potentiate BTN3A1’s P-Ag sensing function. These experiments identified butyrophilin-2A1 (BTN2A1) as essential to Vγ9Vδ2 T cell recognition. BTN2A1 synergised with BTN3A1 in sensitizing P-Ag-exposed cells for Vγ9Vδ2 TCR-mediated responses. Surface plasmon resonance experiments established Vγ9Vδ2 TCRs used germline-encoded Vγ9 regions to directly bind the BTN2A1 CFG-IgV domain surface. Notably, somatically recombined CDR3 loops implicated in P-Ag recognition were uninvolved. Immunoprecipitations demonstrated close cell-surface BTN2A1-BTN3A1 association independent of P-Ag stimulation. Thus, BTN2A1 is a BTN3A1-linked co-factor critical to Vγ9Vδ2 TCR recognition. Furthermore, these results suggest a composite-ligand model of P-Ag sensing wherein the Vγ9Vδ2 TCR directly interacts with both BTN2A1 and an additional ligand recognized in a CDR3-dependent manner., Graphical Abstract, Highlights • Radiation hybrids identify BTN2A1 as crucial for Vγ9Vδ2 phosphoantigen (P-Ag) sensing • BTN2A1 binds directly to the T cell receptor via germline-encoded regions of Vγ9 • Cell-surface BTN2A1 associates directly with BTN3A1 independent of P-Ag stimulation • The Vγ9-BTN2A1 interaction modality suggests an additional CDR3-dependent TCR ligand, Karunakaran et al. find that butyrophilin 2A1 (BTN2A1) associates with BTN3A1 on the cell surface and binds directly to germline-encoded regions of the Vγ9 chain of the Vγ9Vδ2 TCR. Thus, BTN2A1 collaborates with BTN3A1 to potentiate Vγ9Vδ2 T cell recognition, playing an essential role in phosphoantigen sensing.
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- 2020
19. Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2
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Benjamin E. Willcox, Angela Pappalardo, Christelle Harly, Camille Khairallah, Sonia Netzer, Emmanuel Scotet, Benjamin Faustin, Anne-Marie Lomenech, Romain Marlin, Hannah Kaminski, Marc Bonneville, Vincent Pitard, Jean-François Moreau, Carrie R. Willcox, Julie Déchanet-Merville, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Département de Transplantation Rénale [CHU Bordeau], CHU Bordeaux [Bordeaux], Cancer Immunology and Immunotherapy Centre [Birmingham, UK], Institute of Immunology and Immunotherapy [Birmingham, UK]-University of Birmingham [UK], Flow Cytometry Facility / TransBioMed Core [Bordeaux] (INSERM US005 - CNRS UMS 3427 - UB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Proteomic Facility [Bordeaux] (Functional Genomic Center), Université de Bordeaux (UB), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'immunologie et d'immunogénétique [CHU Bordeaux], This work was supported in part by grants from the Centre National de la Recherche Scientifique, the Institut National du Cancer (PLBIO10-189 TUMOSTRESS, TRANSLA14 GDSTRESS), Fondation pour la Recherche Médicale (DEQ20110421287), the Agence National de la Recherche (ANR-12-BSV3-0024-02), the Ligue Nationale contre le Cancer (Comités Départementaux d’Aquitaine), and the SIRIC Brio (FAC 2014 DECAMET). B.F. and A.P. were supported by the Conseil Régional d’Aquitaine., Immunology from Concept and Experiments to Translation ( ImmunoConcept ), Université de Bordeaux ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Flow Cytometry Facility / TransBioMed Core [Bordeaux] ( INSERM US005 - CNRS UMS 3427 - UB ), Université de Bordeaux ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Proteomic Facility [Bordeaux] ( Functional Genomic Center ), Université de Bordeaux ( UB ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), and Bernardo, Elizabeth
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0301 basic medicine ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,medicine.disease_cause ,Ligands ,Lymphocyte Activation ,Peripheral blood mononuclear cell ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,innate-like lymphocytes ,Antigen ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Annexin ,Stress, Physiological ,T-Lymphocyte Subsets ,Cell Line, Tumor ,Neoplasms ,Medicine ,Humans ,cell stress surveillance ,tumor immunology ,Receptor ,Antibodies, Blocking ,cytomegalovirus ,Annexin A2 ,Multidisciplinary ,business.industry ,T-cell receptor ,Antibodies, Monoclonal ,gamma-delta T cells ,Receptors, Antigen, T-Cell, gamma-delta ,Biological Sciences ,Immunity, Innate ,Cell biology ,Cell stress ,Oxidative Stress ,030104 developmental biology ,Immunology ,Cytomegalovirus Infections ,business ,Oxidative stress ,Protein Binding ,Signal Transduction - Abstract
International audience; Human γδ T cells comprise a first line of defense through T-cell receptor (TCR) recognition of stressed cells. However, the molecular determinants and stress pathways involved in this recognition are largely unknown. Here we show that exposure of tumor cells to various stress situations led to tumor cell recognition by a Vγ8Vδ3 TCR. Using a strategy that we previously developed to identify antigenic ligands of γδ TCRs, annexin A2 was identified as the direct ligand of Vγ8Vδ3 TCR, and was found to be expressed on tumor cells upon the stress situations tested in a reactive oxygen species-dependent manner. Moreover, purified annexin A2 was able to stimulate the proliferation of a Vδ2 neg γδ T-cell subset within peripheral blood mononuclear cells and other annexin A2-specific Vδ2 neg γδ T-cell clones could be derived from peripheral blood mononuclear cells. We thus propose membrane exposure of annexin A2 as an oxidative stress signal for some Vδ2 neg γδ T cells that could be involved in an adaptive stress surveillance.
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- 2017
20. Cytomegalovirus-Induced γδ T Cells Associate with Reduced Cancer Risk after Kidney Transplantation
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Isabelle Garrigue, François Siberchicot, Julie Déchanet-Merville, Nicholas Moore, Omar Hawchar, Yann Levaillant, Pierre Merville, Jean-François Moreau, Lionel Couzi, Vincent Pitard, Abdellah Jamai, Karin Martin, and Régis Lassalle
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Adult ,Male ,Nephrology ,medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Cytomegalovirus ,Risk Factors ,Clinical Research ,Internal medicine ,medicine ,Humans ,Longitudinal Studies ,Kidney transplantation ,Retrospective Studies ,Immunosuppression Therapy ,business.industry ,Cancer ,Receptors, Antigen, T-Cell, gamma-delta ,Immunosuppression ,General Medicine ,Middle Aged ,medicine.disease ,Kidney Transplantation ,Kidney Neoplasms ,Transplantation ,medicine.anatomical_structure ,Case-Control Studies ,Cytomegalovirus Infections ,Immunology ,Female ,business ,Kidney cancer ,Follow-Up Studies ,Kidney disease - Abstract
An increase in the number of blood gammadelta T cells follows cytomegalovirus (CMV) infection in kidney transplant recipients. These cells react against CMV-infected cells and tumor epithelial cells in vitro. We hypothesized that these CMV-induced gammadelta T cells play a protective role against cancer in kidney transplant recipients. We performed a longitudinal case-control study involving 18 recipients who developed cancer between 2 and 6 yr after transplantation and 45 recipients who did not. The median percentage of gammadelta T cells among total lymphocytes in patients with malignancies was significantly lower compared with that in control patients at 6, 12, and 18 mo before the diagnosis of cancer. Patients with a gammadelta T cell percentage of more than 4% were protected from cancer. An increase of the Vdelta2(neg) gammadelta T cell subset significantly associated with lower incidence of cancer only in recipients who experienced pre- or postgraft CMV infection. Finally, a retrospective follow-up of 131 recipients for 8 yr revealed that CMV-naive recipients had an approximately 5-fold higher risk of cancer compared with CMV-exposed patients. In summary, these results suggest a protective role of CMV exposure against cancer in kidney transplant recipients.
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- 2010
21. Common Features of γδ T Cells and CD8+αβ T Cells Responding to Human Cytomegalovirus Infection in Kidney Transplant Recipients
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Jean-Luc Taupin, Vincent Pitard, Lionel Couzi, Isabelle Garrigue, Jean-François Moreau, Marie-Edith Lafon, Pierre Merville, Sonia Netzer, and Julie Déchanet-Merville
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T cell ,virus diseases ,CD28 ,hemic and immune systems ,chemical and pharmacologic phenomena ,T lymphocyte ,Biology ,Natural killer T cell ,Virology ,Interleukin 21 ,Infectious Diseases ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,CD8 - Abstract
Background Kidney transplant recipients infected with cytomegalovirus (CMV) undergo a persistent gammadelta T cell expansion in their peripheral blood. The anti-CMV function of these cells was previously demonstrated by their ability to kill CMV-infected cells in vitro. Methods To gain insight into the role of gammadelta T cells within the antiviral immune network, we compared the expansion kinetics of these T cells with that of CMV pp65-specific CD8(+) alphabeta T cells in the peripheral blood of twenty-one kidney transplant recipients. Results Both the percentage and the absolute number of pp65-specific CD8(+) T cells and gammadelta T cells showed a concomitant increase and persistence in most of the kidney transplant recipients with CMV infection. Both cell subsets exhibited an effector/memory phenotype (CD28(-), CD27(-), and CD45RA(+)) that predominated for the entire follow-up period. Conclusions In conclusion, CMV-specific CD8(+) alphabeta T cells and gammadelta T cells share common expansion kinetics and a common effector phenotype, suggesting that these cell types act similarly in response to CMV infection.
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- 2009
22. Antitumor Activity of γδ T Cells Reactive against Cytomegalovirus-Infected Cells in a Mouse Xenograft Tumor Model
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Christel Devaud, Vincent Pitard, Charlotte Behr, Julie Déchanet-Merville, Séverine Loizon, Eric Bilhere, Myriam Capone, and Jean-François Moreau
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Cancer Research ,Chemokine ,Receptors, CXCR3 ,Skin Neoplasms ,Receptors, CCR3 ,T-Lymphocytes ,Cytomegalovirus ,Biology ,Immunotherapy, Adoptive ,Mice ,HT29 Cells ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Monocyte ,Cancer ,Receptors, Antigen, T-Cell, gamma-delta ,T lymphocyte ,medicine.disease ,Xenograft Model Antitumor Assays ,medicine.anatomical_structure ,Oncology ,Colonic Neoplasms ,Cytomegalovirus Infections ,Immunology ,Cancer cell ,biology.protein ,Caco-2 Cells ,Chemokines ,Antibody - Abstract
gammadelta T cells recognize stress-induced autoantigens and contribute to immunity against infections and cancer. Our previous study revealed that Vdelta2-negative ((neg)) gammadelta T lymphocytes isolated from transplant recipients infected by cytomegalovirus (CMV) killed both CMV-infected cells and HT29 colon cancer cells in vitro. To investigate the antitumor effects of Vdelta2(neg) clones in vivo, we generated hypodermal HT29 tumors in immunodeficient mice. Concomitant injections of Vdelta2(neg)clones, in contrast to Vdelta2(+) cells, prevented the development of HT29 tumors. Vdelta2(neg) clones expressed chemokine C-C motif receptor 3 (CCR3) and migrated in vitro in response to chemokines secreted by HT29 cells, among which were the CCR3 ligands macrophage inflammatory protein-1delta and monocyte chemoattractant protein-4. More importantly, a systemic i.p. treatment with Vdelta2(neg) clones delayed the growth of HT29 s.c. tumors. The effect of in vivo gammadelta T-cell passive immunotherapy on tumor growth could be reverted by addition of a blocking anti-CCR3 antibody. gammadelta T-cell passive immunotherapy was dependent on the cytotoxic activity of the gammadelta effectors toward their targets because Vdelta2(neg) clones were not able to inhibit the growth of A431 hypodermal tumors. Our findings suggest that CMV-specific Vdelta2(neg) cells could target in vivo cancer cells, making them an attractive candidate for antitumor immunotherapy.
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- 2009
23. Long-term expansion of effector/memory Vδ2− γδ T cells is a specific blood signature of CMV infection
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Pierre Merville, David Roumanes, Vincent Pitard, Julie Déchanet-Merville, Isabelle Garrigue, Xavier Lafarge, Lionel Couzi, Jean-François Moreau, and Marie-Edith Lafon
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education.field_of_study ,T cell ,Immunology ,Population ,virus diseases ,Cytomegalovirus ,Cell Biology ,Hematology ,Biology ,medicine.disease_cause ,Acquired immune system ,Biochemistry ,Virology ,medicine.anatomical_structure ,Immune system ,Antigen ,Immunity ,medicine ,Cytotoxic T cell ,education - Abstract
The ability of human γδ T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of Vδ2− γδ T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. Vδ2− γδ T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas Vδ2− γδ T cells were found as naive cells in CMV− patients, they virtually all exhibited the cytotoxic effector/memory phenotype in CMV+ patients, which is also observed in transplanted patients challenged with CMV. This long-term complete remodeling of the Vδ2− γδ T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster γδ T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effector-memory Vδ2− γδ T cells in the peripheral blood is a specific signature of an adaptive immune response to CMV infection of both immunocompetent and immunosuppressed patients.
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- 2008
24. Modulation of Lymphocyte Proliferation Induced by Gastric MALT Lymphoma-Associated Helicobacter pylori Strains
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Phillippe Lehours, David Roumanes, Jonathan Ferrand, Francis Mégraud, Vincent Pitard, and Jean-François Moreau
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biology ,Lymphocyte ,Gastroenterology ,MALT lymphoma ,General Medicine ,Lymphocyte proliferation ,Helicobacter pylori ,medicine.disease ,biology.organism_classification ,Lymphoma ,Microbiology ,Infectious Diseases ,Lymphatic system ,medicine.anatomical_structure ,In vivo ,hemic and lymphatic diseases ,medicine ,B cell - Abstract
Background: Helicobacter pylori infection leads to different chronic diseases, suggesting that this bacterium can evade the host immune defense system. The ability to control lymphocyte proliferation may be a mechanism leading to the development of gastric pathologies. Our aim was to characterize the effects of mucosa-associated lymphoid tissue (MALT) associated H. pylori strains on lymphocyte proliferation. Materials and methods: We measured the in vitro proliferation of human lymphocytes originally from blood or tonsil samples in the presence or absence of viable bacteria or lysates. Results: We showed that MALT lymphoma-associated strains are not likely to be directly responsible for anarchical B-cell proliferation in vitro. On the other hand, proliferation of prestimulated T lymphocytes was abolished in vitro by the presence of all H. pylori strains, whether associated with MALT lymphoma or not. Conclusion: Inhibition of T-cell proliferation may be of major importance in the gastric colonization and in the persistence of the infection. Furthermore, this inhibition may favor anarchical B-cell proliferation in vivo and predispose the host to gastric MALT lymphoma, whereas MALT-associated H. pylori strains do not appear to possess a specific capability to directly stimulate B-lymphocyte proliferation.
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- 2008
25. Expression of MHC class I receptors confers functional intraclonal heterogeneity to a reactive expansion of γδ T cells
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Pascale Paul, Vincent Pitard, David Roumanes, Franck Halary, Jean-François Moreau, Claire Dromer, Eric Vivier, Sophie Ravet, Julie Déchanet-Merville, and Xavier Lafarge
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T-Lymphocytes ,T cell ,Molecular Sequence Data ,Immunology ,Population ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,Receptors, KIR ,Antigen ,Antigens, CD ,MHC class I ,medicine ,Humans ,Immunology and Allergy ,Lectins, C-Type ,Amino Acid Sequence ,Receptors, Immunologic ,Receptor ,education ,education.field_of_study ,Base Sequence ,biology ,Histocompatibility Antigens Class I ,Receptors, Antigen, T-Cell, gamma-delta ,Middle Aged ,Molecular biology ,medicine.anatomical_structure ,Receptors, KIR2DL3 ,Receptors, KIR2DL2 ,Cytomegalovirus Infections ,Monoclonal ,biology.protein ,Receptors, Natural Killer Cell ,Female ,NK Cell Lectin-Like Receptor Subfamily C ,Clone (B-cell biology) ,NK Cell Lectin-Like Receptor Subfamily D ,Lung Transplantation - Abstract
NK cell receptors for MHC class I molecules (MHC-NKR) can be expressed by T cell subsets. The restricted repertoire and phenotypic characteristics of MHC-NKR(+) T cells indicate that expression of MHC-NKR is acquired upon antigenic challenge and might promote expansion of T cells. Previous studies performed on in vitro generated alphabeta T cell clones concluded that MHC-NKR expression was not a clonal attribute. Here, we examined a massive monoclonal expansion of a non-leukemic gammadelta T cell population found in the peripheral blood of a lung-transplanted patient who suffered from a cytomegalovirus infection. Despite their monoclonality, these T cells displayed a heterogeneous and stable in vivo Ig- and lectin-like MHC-NKR phenotype. Twenty percent of the cells displayed a CD94(+)NKG2A(+) phenotype, and 10% were labeled with an anti-CD158b1/b2/j monoclonal antibody. A CD158b/j(+) gammadelta T cell clone derived in vitro from patient's peripheral blood lymphocytes was shown to express the activating form CD158j (KIR2DS2), which once cross-linked stimulated the clone cytolytic function and costimulated the TCR-induced production of cytokines, independently of the killer-activating receptor-associated protein (KARAP). In conclusion, heterogeneity of MHC-NKR expression confers a functional intraclonal diversity that may participate to induction of specific gammadelta T cell effector functions or proliferation upon pathogen challenge.
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- 2005
26. Shared reactivity of Vδ2neg γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells
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Pierre Merville, Roman Krzysiek, Franck Halary, Dominique Emilie, Jean-François Moreau, Vincent Pitard, Julie Déchanet-Merville, Dorota Dlubek, and Claire Dromer
- Subjects
Cytotoxicity, Immunologic ,T cell ,Immunology ,Gene Rearrangement, delta-Chain T-Cell Antigen Receptor ,Receptors, Lymphocyte Homing ,Cytomegalovirus ,Genes, MHC Class I ,Streptamer ,Major histocompatibility complex ,Lymphocyte Activation ,Article ,Cell Line ,Interleukin 21 ,Immune system ,Antigens, Neoplasm ,T-Lymphocyte Subsets ,Intestinal Neoplasms ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,IL-2 receptor ,Intestinal Mucosa ,Antigens, Viral ,biology ,Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ,Tumor Necrosis Factor-alpha ,Epithelial Cells ,Receptors, Antigen, T-Cell, gamma-delta ,NKG2D ,medicine.anatomical_structure ,Cytomegalovirus Infections ,biology.protein - Abstract
Long-lasting expansion of Vdelta2(neg) gammadelta T cells is a hallmark of cytomegalovirus (CMV) infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, we generated gammadelta T cell clones from several transplanted patients. Numerous patient Vdelta1(+), Vdelta3(+), and Vdelta5(+) gammadelta T cell clones expressing diverse Vgamma chains, but not control Vgamma9Vdelta2(+) T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of tumor necrosis factor-alpha. Vdelta2(neg) gammadelta T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required T cell receptor engagement, but did not involve major histocompatibility complex class I molecules or NKG2D. Vdelta2(neg) gammadelta T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific Vdelta2(neg) gammadelta T lymphocytes were found among patients' gammadelta T cells. In conclusion, Vdelta2(neg) gammadelta T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from Vgamma9Vdelta2(+) T cells.
- Published
- 2005
27. Membrane-anchored CD40 Is Processed by the Tumor Necrosis Factor-α-converting Enzyme
- Author
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Toshimitsu Itai, Vincent Pitard, Cécile Contin, Shigekazu Nagata, Jean Francois Moreau, and Julie Déchanet-Merville
- Subjects
Metalloproteinase ,Cell Biology ,Biology ,Biochemistry ,Fusion protein ,Molecular biology ,GM6001 ,In vitro ,chemistry.chemical_compound ,chemistry ,Ectodomain ,Disintegrin ,biology.protein ,Tumor necrosis factor alpha ,CD154 ,Molecular Biology - Abstract
The soluble form of CD40 (sCD40), which co-exists with the membrane-anchored form (mCD40), is a natural antagonist of mCD40/CD154 interaction. However, the mechanism leading to the production of sCD40 has never been investigated. Here, we show that the engagement of mCD40 on the surface of B lymphocytes by anti-CD40 antibody led to enhanced sCD40 release associated with decreased amounts of mCD40. This sCD40 production was not affected by vesicular traffic inhibitors but was completely blocked by a broad-spectrum synthetic metalloproteinase (MP) inhibitor (GM6001) or a membrane-anchored MP-specific inhibitor (dec-RVKR-cmk). Recombinant MP disintegrin tumor necrosis factor-α converting enzyme (TACE) cleaved the purified CD40 ectodomain/Fc chimeric protein in vitro, giving rise to an sCD40 form similar to that shed from B cell cultures. Moreover, spontaneous production of sCD40 by mCD40-transfected human embryonic kidney cells (constitutively expressing TACE) was enhanced by the overexpression of TACE and abrogated by co-transfection with a dominant-negative TACE mutant. These results provide strong evidence that sCD40 production is an active process regulated by the engagement of mCD40 and its proteolytic cleavage by TACE or a related MP disintegrin. Given the antagonistic activity of sCD40 on the CD40/CD154 interaction, this shedding mechanism might represent an important negative feedback control of CD40 functions.
- Published
- 2003
28. T-lymphocyte populations in hepatitis C and HIV co-infected patients treated with interferon-alfa-2a and ribavirin
- Author
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JM Ragnaud, Jean-François Moreau, T Galpérine, M Neau-Cransac, Vincent Pitard, ME Lafon, Didier Neau, E Legrand, H Fleury, and M Dupon
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,CD3 Complex ,CD3 ,HIV Infections ,Human leukocyte antigen ,CD8-Positive T-Lymphocytes ,Interferon alpha-2 ,Antiviral Agents ,Group A ,Drug Administration Schedule ,Group B ,chemistry.chemical_compound ,Antigen ,T-Lymphocyte Subsets ,Ribavirin ,medicine ,Humans ,Pharmacology (medical) ,Lymphocyte Count ,biology ,business.industry ,Health Policy ,Interferon-alpha ,Hepatitis C ,T lymphocyte ,Hepatitis C, Chronic ,Middle Aged ,Viral Load ,medicine.disease ,Combined Modality Therapy ,Recombinant Proteins ,Infectious Diseases ,chemistry ,Case-Control Studies ,Immunology ,HIV-1 ,biology.protein ,RNA, Viral ,Female ,business - Abstract
Objective The effects on T-lymphocyte populations of two interferon-alfa-2a (IFN) regimens associated with ribavirin were evaluated in 36 HCV-HIV co-infected patients with chronic hepatitis C, T-CD4 cell count > 250 cells/µL and a plasma viral load of
- Published
- 2003
29. Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)-4- and VLA-5-dependent mechanism
- Author
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Christophe Grosset, Jean-François Viallard, Pascale Duchez, Laure Coulombel, A. Solanilla, Patrick Legembre, Josy Reiffers, Jean-Michel Boiron, Jean Ripoche, Maryse Dupouy, Francis Belloc, and Vincent Pitard
- Subjects
0303 health sciences ,Cell adhesion molecule ,Growth factor ,medicine.medical_treatment ,Integrin ,hemic and immune systems ,Hematology ,Biology ,Umbilical vein ,Cell biology ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Bone marrow ,Progenitor cell ,030304 developmental biology ,Homing (hematopoietic) - Abstract
Summary. The adhesion of haematopoietic progenitor cells (HPC) to the bone marrow microenvironment is a process regulated by cytokines. In this study, we have shown that flt3-ligand (FL), a growth factor that controls early haematopoiesis, regulated the function and expression of the beta-1 integrins, very late antigen (VLA)-4 and VLA-5 on HPC. The modulation of the adhesiveness of HPC by FL was studied by adhesion assays on umbilical vein endothelial cells (HUVEC). Stimulation by FL induced two peaks of increased adhesiveness of HPC. The first peak was at around 30 min and was mechanistically related to an activation of the beta-1 integrins, mainly VLA-4 and VLA-5. The second peak was at around 12 h and was related to increased expression of VLA-4 and VLA-5. The control of HPC adhesiveness by FL is a previously unreported property of FL that may be important for the homing and the retention of flt3-expressing HPC within the bone marrow microenvironment.
- Published
- 2003
30. CD4 T Lymphocyte Proliferative Responses to Hepatitis C Virus (HCV) Antigens in Patients Coinfected with HCV and Human Immunodeficiency Virus Who Responded to Anti‐HCV Treatment
- Author
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Vincent Pitard, Jean-Yves Lacut, Pascale Trimoulet, Marie-Edith Lafon, Jean-François Moreau, Hervé Fleury, Brigitte Le Bail, Elisabeth Legrand, Didier Neau, Michael Houghton, Noëlle Bernard, Evelyne Schvoerer, Tatiana Galpérine, Michel Dupon, and Jean-Marie Ragnaud
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Hepatitis C virus ,HIV Core Protein p24 ,HIV Infections ,Hepacivirus ,Interferon alpha-2 ,Biology ,Lymphocyte Activation ,Tuberculin ,medicine.disease_cause ,Antiviral Agents ,Statistics, Nonparametric ,Virus ,chemistry.chemical_compound ,Immune system ,Antigen ,Immunopathology ,Ribavirin ,medicine ,Humans ,Immunology and Allergy ,Interferon-alpha ,virus diseases ,Hepatitis C ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,Acquired immune system ,Virology ,Recombinant Proteins ,digestive system diseases ,Infectious Diseases ,chemistry ,Immunology ,HIV-1 ,Female ,Hepatitis C Antigens - Abstract
CD4 T lymphocyte proliferative responses to hepatitis C virus (HCV) antigens were evaluated before and during an anti-HCV regimen (interferon-alpha2a and ribavirin) in 36 patients coinfected with HCV and human immunodeficiency virus (HIV), to determine whether immune responses against HCV antigens are present in such patients, whether these responses are modified by anti-HCV treatment, and whether they are correlated with treatment efficacy. The CD4 responses against HCV antigens (primarily core antigens) detected at study entry in one-half of the patients did not correlate with anti-HCV treatment efficacy. Of 36 patients, 8 had patterns of persistent immune response to infection by genotypes 3 or 4 that were significantly correlated with sustained virologic response. Persistent immunologic reactivity and sustained virologic response coexisted only in patients infected with genotype 3. These findings suggest that HCV genotype may influence specific immune response, which, in turn, is implicated in virologic control.
- Published
- 2002
31. Gamma-delta T cell expansion is closely associated with cytomegalovirus infection in all solid organ transplant recipients
- Author
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Marc-Alain Billes, Julie Déchanet-Merville, Xavier Lafarge, Lionel Couzi, Vincent Pitard, Florence Lacaille, Claire Dromer, Jean-François Moreau, Pierre Merville, and Martine Neau-Cransac
- Subjects
Cytomegalovirus infection ,Transplantation ,medicine.anatomical_structure ,business.industry ,Immunology ,Medicine ,business ,Gamma delta T cell ,Solid organ transplantation - Published
- 2011
32. Cytomegalovirus-responsive γδ T cells: novel effector cells in antibody-mediated kidney allograft microcirculation lesions
- Author
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Sébastien Lepreux, Pierre Merville, Claire Rigothier, Lionel Couzi, Jean-François Moreau, Thomas Bachelet, Julie Déchanet-Merville, Vincent Pitard, Jean-Luc Taupin, and Xavier Sicard
- Subjects
Human cytomegalovirus ,Adult ,Graft Rejection ,Male ,Pore Forming Cytotoxic Proteins ,Stromal cell ,Endothelium ,Adolescent ,T cell ,Congenital cytomegalovirus infection ,GPI-Linked Proteins ,Young Adult ,Antigen ,Isoantibodies ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Transplantation, Homologous ,Aged ,Cell Line, Transformed ,biology ,Perforin ,Histocompatibility Testing ,Microcirculation ,Receptors, IgG ,Receptors, Antigen, T-Cell, gamma-delta ,General Medicine ,Fibroblasts ,Middle Aged ,medicine.disease ,Kidney Transplantation ,Killer Cells, Natural ,medicine.anatomical_structure ,Basic Research ,Nephrology ,Immunology ,Cytomegalovirus Infections ,biology.protein ,Female ,Endothelium, Vascular ,Antibody - Abstract
Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large γδ T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive γδ T cells express the Fcγ-receptor CD16, suggesting that γδ T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16(pos) γδ T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating γδ T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced γδ T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced γδ T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.
- Published
- 2014
33. Identification of Agonistic and Antagonistic Antibodies against gp190, the Leukemia Inhibitory Factor Receptor, Reveals Distinct Roles for Its Two Cytokine-binding Domains
- Author
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Patrick Legembre, Sophie Daburon, Juliette Bitard, Jean-Luc Taupin, Yannick Jacques, Jean-François Moreau, Vincent Pitard, Laurence Duplomb, Frédéric Blanchard, and Anne Godard
- Subjects
endocrine system ,Leukemia Inhibitory Factor Receptor alpha Subunit ,Receptors, OSM-LIF ,medicine.drug_class ,Leukemia inhibitory factor receptor ,Monoclonal antibody ,Biochemistry ,Cell Line ,Epitopes ,Structure-Activity Relationship ,Cricetinae ,parasitic diseases ,medicine ,Animals ,Humans ,Receptors, Cytokine ,Cytokine binding ,Receptor ,Molecular Biology ,biology ,Oncostatin M ,Antibodies, Monoclonal ,Cell Biology ,Flow Cytometry ,Glycoprotein 130 ,Molecular biology ,biology.protein ,Cytokines ,Cytokine receptor ,Leukemia inhibitory factor ,Cell Division ,hormones, hormone substitutes, and hormone antagonists - Abstract
The receptor for the cytokine leukemia inhibitory factor (LIF) associates the low affinity binding component gp190 and the high affinity converter gp130, both of which are members of the family of hematopoietic receptors characterized by the cytokine receptor homology (CRH) domain. The gp190 is among the very few members of this large family to contain two CRH domains. The membrane-distal one (herein called D1) is followed by an Ig-like domain, a membrane-proximal CRH domain called D2, and three type III fibronectin repeats. We raised a series of monoclonal antibodies specific for the human gp190. Among them was the blocking antibody 1C7, which was directed against the D1Ig region and which impaired the binding of LIF to gp190. Another blocking antibody, called 12D3, was directed against domain D2 and interfered with the reconstitution of the high affinity receptor complex, independently of the interaction between LIF and gp190. The blocking effect of these two antibodies concerned four cytokines known to use gp190, i.e. LIF, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1. Among 23 antibodies tested alone or in combination (two anti-D2 and 21 anti-D1Ig), only the mixture of the two anti-D2 antibodies displayed agonistic activity in the absence of the cytokine. Taken together, these results demonstrate that the two CRH domains of gp190 play different functions in ligand binding and receptor activation.
- Published
- 2001
34. Role of Campylobacter jejuni gamma-glutamyl transpeptidase on epithelial cell apoptosis and lymphocyte proliferation
- Author
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Jean-William Dupuy, Marc Bonneu, Anaïs Hocès de la Guardia, Philippe Lehours, Vincent Pitard, Vincent Pey, Francis Mégraud, Michel Castroviejo, Pauline Floch, Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Infection à helicobacter, inflammation et cancer, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bactériologie, and CHU Bordeaux [Bordeaux]
- Subjects
Helicobacter bilis ,Cell cycle checkpoint ,Lymphocyte proliferation ,Epithelial cells ,Microbiology ,Campylobacter jejuni ,digestive system ,Flow cytometry ,Virology ,medicine ,Helicobacter ,Lymphocytes ,ComputingMilieux_MISCELLANEOUS ,biology ,medicine.diagnostic_test ,Research ,Gastroenterology ,Helicobacter pylori ,bacterial infections and mycoses ,biology.organism_classification ,digestive system diseases ,GGT ,Infectious Diseases ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Cell culture ,Parasitology - Abstract
Background A gamma-glutamyl transpeptidase (GGT) is produced by up to 31% of strains of Campylobacter jejuni isolates. C. jejuni GGT is close to Helicobacter pylori GGT suggesting a conserved activity but unlike the latter, C. jejuni GGT has not been studied extensively. In line with the data available for H. pylori, our objectives were to purify C. jejuni GGT from the bacteria, and to evaluate its inhibitory and proapoptotic activities on epithelial cells and human lymphocytes. Methods C. jejuni GGT was purified from culture supernatants by chromatography. After verification of the purity by using mass spectrometry of the purified enzyme, its action on two epithelial cell lines and human lymphocytes was investigated. Cell culture as well as flow cytometry experiments were developed for these purposes. Results This study demonstrated that C. jejuni GGT is related to Helicobacter GGTs and inhibits the proliferation of epithelial cells with no proapoptotic activity. C. jejuni GGT also inhibits lymphocyte proliferation by causing a cell cycle arrest in the G0/G1 phase. These effects are abolished in the presence of a specific pharmacological inhibitor of GGT. Conclusion C. jejuni GGT activity is comparable to that of other Epsilonproteobacteria GGTs and more generally to Helicobacter bilis (inhibition of epithelial cell and lymphocyte proliferation, however with no proapoptotic activity). It could therefore be considered as a pathogenicity factor and promote, via the inhibition of lymphocyte proliferation, the persistence of the bacteria in the host. These observations are consistent with a role of this enzyme in the pathophysiology of chronic infections associated with C. jejuni.
- Published
- 2013
35. Different epitopes are required for gp130 activation by interleukin-6, oncostatin M and leukemia inhibitory factor
- Author
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Gerhard Müller-Newen, Vincent Pitard, Peter C. Heinrich, Stefan Pflanz, Joachim Grötzinger, Ingo Kurth, Andreas Timmermann, and Andrea Küster
- Subjects
Models, Molecular ,Leukemia inhibitory factor receptor ,Leukemia Inhibitory Factor ,Biochemistry ,Protein Structure, Secondary ,Epitopes ,Structural Biology ,Cytokine Receptor gp130 ,Lymphokines ,Membrane Glycoproteins ,biology ,digestive, oral, and skin physiology ,Oncostatin M ,Oncostatin M receptor ,Growth Inhibitors ,Recombinant Proteins ,COS Cells ,biological phenomena, cell phenomena, and immunity ,Dimerization ,hormones, hormone substitutes, and hormone antagonists ,Receptor ,Signal Transduction ,Receptors, OSM-LIF ,Biophysics ,Transfection ,digestive system ,gp130 ,Ba/F3 cell ,Antigens, CD ,Genetics ,Animals ,Point Mutation ,Ciliary Neurotrophic Factor ,Receptors, Cytokine ,Cytokine binding ,Interleukin 6 ,Cytokine ,Molecular Biology ,Binding Sites ,Interleukin-6 ,Receptors, Oncostatin M ,Cell Biology ,Glycoprotein 130 ,Molecular biology ,biological factors ,Mutagenesis, Site-Directed ,biology.protein ,STAT protein ,Peptides ,Leukemia inhibitory factor - Abstract
Gp130 is the common signal transducing receptor subunit of interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor and cardiotrophin-1. IL-6 and IL-11 induce gp130 homodimerization whereas the others lead to the formation of heterodimers with LIFR or OSMR. Binding epitopes for IL-6 and IL-11 are located in the immunoglobulin-like domain and the cytokine binding module (CBM). Here we show that a gp130 mutant lacking domain 1, although unresponsive to IL-6 and IL-11, can still activate signal transducer and activator of transcription (STAT) transcription factors in response to LIF or OSM. Moreover, point mutations in the CBM of gp130 (F191E and V252D) that severely impair signal transduction in response to IL-6 and IL-11 differentially interfere with gp130 activation in response to LIF and OSM. Thus, epitopes involved in gp130 homodimerization are distinct from those leading to the formation of gp130/LIFR or gp130/OSMR heterodimers. These findings may serve as the base for rational design of gp130 antagonists that specifically interfere with bioactivity of distinct IL-6-type cytokines.
- Published
- 2000
36. Implication of γδ T cells in the human immune response to cytomegalovirus
- Author
-
Xavier Lafarge, Christelle Retière, Jean-François Moreau, Claude Meric, Pierre Merville, Annick Lim, Susan Michelson, Philippe Kourilsky, Luc Potaux, Julie Dechanet, Marc Bonneville, Vincent Pitard, and M M Hallet
- Subjects
Adult ,Male ,Time Factors ,Adolescent ,medicine.drug_class ,Molecular Sequence Data ,Population ,Congenital cytomegalovirus infection ,Cytomegalovirus ,In Vitro Techniques ,Biology ,Lymphocyte Activation ,Monoclonal antibody ,Article ,Immune system ,T-Lymphocyte Subsets ,medicine ,Humans ,Amino Acid Sequence ,Child ,Receptor ,education ,DNA Primers ,education.field_of_study ,Base Sequence ,T-cell receptor ,Receptors, Antigen, T-Cell, gamma-delta ,General Medicine ,Middle Aged ,medicine.disease ,Kidney Transplantation ,Virology ,Junctional diversity ,In vitro ,Cytomegalovirus Infections ,Immunology ,Female - Abstract
In normal individuals, gammadelta T cells account for less than 6% of total peripheral T lymphocytes and mainly express T-cell receptor (TCR) Vdelta2-Vgamma9 chains. We have previously observed a dramatic expansion of gammadelta T cells in the peripheral blood of renal allograft recipients only when they developed cytomegalovirus (CMV) infection. This increase was long lasting (more than 1 year), was associated with an activation of gammadelta T cells, and concerned only Vdelta1 or Vdelta3 T-cell subpopulations. Analysis of gammadelta TCR junctional diversity revealed that CMV infection in these patients was accompanied by (a) a marked restriction of CDR3 size distribution in Vdelta3 and, to a lesser extent, in Vdelta1 chains; and (b) a selective expansion of Vdelta1 cells bearing recurrent junctional amino acid motifs. These features are highly suggestive of an in vivo antigen-driven selection of gammadelta T-cell subsets during the course of CMV infection. Furthermore, Vdelta1 and Vdelta3 T cells from CMV-infected kidney recipients were able to proliferate in vitro in the presence of free CMV or CMV-infected fibroblast lysates but not uninfected or other herpes virus-infected fibroblast lysates. This in vitro expansion was inhibited by anti-gammadelta TCR mAb's. These findings suggest that a population of gammadelta T cells might play an important role in the immune response of immunosuppressed patients to CMV infection.
- Published
- 1999
37. Human γδ T cells and viruses
- Author
-
Xavier Lafarge, Vincent Pitard, Julie Déchanet, Jean-François Moreau, and Pierre Merville
- Subjects
Human cytomegalovirus ,Cellular immunity ,biology ,Immunology ,T lymphocyte ,biology.organism_classification ,medicine.disease ,medicine.disease_cause ,Microbiology ,Virology ,Virus ,Herpesviridae ,Infectious Diseases ,Immune system ,Betaherpesvirinae ,medicine ,Viral disease - Published
- 1999
38. A functional screening identifies five micrornas controlling glypican-3: role of mir-1271 down-regulation in hepatocellular carcinoma
- Author
-
Paulette Bioulac-Sage, Benoît Laloo, Francis Sagliocco, Chantal Combe, Christophe Grosset, Sandra Jalvy, Hélène Jacquemin-Sablon, Vincent Pitard, Yannick Ladeiro, Marion Maurel, Jessica Zucman-Rossi, Laetitia Vachet, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique fonctionnelle des tumeurs solides (U674), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology (Sorbonne Paris Cité - Faculté de Médecine), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), and Grosset, Christophe
- Subjects
Untranslated region ,Carcinoma, Hepatocellular ,Repressor ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Glypican 3 ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Glypicans ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,RNA Processing, Post-Transcriptional ,Gene ,3' Untranslated Regions ,030304 developmental biology ,0303 health sciences ,Messenger RNA ,Hepatology ,Liver Neoplasms ,medicine.disease ,Molecular biology ,Phenotype ,digestive system diseases ,3. Good health ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Hepatocytes - Abstract
International audience; Hepatocellular carcinoma (HCC) is the major primary liver cancer. Glypican-3 (GPC3), one of the most abnormally expressed genes in HCC, participates in liver carcinogenesis. Based on data showing that GPC3 expression is posttranscriptionally altered in HCC cells compared to primary hepatocytes, we investigated the implication of microRNAs (miRNAs) in GPC3 overexpression and HCC. To identify GPC3-regulating miRNAs, we developed a dual-fluorescence FunREG (functional, integrated, and quantitative method to measure posttranscriptional regulations) system that allowed us to screen a library of 876 individual miRNAs. Expression of candidate miRNAs and that of GPC3 messenger RNA (mRNA) was measured in 21 nontumoral liver and 112 HCC samples. We then characterized the phenotypic consequences of modulating expression of one candidate miRNA in HuH7 cells and deciphered the molecular mechanism by which this miRNA controls the posttranscriptional regulation of GPC3. We identified five miRNAs targeting GPC3 3'-untranslated region (UTR) and regulating its expression about the 876 tested. Whereas miR-96 and its paralog miR-1271 repressed GPC3 expression, miR-129-1-3p, miR-1291, and miR-1303 had an inducible effect. We report that miR-1271 expression is down-regulated in HCC tumor samples and inversely correlates with GPC3 mRNA expression in a particular subgroup of HCC. We also report that miR-1271 inhibits the growth of HCC cells in a GPC3-dependent manner and induces cell death.CONCLUSION:Using a functional screen, we found that miR-96, miR-129-1-3p, miR-1271, miR-1291, and miR-1303 differentially control GPC3 expression in HCC cells. In a subgroup of HCC, the up-regulation of GPC3 was associated with a concomitant down-regulation of its repressor miR-1271. Therefore, we propose that GPC3 overexpression and its associated oncogenic effects are linked to the down-regulation of miR-1271 in HCC.
- Published
- 2013
39. Anti-metastatic potential of human Vδ1(+) γδ T cells in an orthotopic mouse xenograft model of colon carcinoma
- Author
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Franck Couillaud, Pierre Costet, Camille Khairallah, Christel Devaud, Benoit Rousseau, Vincent Pitard, Julie Déchanet-Merville, Sonia Netzer, Myriam Capone, Jean-François Moreau, and Christian Paroissin
- Subjects
Cancer Research ,Colorectal cancer ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Immunology ,Cytomegalovirus ,Mice, SCID ,HT29 Cells ,Mice ,Immune system ,Antigen ,Mice, Inbred NOD ,T-Lymphocyte Subsets ,Cell Line, Tumor ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Bioluminescence imaging ,Animals ,Humans ,Neoplasm Metastasis ,Mice, Knockout ,business.industry ,Receptors, Antigen, T-Cell, gamma-delta ,Immunotherapy ,medicine.disease ,Xenograft Model Antitumor Assays ,medicine.anatomical_structure ,Oncology ,Colonic Neoplasms ,Cytomegalovirus Infections ,business ,Neoplasm Transplantation - Abstract
The role of human intraepithelial Vδ1(+) γδ T cell cytotoxic effectors in the immune surveillance against metastatic colon cancer has never been addressed, despite their reported capacity to infiltrate colon carcinomas and to kill colonic cancer cells in vitro. We previously showed that Vδ1(+) γδ T cells are enriched in blood in response to cytomegalovirus (CMV) infection, and that such increase may be protective against epithelial cancers. The objective of the present study was to investigate whether CMV-induced Vδ1(+) γδ T lymphocytes could inhibit the propagation of human colon tumors in vivo, in order to evaluate their immunotherapeutic potential in this context. Even though metastases are an important cause of death in various cancers including colorectal cancer (CRC), the anti-metastatic effect of immune effectors has been poorly analyzed. To this purpose, we set up a reliable model of metastatic colon cancer through orthotopic implantation of luciferase-expressing human HT29 cells in immunodeficient mice. Using bioluminescence imaging to follow the outcome of colonic cancer cells, we showed that a systemic treatment with CMV-induced Vδ1(+) γδ T cells could not only inhibit primary colon tumor growth but also the emergence of secondary tumor foci in the lungs and liver. Finally, our data lead to propose that Vδ1(+) γδ T lymphocytes may directly influence the appearance of metastases independently from their control of primary tumor size. These findings, which extend our previous work, pave the road for the potential manipulation of Vδ1(+) γδ T lymphocytes in novel anti-CRC immunotherapeutic protocols.
- Published
- 2012
40. Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor
- Author
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Sonia Netzer, Adrian Hayday, Benjamin E. Willcox, Carrie R. Willcox, Vincent Pitard, Tobias Silberzahn, Mahboob Salim, Jean-François Moreau, Lionel Couzi, and Julie Déchanet-Merville
- Subjects
T cell ,T-Lymphocytes ,Immunology ,Immunoblotting ,Cytomegalovirus ,chemical and pharmacologic phenomena ,Receptors, Cell Surface ,Antigen ,Antigens, CD ,Stress, Physiological ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Immunoprecipitation ,IL-2 receptor ,Neoplasms, Glandular and Epithelial ,Antigen-presenting cell ,Immunologic Surveillance ,Endothelial protein C receptor ,biology ,T-cell receptor ,Endothelial Protein C Receptor ,Receptors, Antigen, T-Cell, gamma-delta ,Cell biology ,medicine.anatomical_structure ,CD1D ,Cytomegalovirus Infections ,biology.protein ,Protein Binding - Abstract
T cells bearing γδ T cell antigen receptors (TCRs) function in lymphoid stress surveillance. However, the contribution of γδ TCRs to such responses is unclear. Here we found that the TCR of a human V(γ)4V(δ)5 clone directly bound endothelial protein C receptor (EPCR), which allowed γδ T cells to recognize both endothelial cells targeted by cytomegalovirus and epithelial tumors. EPCR is a major histocompatibility complex-like molecule that binds lipids analogously to the antigen-presenting molecule CD1d. However, the V(γ)4V(δ)5 TCR bound EPCR independently of lipids, in an antibody-like way. Moreover, the recognition of target cells by γδ T cells required a multimolecular stress signature composed of EPCR and costimulatory ligand(s). Our results demonstrate how a γδ TCR mediates recognition of broadly stressed human cells by engaging a stress-regulated self antigen.
- Published
- 2012
41. Comparable Immune Reconstitution Between Ex Vivo Amplification and Un-Manipulated Umbilical Cord Blood Transplantation
- Author
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Arnaud Pigneux, Céline Cognet, Vincent Pitard, Pascale Duchez, Sophie Daburon, Noel Milpied, Jean-Luc Taupin, Reza Tabrizi, Edouard Forcade, Emmanuel Clave, Mathieu Sauvezie, Jean-François Moreau, Zoran Ivanovic, Julie Déchanet-Merville, Antoine Toubert, Stephane Vigouroux, and Xavier Sicard
- Subjects
Myeloid ,business.industry ,ELISPOT ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Transplantation ,Andrology ,Immune system ,medicine.anatomical_structure ,Antigen ,Cord blood ,medicine ,business ,CD8 - Abstract
Umbilical cord blood transplantation (UCBT) is an alternative in the absence of related or unrelated HLA-matched donor. Defects in the mechanisms of immuno-surveillance, due to the absence of antigen-experienced lymphoid subsets transferred in the cord blood unit (CBU), render recipients more prone to viral infections. Our center conducted a clinical trial testing the benefit of ex vivo amplification of the CD34+ fraction (using SCF, FLT3L, TPO and GCSF) enriched from one CBU on hematopoietic reconstitution, while the CD34- fraction was infused at the same time as the expanded fraction (NCT01034449). We intended to simultaneously evaluate the potential impact of such a procedure on the immune reconstitution following freeze-thaw cycle for the CD34- fraction and on the expansion potential of lymphoid progenitors from CD34+ fraction. We prospectively analyzed fresh patient samples from the clinical trial (called the EVEX), at different time points (Day 42, D100, D180, D360), and, in parallel, from patients receiving one or two un-manipulated CBU during the same period (Control group - CTRL). Immune monitoring included flow cytometry analysis of T-cells (CD3+, CD4+, CD8+) and sub-compartments, B-cells (CD19+), NK cells (CD3-CD16+CD56+) and Dendritic cells (DC). Sixteen patients were included in EVEX, of which 12 were analyzed (4 excluded: 1 not grafted, 1 graft infection, 2 primary rejections before Day 42) and 12 patients in CTRL. In the EVEX group, all patients received reduced intensity conditioning, compared to 6 out of 12 in the CTRL group. GVHD prophylaxis was similar. EVEX showed a shorter duration of neutropenia compared to the CTRL (8.5 versus 17 days, p=0.02). NK and B-cell subsets recovered earlier than T-cells, reaching median normal values at 3 and 6 months, respectively. NK cell count tended to be lower in EVEX, starting at 3 months until 1 year. B-cell counts were lower for EVEX at D360. Both groups recovered T-cells within 12 months, but, interestingly, EVEX recovered earlier, reaching Healthy Donor (HD) median values as soon as D180. The CD4+ T-cells (CD4+T) recovered within 12 months for both groups, with EVEX values tending to plateau at low normal values (Fig 1). CD8+ T-cells (CD8+T) reached HD values within 12 months with an earlier recovery for EVEX (Fig 1). We characterized CD4+T and CD8+T compartments with CD45RA and CD27 delineating: naïve (TN: CD45RA+CD27+), central memory (TCM: CD45RA-CD27+), effector memory (TEM: CD45RA-CD27-) and late effector (TEMRA: CD45RA+CD27-) T-cells. Among the CD4+T, TN and TCM gradually increased until D360 for CTRL, while EVEX reached a plateau at D180. EVEX showed a higher TEMRA CD4+T count at D360. Thus, the plateau observed in the whole CD4+T at D180 in EVEX suggested an altered capacity to induce new CD4+T (thymic output or peripheral expansion), or an exhaustion phenomenon. To this end, we evaluated thymic function via CD31 expression among TN CD4+T and TREC analysis by qPCR. Both methods showed a decreased thymic function in EVEX after D180, probably related to the age difference observed (median: 52 vs. 26 years old for EVEX and CTRL, respectively). TEM and TEMRA CD8+T subsets were higher starting at D180 for the EVEX group. There was no difference between groups for myeloid or plasmacytoid DC. Group outcomes differed in terms of chronic GVHD (cGVHD) (1 vs. 6 patients for EVEX and CTRL respectively, p=0.024). Among the subsets playing a role in cGVHD pathogeny, no difference was found in Treg/Tcon ratio (Treg = CD25hiCD127lo CD4+T, Tcon = non-Treg CD4+T), but memory B-cell subset tended to be greater in CTRL from D42 to D180 (median time of cGVHD onset = 186.5 days). CMV reactivation rate was similar in both groups, occurring around 42 days post transplant. Vdelta-2 negative γd T-cells were greater in EVEX early after infection (D42), suggesting a comparable anti-CMV innate function. However, when looking at adaptive anti-CMV immunity with ELISpot, we found reduced IFNg-secreting cells in EVEX, although group size was small. In conclusion, patients receiving ex vivo expanded CBU showed faster hematopoietic reconstitution than un-manipulated CBU and comparable recovery of the main immune subsets. Baseline clinical differences observed between groups may have impacted on some of the immune findings. A prospective and randomized trial would help to better analyze if the expansion procedure has an impact on immune reconstitution. Disclosures Milpied: Celgene: Honoraria, Research Funding.
- Published
- 2015
42. Antibody-dependent anti-cytomegalovirus activity of human γδ T cells expressing CD16 (FcγRIIIa)
- Author
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Vincent Pitard, Julie Déchanet-Merville, Lionel Couzi, Xavier Sicard, Jean-François Moreau, Isabelle Garrigue, Pierre Merville, and Omar Hawchar
- Subjects
Human cytomegalovirus ,viruses ,T cell ,T-Lymphocytes ,Immunology ,Cytomegalovirus ,CD16 ,Lymphocyte Activation ,Virus Replication ,Biochemistry ,Polymerase Chain Reaction ,Cell Line ,Immunocompromised Host ,Interferon-gamma ,Antigen ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Humans ,Cells, Cultured ,Antibody-dependent cell-mediated cytotoxicity ,biology ,Receptors, IgG ,Antibody-Dependent Cell Cytotoxicity ,virus diseases ,Receptors, Antigen, T-Cell, gamma-delta ,Cell Biology ,Hematology ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Flow Cytometry ,Virology ,medicine.anatomical_structure ,Immunoglobulin G ,Host-Pathogen Interactions ,biology.protein ,Interleukin 12 ,Antibody ,Immunocompetence ,Protein Binding - Abstract
Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in transplant recipients. Long-term protective immunity against HCMV requires both sustained specific T-cell response and neutralizing IgG production, but the interplay between these effector arms remains poorly defined. We previously demonstrated that γδ T cells play a substantial role as anti-HCMV T-cell effectors. The observation that CD16 (FcγRIIIA) was specifically expressed by the majority of HCMV-induced γδ T cells prompted us to investigate their cooperation with anti-HCMV IgG. We found that CD16 could stimulate γδ T cells independently of T-cell receptor (TCR) engagement and provide them with an intrinsic antibody-dependent cell-mediated cytotoxic (ADCC) potential. Although CD16+γδ T cells did not mediate ADCC against HCMV-infected cells, in accordance with the low level of anti-HCMV IgGs recognizing infected cells, they produced IFNγ when incubated with IgG-opsonized virions. This CD16-induced IFNγ production was greatly enhanced by IL12 and IFNα, 2 cytokines produced during HCMV infection, and conferred to γδ T cells the ability to inhibit HCMV multiplication in vitro. Taken together, these data identify a new antiviral function for γδ T cells through cooperation with anti-HCMV IgG that could contribute to surveillance of HCMV reactivation in transplant recipients.
- Published
- 2011
43. Control of Plasmodium falciparum erythrocytic cycle: γδ T cells target the red blood cell-invasive merozoites
- Author
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Marita Troye-Blomberg, Iulia Mocan, Franck Halary, Séverine Loizon, Geneviève de Saint-Basile, Jean-François Moreau, Marianne Guenot, Julie Déchanet-Merville, Giulia Costa, Odile Mercereau-Puijalon, Charlotte Behr, and Vincent Pitard
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Erythrocytes ,T cell ,T-Lymphocytes ,Immunology ,Blotting, Western ,Plasmodium falciparum ,Schizonts ,Lymphocyte Activation ,Biochemistry ,Host-Parasite Interactions ,Immunophenotyping ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Lysosomal-Associated Membrane Protein 1 ,parasitic diseases ,medicine ,Animals ,Humans ,Granulysin ,Malaria, Falciparum ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Life Cycle Stages ,biology ,Merozoites ,Perforin ,Receptors, Antigen, T-Cell, gamma-delta ,Cell Biology ,Hematology ,medicine.disease ,biology.organism_classification ,Flow Cytometry ,Virology ,3. Good health ,Red blood cell ,medicine.anatomical_structure ,Mutation ,RNA Interference ,Malaria ,030215 immunology - Abstract
The control of Plasmodium falciparum erythrocytic parasite density is essential for protection against malaria, because it prevents pathogenesis and progression toward severe disease. P falciparum blood-stage parasite cultures are inhibited by human Vγ9Vδ2 γδ T cells, but the underlying mechanism remains poorly understood. Here, we show that both intraerythrocytic parasites and the extracellular red blood cell–invasive merozoites specifically activate Vγ9Vδ2 T cells in a γδ T cell receptor–dependent manner and trigger their degranulation. In contrast, the γδ T cell–mediated antiparasitic activity only targets the extracellular merozoites. Using perforin-deficient and granulysin-silenced T-cell lines, we demonstrate that granulysin is essential for the in vitro antiplasmodial process, whereas perforin is dispensable. Patients infected with P falciparum exhibited elevated granulysin plasma levels associated with high levels of granulysin-expressing Vδ2+ T cells endowed with parasite-specific degranulation capacity. This indicates in vivo activation of Vγ9Vδ2 T cells along with granulysin triggering and discharge during primary acute falciparum malaria. Altogether, this work identifies Vγ9Vδ2 T cells as unconventional immune effectors targeting the red blood cell–invasive extracellular P falciparum merozoites and opens novel perspectives for immune interventions harnessing the antiparasitic activity of Vγ9Vδ2 T cells to control parasite density in malaria patients.
- Published
- 2011
44. Modeling of congenital erythropoietic porphyria by RNA interference: a new tool for preclinical gene therapy evaluation
- Author
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Isabelle Lamrissi-Garcia, Cécile Ged, Véronique Guyonnet-Dupérat, Vincent Pitard, Elodie Robert-Richard, Emmanuel Richard, Magalie Lalanne, François Moreau-Gaudry, Hubert de Verneuil, and Frédéric Mazurier
- Subjects
Genetic enhancement ,Porphyria, Erythropoietic ,Congenital erythropoietic porphyria ,Biology ,Small hairpin RNA ,Mice ,RNA interference ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Lentivirus ,Hematopoietic stem cell ,Genetic Therapy ,Hematopoietic Stem Cells ,Uroporphyrinogen III Synthetase ,Haematopoiesis ,Disease Models, Animal ,medicine.anatomical_structure ,Cord blood ,Immunology ,Molecular Medicine ,RNA Interference ,Bone marrow ,K562 Cells - Abstract
Background Congenital erythropoietic porphyria (CEP) is a severe autosomal recessive disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. We recently demonstrated the definitive cure of a murine model of CEP by lentiviral vector-mediated hematopoietic stem cell (HSC) gene therapy. In the perspective of a gene therapy clinical trial, human cellular models are required to evaluate the therapeutic potential of lentiviral vectors in UROS-deficient cells. However, the rare incidence of the disease makes difficult the availability of HSCs derived from patients. Methods RNA interference (RNAi) has been used to develop a new human model of the disease from normal cord blood HSCs. Lentivectors were developed for this purpose. Results We were able to down-regulate the level of human UROS in human cell lines and primary hematopoietic cells. A 97% reduction of UROS activity led to spontaneous uroporphyrin accumulation in human erythroid bone marrow cells of transplanted immune-deficient mice, recapitulating the phenotype of cells derived from patients. A strong RNAi-induced UROS inhibition allowed us to test the efficiency of different lentiviral vectors with the aim of selecting a safer vector. Restoration of UROS activity in these small hairpin RNA-transduced CD34+ cord blood cells by therapeutic lentivectors led to a partial correction of the phenotype in vivo. Conclusions The RNAi strategy is an interesting new tool for preclinical gene therapy evaluation. Copyright © 2010 John Wiley & Sons, Ltd.
- Published
- 2010
45. Common features of gammadelta T cells and CD8(+) alphabeta T cells responding to human cytomegalovirus infection in kidney transplant recipients
- Author
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Lionel, Couzi, Vincent, Pitard, Sonia, Netzer, Isabelle, Garrigue, Marie-Edith, Lafon, Jean-François, Moreau, Jean-Luc, Taupin, Pierre, Merville, and Julie, Déchanet-Merville
- Subjects
Adult ,Male ,Immunity, Cellular ,Pilot Projects ,CD8-Positive T-Lymphocytes ,Middle Aged ,Kidney Transplantation ,T-Lymphocyte Subsets ,Case-Control Studies ,Cytomegalovirus Infections ,Humans ,Female ,Longitudinal Studies ,Prospective Studies ,Cell Proliferation - Abstract
Kidney transplant recipients infected with cytomegalovirus (CMV) undergo a persistent gammadelta T cell expansion in their peripheral blood. The anti-CMV function of these cells was previously demonstrated by their ability to kill CMV-infected cells in vitro.To gain insight into the role of gammadelta T cells within the antiviral immune network, we compared the expansion kinetics of these T cells with that of CMV pp65-specific CD8(+) alphabeta T cells in the peripheral blood of twenty-one kidney transplant recipients.Both the percentage and the absolute number of pp65-specific CD8(+) T cells and gammadelta T cells showed a concomitant increase and persistence in most of the kidney transplant recipients with CMV infection. Both cell subsets exhibited an effector/memory phenotype (CD28(-), CD27(-), and CD45RA(+)) that predominated for the entire follow-up period.In conclusion, CMV-specific CD8(+) alphabeta T cells and gammadelta T cells share common expansion kinetics and a common effector phenotype, suggesting that these cell types act similarly in response to CMV infection.
- Published
- 2009
46. Long-term expansion of effector/memory Vdelta2-gammadelta T cells is a specific blood signature of CMV infection
- Author
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Vincent, Pitard, David, Roumanes, Xavier, Lafarge, Lionel, Couzi, Isabelle, Garrigue, Marie-Edith, Lafon, Pierre, Merville, Jean-François, Moreau, and Julie, Déchanet-Merville
- Subjects
Cytotoxicity, Immunologic ,Immunity, Cellular ,T-Lymphocytes ,Cytomegalovirus Infections ,virus diseases ,Humans ,Receptors, Antigen, T-Cell, gamma-delta ,Lymphocyte Count ,Immunologic Memory ,Cells, Cultured ,Cell Proliferation ,Immunobiology - Abstract
The ability of human gammadelta T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of Vdelta2- gammadelta T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. Vdelta2- gammadelta T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas Vdelta2- gammadelta T cells were found as naive cells in CMV- patients, they virtually all exhibited the cytotoxic effector/memory phenotype in CMV+ patients, which is also observed in transplanted patients challenged with CMV. This long-term complete remodeling of the Vdelta2- gammadelta T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster gammadelta T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effector-memory Vdelta2- gammadelta T cells in the peripheral blood is a specific signature of an adaptive immune response to CMV infection of both immunocompetent and immunosuppressed patients.
- Published
- 2008
47. Modulation of lymphocyte proliferation induced by gastric MALT lymphoma-associated Helicobacter pylori strains
- Author
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Jonathan, Ferrand, David, Roumanes, Vincent, Pitard, Jean-François, Moreau, Francis, Mégraud, and Philippe, Lehours
- Subjects
Helicobacter pylori ,Gastric Mucosa ,Humans ,Lymphocytes ,Lymphoma, B-Cell, Marginal Zone ,Lymphocyte Activation ,Cell Proliferation ,Helicobacter Infections - Abstract
Helicobacter pylori infection leads to different chronic diseases, suggesting that this bacterium can evade the host immune defense system. The ability to control lymphocyte proliferation may be a mechanism leading to the development of gastric pathologies. Our aim was to characterize the effects of mucosa-associated lymphoid tissue (MALT) associated H. pylori strains on lymphocyte proliferation.We measured the in vitro proliferation of human lymphocytes originally from blood or tonsil samples in the presence or absence of viable bacteria or lysates.We showed that MALT lymphoma-associated strains are not likely to be directly responsible for anarchical B-cell proliferation in vitro. On the other hand, proliferation of prestimulated T lymphocytes was abolished in vitro by the presence of all H. pylori strains, whether associated with MALT lymphoma or not.Inhibition of T-cell proliferation may be of major importance in the gastric colonization and in the persistence of the infection. Furthermore, this inhibition may favor anarchical B-cell proliferation in vivo and predispose the host to gastric MALT lymphoma, whereas MALT-associated H. pylori strains do not appear to possess a specific capability to directly stimulate B-lymphocyte proliferation.
- Published
- 2008
48. TCR-dependent sensitization of human γδ T cells to non-myeloid IL-18 in cytomegalovirus and tumor stress surveillance
- Author
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Lionel Couzi, Sophie Daburon, Lydia Lartigue, Vincent Pitard, Séverine Loizon, Florent Guerville, Romain Marlin, Jean-François Moreau, Benjamin Faustin, and Julie Déchanet-Merville
- Subjects
Innate immune system ,Immunology ,T-cell receptor ,caspase-1 ,Biology ,γδ T cells ,Interleukin 21 ,Oncology ,inflammasome ,medicine ,Interleukin 12 ,cancer ,Immunology and Allergy ,Cytotoxic T cell ,Interferon gamma ,IL-2 receptor ,cytomegalovirus ,IL-18 ,TCR ,Original Research ,medicine.drug ,Interleukin 3 - Abstract
Human γδ T cells contribute to tissue homeostasis under normal conditions and participate in lymphoid stress surveillance against infection and tumors. However, the molecular mechanisms underlying the recognition of complex cell stress signatures by γδ T cells are still unclear. Tumor cells and human cytomegalovirus (HCMV)-infected cells are known targets of γδ T cells. We show here that many tumor and CMV-infected cells express caspase-1 inflammasomes and release interleukin (IL)-18. Engagement of the T-cell receptor (TCR) on Vδ2neg γδ T cells controlled the direct innate immune sensing of IL-18 that enhanced cytotoxicity and interferon gamma (IFNγ) production. This TCR-dependent sensitization to IL-18 was mediated by the upregulation of the innate IL-18 receptor β chain (IL-18Rβ) expression. These findings shed light on inflammasomes as a unified stress signal of tumor and infected cells to alert γδ T cells. Moreover, uncovering the TCR-mediated sensitization of γδ T cells to inflammatory mediators establishes a molecular link between the innate and adaptive immune functions of γδ T cells that could fine tune the commitment of antigen-experienced γδ T cells to inflammatory responses.
- Published
- 2015
49. Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus
- Author
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Jean-François Viallard, Patrick Blanco, Vincent Pitard, Jean-Luc Taupin, Jean-Luc Pellegrin, and Jean-François Moreau
- Subjects
Adult ,Male ,Pore Forming Cytotoxic Proteins ,Adolescent ,Immunology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Autoantigens ,Severity of Illness Index ,T-Lymphocytes, Regulatory ,Granzymes ,Interleukin 21 ,Rheumatology ,immune system diseases ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Lupus Erythematosus, Systemic ,Pharmacology (medical) ,skin and connective tissue diseases ,Aged ,Autoantibodies ,Systemic lupus erythematosus ,Lupus erythematosus ,Membrane Glycoproteins ,biology ,business.industry ,Perforin ,Serine Endopeptidases ,Cell Differentiation ,Dendritic Cells ,Middle Aged ,medicine.disease ,Nucleosomes ,Granzyme B ,Phenotype ,Granzyme ,biology.protein ,Female ,business ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Objective Cytotoxic T lymphocyte–mediated killing using granzyme B has recently been proposed to be a preferential and selective source of autoantigens in systemic autoimmune diseases, including systemic lupus erythematosus (SLE), while other reports have indicated that cytolytic activity in SLE patients was decreased. The aim of this study was to examine the phenotypic and functional status of the CD8+ T cells in SLE patients. Methods Phenotype analysis of CD8+ T cells was carried out using flow cytometry. The cytotoxic potential of CD8+ T cells and its consequences were examined in redirected-killing experiments. SLE patients with quiescent disease (n = 41) were compared with SLE patients with active disease (n = 20), normal individuals (n = 36), and control patients with vasculitis (n = 14). Cytotoxic CD8+ T cell differentiation was examined by coculture with differentiated dendritic cells (DCs) in the presence of SLE patient sera. Results Patients with disease flares were characterized by higher proportions of perforin- and/or granzyme B–positive lymphocytes with a differentiated effector phenotype (CCR7− and CD45RA+). The frequency of these cells in peripheral blood correlated with clinical disease activity as assessed by the SLE Disease Activity Index. These cells generated high amounts of soluble nucleosomes as well as granzyme B–dependent unique autoantigen fragments. Finally, the activation of DCs with serum from a patient with active lupus induced granzyme B expression in CD8+ T lymphocytes. Conclusion DCs generated in the presence of sera from SLE patients with active disease could promote the differentiation of CD8+ effector T lymphocytes that are fully functional and able to generate SLE autoantigens. Our data disclose a new and pivotal role of activated CD8+ T lymphocytes in SLE pathogenesis.
- Published
- 2005
50. Coordinated expression of Ig-like inhibitory MHC class I receptors and acquisition of cytotoxic function in human CD8+ T cells
- Author
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Nicolas Anfossi, Alain Venet, David Bossy, Jean-François Delfraissy, Olivia Bonnaud, Marc Bonneville, Marie-Alix Peyrat, Eric Vivier, Jean-Marc Doisne, Pierre Merville, Julie Déchanet-Merville, Jean-François Moreau, Vincent Pitard, Sophie Ugolini, Innate Pharma, Immunologie antivirale systémique et cérébrale, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunointervention dans les allo et xénotransplantations, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)-ITUN, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Pathologies infectieuses et cancers : aspects biologiques et thérapeutiques (PICABT), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie, Démographie et Sciences Sociales: santé reproductive, sexualité et infection à VIH (Inserm U569), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d'études démographiques (INED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Cytotoxicity, Immunologic ,Male ,T cell ,[SDV]Life Sciences [q-bio] ,Immunology ,CD1 ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Immunophenotyping ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,Leukocyte Immunoglobulin-like Receptor B1 ,Receptors, KIR ,Antigens, CD ,MHC class I ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Receptors, Immunologic ,Antigen-presenting cell ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Histocompatibility Antigens Class I ,MHC restriction ,Cytotoxicity Tests, Immunologic ,Kidney Transplantation ,3. Good health ,Cell biology ,Clone Cells ,medicine.anatomical_structure ,Cytomegalovirus Infections ,biology.protein ,HIV-1 ,Immunologic Memory ,CD8 ,030215 immunology - Abstract
MHC class I-specific inhibitory receptors are expressed by a subset of memory-phenotype CD8+ T cells. Similar to NK cells, MHC class I-specific inhibitory receptors might subserve on T cells an important negative control that participates to the prevention of autologous damage. We analyzed here human CD8+ T cells that express the Ig-like MHC class I-specific inhibitory receptors: killer cell Ig-like receptor (KIR) and CD85j. The cell surface expression of Ig-like inhibitory MHC class I receptors was found to correlate with an advanced stage of CD8+ T cell maturation as evidenced by the reduced proliferative potential of KIR+ and CD85j+ T cells associated with their high intracytoplasmic perforin content. This concomitant regulation might represent a safety mechanism to control potentially harmful cytolytic CD8+ T cells, by raising their activation threshold. Yet, KIR+ and CD85j+ T cells present distinct features. KIR+CD8+ T cells are poor IFN-γ producers upon TCR engagement. In addition, KIR are barely detectable at the surface of virus-specific T cells during the course of CMV or HIV-1 infection. By contrast, CD85j+CD8+ T cells produce IFN-γ upon TCR triggering, and represent a large fraction of virus-specific T cells. Thus, the cell surface expression of Ig-like inhibitory MHC class I receptors is associated with T cell engagement into various stages of the cytolytic differentiation pathway, and the cell surface expression of CD85j or KIR witnesses to the history of qualitatively and/or quantitatively distinct T cell activation events.
- Published
- 2004
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