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1. The proteome and transcriptome of stress granules and P bodies during human T lymphocyte activation

Author

Nicolas Curdy, Olivia Lanvin, Juan-Pablo Cerapio, Fréderic Pont, Marie Tosolini, Emeline Sarot, Carine Valle, Nathalie Saint-Laurent, Emeline Lhuillier, Camille Laurent, Jean-Jacques Fournié, and Don-Marc Franchini

Subjects
CP: Immunology, CP: Molecular biology, Biology (General), QH301-705.5
Abstract

Summary: Stress granules (SGs) and processing bodies (PBs) are membraneless cytoplasmic assemblies regulating mRNAs under environmental stress such as viral infections, neurological disorders, or cancer. Upon antigen stimulation, T lymphocytes mediate their immune functions under regulatory mechanisms involving SGs and PBs. However, the impact of T cell activation on such complexes in terms of formation, constitution, and relationship remains unknown. Here, by combining proteomic, transcriptomic, and immunofluorescence approaches, we simultaneously characterized the SGs and PBs from primary human T lymphocytes pre and post stimulation. The identification of the proteomes and transcriptomes of SGs and PBs indicate an unanticipated molecular and functional complementarity. Notwithstanding, these granules keep distinct spatial organizations and abilities to interact with mRNAs. This comprehensive characterization of the RNP granule proteomic and transcriptomic landscapes provides a unique resource for future investigations on SGs and PBs in T lymphocytes.

Published
2023
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2. Stress Granules in the Post-transcriptional Regulation of Immune Cells

Author

Nicolas Curdy, Olivia Lanvin, Sarah Cadot, Camille Laurent, Jean-Jacques Fournié, and Don-Marc Franchini

Subjects
stress granules (SG), immune cells, post-transcriptional regulation, translation, mRNA, RNA-binding proteins (RBP), Biology (General), QH301-705.5
Abstract

Immune cell activation triggers transcriptional and translational programs eliciting cellular processes, such as differentiation or proliferation, essential for an efficient immune response. These dynamic processes require an intricate orchestration of regulatory mechanisms to control the precise spatiotemporal expression of proteins. Post-transcriptional regulation ensures the control of messenger RNA metabolism and appropriate translation. Among these post-transcriptional regulatory mechanisms, stress granules participate in the control of protein synthesis. Stress granules are ribonucleoprotein complexes that form upon stress, typically under control of the integrated stress response. Such structures assemble upon stimulation of immune cells where they control selective translational programs ensuring the establishment of accurate effector functions. In this review, we summarize the current knowledge about post-transcriptional regulation in immune cells and highlight the role of stress sensors and stress granules in such regulation.

Published
2021
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3. Phased differentiation of γδ T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

Author

Juan-Pablo Cerapio, Marion Perrier, Camille-Charlotte Balança, Pauline Gravelle, Fréderic Pont, Christel Devaud, Don-Marc Franchini, Virginie Féliu, Marie Tosolini, Carine Valle, Fréderic Lopez, Anne Quillet-Mary, Loic Ysebaert, Alejandra Martinez, Jean Pierre Delord, Maha Ayyoub, Camille Laurent, and Jean-Jacques Fournie

Subjects
gamma-delta lymphocyte, scrnaseq, differentiation, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor’s blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.

Published
2021
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4. Baseline SUVmax is related to tumor cell proliferation and patient outcome in follicular lymphoma

Author

Cédric Rossi, Marie Tosolini, Pauline Gravelle, Sarah Pericart, Salim Kanoun, Solene Evrard, Julia Gilhodes, Don-Marc Franchini, Nadia Amara, Charlotte Syrykh, Pierre Bories, Lucie Oberic, Loïc Ysebaert, Laurent Martin, Selim Ramla, Philippine Robert, Claire Tabouret-Viaud, René-Olivier Casasnovas, Jean-Jacques Fournié, Christine Bezombes, and Camille Laurent

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Follicular lymphoma (FL) is the most common indolent lymphoma. Despite the clear benefit of CD20-based therapy, a subset of FL patients still progress to aggressive lymphoma. Thus, identifying early biomarkers that incorporate positron emission tomography metrics could be helpful to identify patients with a high risk of treatment failure with rituximab. We retrospectively included a total of 132 untreated FL patients separated into training and validation cohorts. Optimal threshold of baseline whole-body maximum standardized uptake (SUVmax) was first determined in the training cohort (n=48) to predict progression-free survival (PFS). The PET results were investigated along with the tumor and immune microenvironment, which were determined by immunochemistry and transcriptome studies involving gene set enrichment analyses and immune cell deconvolution, together with the tumor mutation profile. We report that baseline SUVmax>14.5 was associated with poorer PFS than baseline SUVmax≤14.5 (hazard ratio =0.28; P=0.00046). Neither immune T-cell infiltration nor immune checkpoint expression were associated with baseline PET metrics. By contrast, FL samples with Ki-67 staining ≥10% showed enrichment of cell cycle/DNA genes (P=0.013) and significantly higher SUVmax values (P=0.007). Despite similar oncogenic pathway alterations in both SUVmax groups of FL samples, four out of five cases harboring the infrequent FOXO1 transcription factor mutation were seen in FL patients with SUVmax>14.5. Thus, high baseline SUVmax reflects FL tumor proliferation and, together with Ki-67 proliferative index, can be used to identify patients at risk of early relapse with rituximab chemotherapy.

Published
2020
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5. Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma

Author

Cédric Rossi, Pauline Gravelle, Emilie Decaup, Julie Bordenave, Mary Poupot, Marie Tosolini, Don-Marc Franchini, Camille Laurent, Renaud Morin, Jean-Michel Lagarde, Loïc Ysebaert, Laetitia Ligat, Christine Jean, Ariel Savina, Christian Klein, Alba Matas Céspedes, Patricia Perez-Galan, Jean-Jacques Fournié, and Christine Bezombes

Subjects
pd-1, follicular lymphoma, anti-cd20 mabs, 3d model, γδ t cells, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Follicular lymphoma (FL) is a common non Hodgkin’s lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a ‘high’ immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL.

Published
2019
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7. Retention of the Native Epigenome in Purified Mammalian Chromatin.

Author

Andreas H Ehrensberger, Don-Marc Franchini, Philip East, Roger George, Nik Matthews, Sarah L Maslen, and Jesper Q Svejstrup

Subjects
Medicine, Science
Abstract

A protocol is presented for the isolation of native mammalian chromatin as fibers of 25-250 nucleosomes under conditions that preserve the natural epigenetic signature. The material is composed almost exclusively of histones and DNA and conforms to the structure expected by electron microscopy. All sequences probed for were retained, indicating that the material is representative of the majority of the genome. DNA methylation marks and histone marks resembled the patterns observed in vivo. Importantly, nucleosome positions also remained largely unchanged, except on CpG islands, where nucleosomes were found to be unstable. The technical challenges of reconstituting biochemical reactions with native mammalian chromatin are discussed.

Published
2015
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8. Regulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression

Author

Olivia Lanvin, Jean-Jacques Fournié, Don-Marc Franchini, Camille Laurent, Nicolas Curdy, Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), 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), CCSD, Accord Elsevier, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, antitumor immunity, T-Lymphocytes, medicine.medical_treatment, T cells, Biology, Inhibitory postsynaptic potential, Mice, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Immune system, Cancer immunotherapy, Neoplasms, exhaustion, Tumor Microenvironment, medicine, Animals, Humans, Receptors, Immunologic, Receptor, immune checkpoint, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Viral antigens, 0303 health sciences, Antitumor immunity, Cell Cycle Checkpoints, Cell Biology, Immunotherapy, Immune checkpoint, 3. Good health, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030217 neurology & neurosurgery
Abstract

International audience; T cells responding to persistent tumor or viral antigens progressively lose their functional properties, a feature known as exhaustion. This state is also characterized by cell-surface expression of multiple inhibitory immune checkpoint receptors (IRs). Cancer immunotherapy by immune checkpoint targeting has shown impressive clinical outcomes, but requires substantial improvement given the limited number of patients who benefit from the treatment. Targeting the mechanisms controlling immune checkpoint expression could represent a step towards this aim. Accumulating data indicate that this strategy can limit immune checkpoint expression, in some instances simultaneously inhibiting several immune checkpoints. This review discusses various mechanisms through which IRs are activated or regulated, and ways these mechanisms could be exploited to develop more effective future immunotherapies.

Published
2019
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9. Processive DNA demethylation via DNA deaminase-induced lesion resolution.

Author

Don-Marc Franchini, Chun-Fung Chan, Hugh Morgan, Elisabetta Incorvaia, Gopinath Rangam, Wendy Dean, Fatima Santos, Wolf Reik, and Svend K Petersen-Mahrt

Subjects
Medicine, Science
Abstract

Base modifications of cytosine are an important aspect of chromatin biology, as they can directly regulate gene expression, while DNA repair ensures that those modifications retain genome integrity. Here we characterize how cytosine DNA deaminase AID can initiate DNA demethylation. In vitro, AID initiated targeted DNA demethylation of methyl CpGs when in combination with DNA repair competent extracts. Mechanistically, this is achieved by inducing base alterations at or near methyl-cytosine, with the lesion being resolved either via single base substitution or a more efficient processive polymerase dependent repair. The biochemical findings are recapitulated in an in vivo transgenic targeting assay, and provide the genetic support of the molecular insight into DNA demethylation. This targeting approach supports the hypothesis that mCpG DNA demethylation can proceed via various pathways and mCpGs do not have to be targeted to be demethylated.

Published
2014
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10. Cancer cell adaptability: turning ribonucleoprotein granules into targets

Author

Margot, Lavalée, Nicolas, Curdy, Camille, Laurent, Jean-Jacques, Fournié, and Don-Marc, Franchini

Subjects
Ribonucleoproteins, Neoplasms, Processing Bodies, Cytoplasmic Granules, Stress Granules, Cytoplasmic Ribonucleoprotein Granules
Abstract

Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies.

Published
2021

11. Phased differentiation of γδ T and T CD8 tumorinfiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

Author

Pauline Gravelle, Marie Tosolini, Juan-Pablo Cerapio, Frédéric Pont, Maha Ayyoub, Camille Laurent, Virginie Féliu, Carine Valle, Anne Quillet-Mary, Alejandra Martinez, Loic Ysebaert, Camille-Charlotte Balança, Christel Devaud, Jean-Jacques Fournié, Don-Marc Franchini, Frédéric Lopez, Marion Perrier, Jean Pierre Delord, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d’Excellence ‘TOUCAN’ [Toulouse], Institut Carnot CALYM [Pierre-Benite], CHU Toulouse [Toulouse], Institut Claudius Regaud, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), QUILLET-MARY, Anne, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Carnot Lymphome (CALYM), and Fournié, jean-jacques

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Ontogeny, Single cell transcriptomics, [SDV]Life Sciences [q-bio], Immunology, Antigen specificity, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Biology, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, T-Lymphocyte Subsets, Neoplasms, Animals, Humans, Immunology and Allergy, RC254-282, ComputingMilieux_MISCELLANEOUS, Gamma-delta lymphocyte, Original Research, 030304 developmental biology, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tumor-infiltrating lymphocytes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, scRNAseq, differentiation, RC581-607, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunologic diseases. Allergy, Transcriptome, CD8, CD8/Lymphocytes, Research Article, Homing (hematopoietic)
Abstract

International audience; γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor's blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.

Published
2021
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12. Simultaneous in vitro characterisation of DNA deaminase function and associated DNA repair pathways.

Author

Don-Marc Franchini, Elisabetta Incorvaia, Gopinath Rangam, Heather A Coker, and Svend K Petersen-Mahrt

Subjects
Medicine, Science
Abstract

During immunoglobulin (Ig) diversification, activation-induced deaminase (AID) initiates somatic hypermutation and class switch recombination by catalysing the conversion of cytosine to uracil. The synergy between AID and DNA repair pathways is fundamental for the introduction of mutations, however the molecular and biochemical mechanisms underlying this process are not fully elucidated. We describe a novel method to efficiently decipher the composition and activity of DNA repair pathways that are activated by AID-induced lesions. The in vitro resolution (IVR) assay combines AID based deamination and DNA repair activities from a cellular milieu in a single assay, thus avoiding synthetically created DNA-lesions or genetic-based readouts. Recombinant GAL4-AID fusion protein is targeted to a plasmid containing GAL4 binding sites, allowing for controlled cytosine deamination within a substrate plasmid. Subsequently, the Xenopus laevis egg extract provides a source of DNA repair proteins and functional repair pathways. Our results demonstrated that DNA repair pathways which are in vitro activated by AID-induced lesions are reminiscent of those found during AID-induced in vivo Ig diversification. The comparative ease of manipulation of this in vitro systems provides a new approach to dissect the complex DNA repair pathways acting on defined physiologically lesions, can be adapted to use with other DNA damaging proteins (e.g. APOBECs), and provide a means to develop and characterise pharmacological agents to inhibit these potentially oncogenic processes.

Published
2013
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13. Contrôle de l’activité lymphocytaire par les granules de stress

Author

Nicolas Curdy, Don-Marc Franchini, Olivia Lanvin, and Jean-Jacques Fournié

Subjects
0303 health sciences, business.industry, Chemistry, medicine.medical_treatment, Lymphocyte, General Medicine, Immunotherapy, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Text mining, Stress granule, medicine.anatomical_structure, Immunology, medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published
2019
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14. Initiation of V(D)J recombination by Dbeta-associated recombination signal sequences: a critical control point in TCRbeta gene assembly.

Author

Don-Marc Franchini, Touati Benoukraf, Sébastien Jaeger, Pierre Ferrier, and Dominique Payet-Bornet

Subjects
Medicine, Science
Abstract

T cell receptor (TCR) beta gene assembly by V(D)J recombination proceeds via successive Dbeta-to-Jbeta and Vbeta-to-DJbeta rearrangements. This two-step process is enforced by a constraint, termed beyond (B)12/23, which prohibits direct Vbeta-to-Jbeta rearrangements. However the B12/23 restriction does not explain the order of TCRbeta assembly for which the regulation remains an unresolved issue. The initiation of V(D)J recombination consists of the introduction of single-strand DNA nicks at recombination signal sequences (RSSs) containing a 12 base-pairs spacer. An RSS containing a 23 base-pairs spacer is then captured to form a 12/23 RSSs synapse leading to coupled DNA cleavage. Herein, we probed RSS nicks at the TCRbeta locus and found that nicks were only detectable at Dbeta-associated RSSs. This pattern implies that Dbeta 12RSS and, unexpectedly, Dbeta 23RSS initiate V(D)J recombination and capture their respective Vbeta or Jbeta RSS partner. Using both in vitro and in vivo assays, we further demonstrate that the Dbeta1 23RSS impedes cleavage at the adjacent Dbeta1 12RSS and consequently Vbeta-to-Dbeta1 rearrangement first requires the Dbeta1 23RSS excision. Altogether, our results provide the molecular explanation to the B12/23 constraint and also uncover a 'Dbeta1 23RSS-mediated' restriction operating beyond chromatin accessibility, which directs Dbeta1 ordered rearrangements.

Published
2009
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15. Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes

Author

Frédéric Martins, Sarah Cadot, Carine Valle, Mary Poupot, Marie Tosolini, Anne Quillet-Mary, Francesco Dieli, Camille Laurent, Serena Meraviglia, Jean-Jacques Fournié, Pierre Milpied, Gabriele Pizzolato, Delphine Labourdette, Julie Déchanet-Merville, Don-Marc Franchini, Hannah Kaminski, Loic Ysebaert, Frédéric Pont, Pierre Merville, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), Université de Bordeaux (UB), Immunologie et Cancérologie Intégrative, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Laboratoire de Génétique Cellulaire (LGC), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biopathology and Medical Biotechnologies, University of Palermo, Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Pizzolato, Gabriele, Kaminski, Hannah, Tosolini, Marie, Franchini, Don-Marc, Pont, Fréderic, Martins, Fréderic, Valle, Carine, Labourdette, Delphine, Cadot, Sarah, Quillet-Mary, Anne, Poupot, Mary, Laurent, Camille, Ysebaert, Loic, Meraviglia, Serena, Dieli, Francesco, Merville, Pierre, Milpied, Pierre, Déchanet-Merville, Julie, Fournié, Jean-Jacques, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), ERL 5294, Centre National de la Recherche Scientifique (CNRS), Programme Hospitalo, Universitaire en Cancérologie (CAPTOR), Institut Carnot Lymphome (CALYM), Humanitas University, Università degli studi di Palermo - University of Palermo, Central Laboratory of Advanced Diagnosis and Biomedical Research, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire de Bordeaux (CHU de Bordeaux), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (Inserm), Universite Toulouse III: Paul Sabatier, Laboratoire d'Excellence Toulouse Cancer [ANR11-LABX], Programme Hospitalo-Universitaire en Cancerologie CAPTOR [ANR11-PHUC0001], SIRIC Bordeaux Research in Oncology, Ligue nationale contre le cancer, Fondation pour la Recherche Medicale, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Université de Toulouse, Institut Carnot Lymphome CALYM, CNRS, ImmunoConcEpT, UMR 5164, Université de Bordeaux, PlateformeGeT, Genotoul, Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), ProdInra, Archive Ouverte, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, Lymphocyte, [SDV]Life Sciences [q-bio], CD8-Positive T-Lymphocytes, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Transcriptome, 0302 clinical medicine, T-Lymphocyte Subsets, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cytotoxic T cell, single-cell RNA-sequencing, Cells, Cultured, T-lymphocytes, ComputingMilieux_MISCELLANEOUS, Cancer, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, gamma delta T lymphocyte, Receptors, Antigen, T-Cell, gamma-delta, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, PNAS Plus, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, γδ T lymphocyte, expression des gènes, Adult, T cell, Biology, lymphocyte, Peripheral blood mononuclear cell, 03 medical and health sciences, Antigen, séquençage arnr 16s, medicine, Humans, Cell Proliferation, 030304 developmental biology, human immunology, Base Sequence, Sequence Analysis, RNA, T-cell receptor, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Leukocytes, Mononuclear, Immunologic Memory, transcriptome, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t -distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV + and CMV − donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.

Published
2019
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16. Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma

Author

Renaud Morin, Don-Marc Franchini, Loic Ysebaert, Christine Bezombes, Cédric Rossi, J. M. Lagarde, Jean-Jacques Fournié, Christine Jean, Ariel Savina, Julie Bordenave, Mary Poupot, Patricia Pérez-Galán, Alba Matas Céspedes, Camille Laurent, Pauline Gravelle, Marie Tosolini, Emilie Decaup, Christian Klein, Laetitia Ligat, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CERPER Institut de Recherche Pierre Fabre, Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE-PIERRE FABRE, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre de Physiopathologie Toulouse Purpan (CPTP), Poupot, Mary, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégrative, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Pierre Fabre Dermo-Cosmétique, Pierre Fabre Applied Skin Research Centre, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Surfaces Cellulaires et Signalisation chez les Végétaux (SCSV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut de Mathématiques de Bourgogne [Dijon] (IMB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche Pierre Fabre, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, 3D model, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, [SDV]Life Sciences [q-bio], Immunology, Cell, Follicular lymphoma, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, CD16, lcsh:RC254-282, γδ T cells, 03 medical and health sciences, 0302 clinical medicine, Immune system, follicular lymphoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, PD-1, medicine, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Original Research, Antibody-dependent cell-mediated cytotoxicity, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Lymphoma, Cytolysis, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, anti-CD20 MAbs, lcsh:RC581-607
Abstract

International audience; Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL.

Published
2018
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17. TCRVγ9 γδ T Cell Response to IL-33: A CD4 T Cell–Dependent Mechanism

Author

Caroline Duault, Mary Poupot, Corinne Cayrol, Don Marc Franchini, Jean-Jacques Fournié, Julien Familliades, Jean-Philippe Girard, Stéphane Roga, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), TOUCAN Laboratoire d'Excellence Toulouse Cancer, Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Poupot, Mary, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, T cell, Immunology, Streptamer, Biology, Lymphocyte Activation, Zoledronic Acid, Interferon-gamma, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Antigens, CD, Neoplasms, medicine, Humans, Immunology and Allergy, Cytotoxic T cell, IL-2 receptor, Antigen-presenting cell, Cells, Cultured, Cell Proliferation, Butyrophilins, Diphosphonates, Tumor Necrosis Factor-alpha, Imidazoles, Endothelial Cells, CD28, Receptors, Antigen, T-Cell, gamma-delta, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Th1 Cells, Interleukin-33, Natural killer T cell, 3. Good health, Diphosphates, 030104 developmental biology, medicine.anatomical_structure, Leukocytes, Mononuclear, Cancer research, Interleukin-2, Immunotherapy, 030215 immunology
Abstract

The availability of specific stimuli to induce the anticancer cytotoxicity of human TCRVγ9-expressing T lymphocytes has allowed the development of γδ T cell–based cancer immunotherapies. However, the stringent dependence of such strategies on the inherently toxic IL-2 has raised safety concerns for patients, justifying a search for alternative methods for inducing γδ T cell stimulation. IL-33 is a γ-chain receptor-independent cytokine of the IL-1 superfamily that is expressed by endothelial cells from a tumor microenvironment and can sustain Th1 and Th2 immune responses. Therefore, we investigated its ability to support the stimulation of human TCRVγ9+ γδ T cells. In this study, we report that IL-33 efficiently sustained the in vitro activation of Vγ9 T lymphocytes by synthetic phosphoantigens, zoledronate, and a BTN3A1 Ab in the absence of an exogenous supply of IL-2. IL-33 was as potent as IL-2 in allowing the proliferative amplification of Vγ9 T cells isolated from PBMC following activation by the synthetic phosphoantigen bromohydrin pyrophosphate. IL-33 also induced an identical maturation into TNF-α– and IFN-γ–producing Th1 effector memory cells, and IL-33–stimulated cells showed an equivalent cytotoxicity for various tumor cells in vitro. Finally, we found that the bioactivity of IL-33 on the Vγ9 T cell was indirectly mediated through contact with CD4 T cells and IL-2 production by CD4 T cells and Vγ9 T cells themselves. These data posit IL-33 as an alternative to IL-2 for Vγ9 T cell–based cancer immunotherapies.

Published
2016
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18. Supplementary Information from Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMTs inhibitors

Author

Halby, Ludovic, Marechal, Nils, Pechalrieu, Dany, Cura, Vincent, Don-Marc Franchini, Faux, Céline, Fréderic Alby, Troffer-Charlier, Nathalie, Srikanth Kudithipudi, Jeltsch, Albert, Aouadi, Wahiba, Decroly, Etienne, Guillemot, Jean-Claude, Page, Patrick, Ferroud, Clotilde, Bonnefond, Luc, Guianvarc'h, Dominique, Cavarelli, Jean, and Arimondo, Paola B.

Abstract

NMR attribution, complementary Materials & Methods and Biological results

Published
2018
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19. Microtubule-Driven Stress Granule Dynamics Regulates Inhibitory Immune Checkpoints Expression in T Cells

Author

Camille Laurent, Don-Marc Franchini, Laetitia Ligat, Stefania Millevoi, Frédéric Pont, Morgane Lebras, Paola B. Arimondo, Fabien Despas, Cédric Rossi, Jean-Jacques Fournié, Clara-Maria Scarlata, Emilie Patras de Campaigno, Maryse Lapeyre-Mestre, Maha Ayyoub, Olivia Lanvin, Anne Cammas, Sarah Péricart, and Marie Tosolini

Subjects
Stress granule, Immune system, TIGIT, Cancer immunotherapy, Chemistry, Microtubule, medicine.medical_treatment, medicine, BTLA, Kinesin, Immune checkpoint, Cell biology
Abstract

Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that requires microtubules and the kinesin 1 molecular motor to proceed to translation. Hence PD-1 expression is highly sensitive to microtubule or stress granules inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveal that this mechanism also controls the translation of CTLA4, LAG3, TIM3, TIGIT and BTLA but not of the stimulatory co-receptors OX40, GITR and 4-1BB. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significant higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immune regulation with high importance for cancer immunotherapy.

Published
2018
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20. BTN3A1-antibodies and phosphoantigens: TCRVγ9Vδ2 'see' the difference

Author

Don Marc Franchini, Marie Michelas, Mary Poupot, Olivia Lanvin, Jean-Jacques Fournié, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), Programme Hospitalo-Universitaire en Cancérologie CAPTOR [Cancer Pharmacology of Toulouse and Region] (IUCT Oncopole), IUCT Oncopole - Institut Universitaire du Cancer de Toulouse, and Poupot, Mary

Subjects
0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.drug_class, T-Lymphocytes, Immunology, Biology, Monoclonal antibody, Major histocompatibility complex, Lymphocyte Activation, 03 medical and health sciences, Mice, Antigens, CD, medicine, Immunology and Allergy, Animals, Humans, Butyrophilin, Antigen recognition, Molecular interactions, Gamma delta lymphocyte, Human blood, IL-2, Receptors, Antigen, T-Cell, gamma-delta, Phosphoantigen, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Human cell, BTN3A1, 030104 developmental biology, nervous system, biology.protein, Interleukin-2, Antibody, CD80
Abstract

Comment onButyrophilin 3A (BTN3A, CD277)-specific antibody 20.1 differentially activates Vγ9Vδ2 TCR clonotypes and interferes with phosphoantigen activation. [Eur J Immunol. 2017]; International audience; Human blood γδ T lymphocytes express TCRVγ9Vδ2 and respond to nonpeptide phosphoantigens (PAgs) by a mysterious mechanism involving the BTN3A1 (CD277) molecule . BTN3A1 is a butyrophilin-like protein related to CD80, PD-L1, and MHC, and is either a presenting or a co-stimulatory molecule for PAgs. Although the precise roles and molecular interactions with the TCRVγ9Vδ2 are currently not determined, it is commonly thought that all TCRVγ9Vδ2 lymphocytes 'see' PAg and BTN3A1 together, presumably in a single molecular recognition event. But whether this recognition event could be reproduced in a simplified model was not addressed in previous studies. In this issue, Starick et al. (Eur. J. Immunol. 2017. 47: 982-992) compared the response of three TCRVγ9Vδ2 pairs of murine and human cell transfectants to PAg and anti-BTN3A1 antibodies using IL-2 release as a readout. The authors found that although the two murine transfectants responded similarly to either stimuli, one murine TCRVγ9Vδ2 transfectant reacted to PAgs but not to anti-BTN3A1 (mAb 20.1). Human transductants behave in a similar fashion, demonstrating that TCRVγ9Vδ2 lymphocytes differentiate PAg and BTN3A1 signals, while species of the transductants unmask this differential sensitivity. Indeed, understanding the puzzling mode of antigen recognition by γδ T lymphocytes will be essential for developing γδ T-cell-based immunotherapies, and the authors of this study now demonstrate that TCRVγ9Vδ2 lymphocytes are able to differentiate the PAg and BTN3A1 stimuli.

Published
2017
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21. AID and APOBEC deaminases: balancing DNA damage in epigenetics and immunity

Author

Svend K. Petersen-Mahrt and Don-Marc Franchini

Subjects
APOBEC, Genetics, Cancer Research, DNA damage, DNA repair, Immunity, Immunoglobulins, Somatic hypermutation, Biology, Epigenesis, Genetic, DNA-Binding Proteins, chemistry.chemical_compound, DNA demethylation, chemistry, Cytidine Deaminase, Proto-Oncogene Proteins, APOBEC Deaminases, Animals, Humans, Epigenetics, DNA, DNA Damage
Abstract

DNA mutations and genomic recombinations are the origin of oncogenesis, yet parts of developmental programs as well as immunity are intimately linked to, or even depend on, such DNA damages. Therefore, the balance between deleterious DNA damages and organismal survival utilizing DNA editing (modification and repair) is in continuous flux. The cytosine deaminases AID/APOBEC are a DNA editing family and actively participate in various biological processes. In conjunction with altered DNA repair, the mutagenic potential of the family allows for APOBEC3 proteins to restrict viral infection and transposons propagation, while AID can induce somatic hypermutation and class switch recombination in antibody genes. On the other hand, the synergy between effective DNA repair and the nonmutagenic potential of the DNA deaminases can induce local DNA demethylation to support epigenetic cellular identity. Here, we review the current state of knowledge on the mechanisms of action of the AID/APOBEC family in immunity and epigenetics.

Published
2014
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22. 5-Methylcytosine DNA Demethylation: More Than Losing a Methyl Group

Author

Don-Marc Franchini, Svend K. Petersen-Mahrt, and Kerstin-Maike Schmitz

Subjects
DNA Repair, Transcription, Genetic, DNA damage, DNA repair, Biology, Epigenesis, Genetic, Histones, chemistry.chemical_compound, Transcription (biology), Proto-Oncogene Proteins, Genetics, Animals, Humans, Embryonic Stem Cells, Demethylation, Mammals, DNA Methylation, Chromatin, DNA-Binding Proteins, 5-Methylcytosine, DNA demethylation, chemistry, Biochemistry, Deamination, Mutation, DNA methylation, CpG Islands, DNA, DNA Damage
Abstract

Demethylation of 5-methylcytosine in DNA is integral to the maintenance of an intact epigenome. The balance between the presence or absence of 5-methylcytosine determines many physiological aspects of cell metabolism, with a turnover that can be measured in minutes to years. Biochemically, addition of the methyl group is shared among all living kingdoms and has been well characterized, whereas the removal or reversion of this mark seems diverse and much less understood. Here, we present a summary of how DNA demethylation can be initiated directly, utilizing the ten-eleven translocation (TET) family of proteins, activation-induced deaminase (AID), or other DNA modifying enzymes, or indirectly, via transcription, RNA metabolism, or DNA repair; how intermediates in those pathways are substrates of the DNA repair machinery; and how demethylation pathways are linked and possibly balanced, avoiding mutations.

Published
2012
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23. PD-1 IMMUNE CHECKPOINT BLOCKADE IMPROVES ANTI-CD20 BASED IMMUNOTHERAPY IN FOLLICULAR LYMPHOMA

Author

Don-Marc Franchini, F. Pont, Julie Bordenave, Christian Klein, Camille Laurent, Laetitia Ligat, Jean-Jacques Fournié, Pauline Gravelle, Marie Tosolini, Emilie Decaup, Mary Poupot, Patricia Pérez-Galán, Cédric Rossi, Christine Jean, Ariel Savina, and Christine Bezombes

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Follicular lymphoma, Hematology, General Medicine, Immunotherapy, medicine.disease, Immune checkpoint, Blockade, Oncology, Immunology, Medicine, Anti cd20, business
Published
2017
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24. Boosting Gamma Delta T Cells-Mediated ADCC By PD-1 Blockade in Follicular Lymphoma

Author

J. M. Lagarde, Loic Ysebaert, Camille Laurent, Julie Bordenave, Renaud Morin, Pauline Gravelle, Marie Tosolini, Emilie Decaup, Don-Marc Franchini, Mary Poupot, Jean-Jacques Fournié, Christian Klein, Patricia Pérez-Galán, Cédric Rossi, Christine Bezombes, and Ariel Savina

Subjects
Antibody-dependent cell-mediated cytotoxicity, medicine.medical_treatment, Gamma/Delta T-Lymphocyte, Immunology, Follicular lymphoma, Cell Biology, Hematology, Immunotherapy, Biology, medicine.disease, Biochemistry, Lymphoma, Immune system, medicine.anatomical_structure, medicine, Cancer research, Intraepithelial lymphocyte, Gamma delta T cell
Abstract

Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVgamma9Vdelta2 gamma delta T lymphocytes and high expression of gamma delta cytolytic markers. In a 3D co-culture assay (MALC), gamma delta T cells could mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating gamma delta T lymphocytes with ADCC capacity, impaired these functions. In conclusion, we identify a PD1-regulated gamma delta T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting gamma delta anti-tumor function in FL. Disclosures Morin: IMACTIV-3D: Employment. Lagarde:IMACTIV-3D: Employment. Savina:Institut Roche: Employment. Klein:F. Hoffmann-La Roche Ltd.: Employment, Other: stock, Patents & Royalties.

Published
2018
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25. Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors

Author

Etienne Decroly, Nils Marechal, Jean Cavarelli, V. Cura, Céline Faux, L. Bonnefond, Dominique Guianvarc'h, Frédéric Alby, Patrick Page, Paola B. Arimondo, Ludovic Halby, Jean-Claude Guillemot, Nathalie Troffer-Charlier, Don-Marc Franchini, Srikanth Kudithipudi, Clotilde Ferroud, Dany Pechalrieu, Wahiba Aouadi, Albert Jeltsch, Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacochimie Pierre Fabre Dermo-Cosmétique, Centre de Recherche Pierre Fabre, Universität Stuttgart [Stuttgart], Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE-PIERRE FABRE, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, PRMT inhibitor, Methyltransferase, Chemical biology, DNA methyltransferase, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, chemical probes, Catalytic Domain, Histone methylation, Humans, histone methylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Binding site, DNA methylation, epigenetics, Articles, Methyltransferases, transition state analogues, Methylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 3. Good health, 030104 developmental biology, Biochemistry, chemistry, Peptides, General Agricultural and Biological Sciences, DNA
Abstract

DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound 4 and its derivative 2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound 4 binds to the PRMT4 active site, displacing strongly the S -adenosyl- l -methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.

Published
2018
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26. Regulation of V(D)J recombination

Author

Pierre Ferrier, Salvatore Spicuglia, and Don Marc Franchini

Subjects
Recombination, Genetic, Regulation of gene expression, Genetics, Recombinase activity, Immunology, V(D)J recombination, Models, Immunological, Locus (genetics), Biology, Recombinase, Animals, Humans, Immunology and Allergy, Cre-Lox recombination, VDJ Recombinases, Gene, Alleles, Floxing
Abstract

Adaptive immunity is intimately linked to the expression of antigen-specific immunoglobulin and T cell receptor genes and their recombination assembly from germline V, D and J gene segments. This developmentally regulated process relies on the activity of the Rag1-Rag2 recombinase, on accessibility of target gene segments and on monoallelic gene activation. Recent studies have revealed new mechanisms that, along with recombinase activity and locus accessibility, are likely to contribute to the control of V(D)J recombination, including target-site bias by the recombinase, RNA processing and chromosome positioning.

Published
2006
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27. RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement

Author

Don-Marc Franchini, Emmanuelle Six, Els Verhoeyen, Ludovic Lhermitte, Isabelle André-Schmutz, Vahid Asnafi, Stéphanie Gon, Dominique Payet-Bornet, Laurent Vanhille, Jérôme Larghero, Christian Reimann, Sandrine Le Noir, Salvatore Spicuglia, Agata Cieslak, Bertrand Nadel, Jonathan Bond, Amélie Trinquand, Elizabeth Macintyre, Anton W. Langerak, Mathieu Simonin, Patrick Villarese, CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cellular differentiation, [SDV]Life Sciences [q-bio], Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, Molecular Sequence Data, Immunology, Locus (genetics), chemical and pharmacologic phenomena, Biology, Article, Recombination-activating gene, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, T-Lymphocyte Subsets, hemic and lymphatic diseases, Recombinase, Animals, Humans, Immunology and Allergy, Lymphopoiesis, Binding site, VDJ Recombinases, 030304 developmental biology, Homeodomain Proteins, 0303 health sciences, Binding Sites, Base Sequence, [ SDV ] Life Sciences [q-bio], T-cell receptor, Correction, Cell Differentiation, hemic and immune systems, DNA, Molecular biology, Chromatin, Kinetics, HEK293 Cells, embryonic structures, Core Binding Factor Alpha 2 Subunit, 030215 immunology
Abstract

Within the human TCR-α/δ locus, ordered rearrangements requires RUNX1, which binds to the Dδ2-23RSS and interacts with RAG1 to enhance RAG1 deposition at this site. Absence of this RUNX1 binding site in the homologous murine Dδ1-23RSS offers an explanation for the lack of ordered TCR-δ gene assembly in mice., V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus, Dδ2-Dδ3 rearrangements occur at a very immature thymic, CD34+/CD1a−/CD7+dim stage, before Dδ2(Dδ3)-Jδ1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility. Importantly, direct Dδ2-Jδ1 rearrangements are prohibited by a B12/23 restriction and ordered human TCR-δ gene assembly requires RUNX1 protein, which binds to the Dδ2-23RSS, interacts with RAG1, and enhances RAG1 deposition at this site. This RUNX1-mediated V(D)J recombinase targeting imposes the use of two Dδ gene segments in human TCR-δ chains. Absence of this RUNX1 binding site in the homologous mouse Dδ1-23RSS provides a molecular explanation for the lack of ordered TCR-δ gene assembly in mice and may underlie differences in early lymphoid differentiation between these species.

Published
2014
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28. Processive DNA Demethylation via DNA Deaminase-Induced Lesion Resolution

Author

Elisabetta Incorvaia, Fátima Santos, Hugh Morgan, Svend K. Petersen-Mahrt, Gopinath Rangam, Don-Marc Franchini, Wendy Dean, CF Chan, and Wolf Reik

Subjects
DNA damage, DNA repair, DNA recombination, Immunology, lcsh:Medicine, Gene Expression, Mice, Transgenic, Biochemistry, Antibodies, chemistry.chemical_compound, Mice, Cytidine Deaminase, Molecular Cell Biology, DNA metabolism, Genetics, Animals, Gene Regulation, lcsh:Science, Polymerase, Multidisciplinary, Immune System Proteins, biology, Biology and life sciences, lcsh:R, Proteins, DNA, Cell Biology, DNA Methylation, Molecular biology, Acquired Immune System, Cell biology, Chromatin, DNA demethylation, chemistry, CpG site, Immune System, DNA methylation, biology.protein, lcsh:Q, Epigenetics, CpG Islands, DNA modification, Research Article, DNA Damage
Abstract

Base modifications of cytosine are an important aspect of chromatin biology, as they can directly regulate gene expression, while DNA repair ensures that those modifications retain genome integrity. Here we characterize how cytosine DNA deaminase AID can initiate DNA demethylation. In vitro, AID initiated targeted DNA demethylation of methyl CpGs when in combination with DNA repair competent extracts. Mechanistically, this is achieved by inducing base alterations at or near methyl-cytosine, with the lesion being resolved either via single base substitution or a more efficient processive polymerase dependent repair. The biochemical findings are recapitulated in an in vivo transgenic targeting assay, and provide the genetic support of the molecular insight into DNA demethylation. This targeting approach supports the hypothesis that mCpG DNA demethylation can proceed via various pathways and mCpGs do not have to be targeted to be demethylated.

Published
2014

29. Simultaneous in vitro characterisation of DNA deaminase function and associated DNA repair pathways

Author

Svend K. Petersen-Mahrt, Heather A. Coker, Gopinath Rangam, Elisabetta Incorvaia, and Don-Marc Franchini

Subjects
Cell Extracts, DNA Repair, DNA repair, DNA damage, Xenopus, Somatic hypermutation, lcsh:Medicine, DNA-Directed DNA Polymerase, law.invention, chemistry.chemical_compound, law, Cytidine Deaminase, Animals, Humans, Biotinylation, lcsh:Science, Ovum, Multidisciplinary, biology, lcsh:R, DNA, DNA repair protein XRCC4, Fusion protein, Molecular biology, Proliferating cell nuclear antigen, Cell biology, chemistry, biology.protein, Recombinant DNA, lcsh:Q, Research Article, DNA Damage, Plasmids
Abstract

During immunoglobulin (Ig) diversification, activation-induced deaminase (AID) initiates somatic hypermutation and class switch recombination by catalysing the conversion of cytosine to uracil. The synergy between AID and DNA repair pathways is fundamental for the introduction of mutations, however the molecular and biochemical mechanisms underlying this process are not fully elucidated. We describe a novel method to efficiently decipher the composition and activity of DNA repair pathways that are activated by AID-induced lesions. The in vitro resolution (IVR) assay combines AID based deamination and DNA repair activities from a cellular milieu in a single assay, thus avoiding synthetically created DNA-lesions or genetic-based readouts. Recombinant GAL4-AID fusion protein is targeted to a plasmid containing GAL4 binding sites, allowing for controlled cytosine deamination within a substrate plasmid. Subsequently, the Xenopus laevis egg extract provides a source of DNA repair proteins and functional repair pathways. Our results demonstrated that DNA repair pathways which are in vitro activated by AID-induced lesions are reminiscent of those found during AID-induced in vivo Ig diversification. The comparative ease of manipulation of this in vitro systems provides a new approach to dissect the complex DNA repair pathways acting on defined physiologically lesions, can be adapted to use with other DNA damaging proteins (e.g. APOBECs), and provide a means to develop and characterise pharmacological agents to inhibit these potentially oncogenic processes.

Published
2013

30. AID in Immunodeficiency and Cancer

Author

Svend K. Petersen-Mahrt, Anne Durandy, Pauline Gardès, Katharina L. Willmann, Sven Kracker, Don-Marc Franchini, and Maria T. Simon

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, Cancer, medicine.disease, business, Immunodeficiency
Published
2010
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31. Initiation of V(D)J recombination by Dbeta-associated recombination signal sequences: a critical control point in TCRbeta gene assembly

Author

Sébastien Jaeger, Dominique Payet-Bornet, Touati Benoukraf, Pierre Ferrier, Don-Marc Franchini, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-06-BYOS-0006,IntegraTcells,Analyse et Modélisation Intégrative du Développement des Lymphocytes T(2006), European Project: MRTN-CT-2006-035733, Haon, Marie Laure, Biologie systémique (BIOSYS) - Analyse et Modélisation Intégrative du Développement des Lymphocytes T - - IntegraTcells2006 - ANR-06-BYOS-0006 - BIOSYS - VALID, European Union FP6 Marie Curie Research Training Network - MRTN-CT-2006-035733 - INCOMING, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
MESH: Signal Transduction, Mice, chemistry.chemical_compound, 0302 clinical medicine, Recombination signal sequences, MESH: Animals, MESH: DNA Cleavage, VDJ Recombinases, Gene Rearrangement, Recombination, Genetic, 0303 health sciences, DNA cleavage, Multidisciplinary, Thymocytes, MESH: VDJ Recombinases, V(D)J recombination, Chromatin, Cell biology, Polymerase chain reaction, MESH: DNA, Single-Stranded, Genes, T-Cell Receptor beta, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Recombination, Genetic, Recombination, Research Article, Signal Transduction, [SDV.IMM] Life Sciences [q-bio]/Immunology, DNA recombination, MESH: Gene Rearrangement, Science, Genetic loci, Immunology, MESH: Genes, T-Cell Receptor beta, DNA, Single-Stranded, chemical and pharmacologic phenomena, Biology, Cleavage (embryo), 03 medical and health sciences, MESH: Mice, Inbred C57BL, Animals, Mammalian genomics, Molecular Biology, MESH: Mice, 030304 developmental biology, Molecular Biology/Recombination, T-cell receptor, Gene rearrangement, Molecular biology, Probe hybridization, Mice, Inbred C57BL, chemistry, Immunology/Genetics of the Immune System, DNA, 030215 immunology
Abstract

International audience; T cell receptor (TCR) beta gene assembly by V(D)J recombination proceeds via successive Dbeta-to-Jbeta and Vbeta-to-DJbeta rearrangements. This two-step process is enforced by a constraint, termed beyond (B)12/23, which prohibits direct Vbeta-to-Jbeta rearrangements. However the B12/23 restriction does not explain the order of TCRbeta assembly for which the regulation remains an unresolved issue. The initiation of V(D)J recombination consists of the introduction of single-strand DNA nicks at recombination signal sequences (RSSs) containing a 12 base-pairs spacer. An RSS containing a 23 base-pairs spacer is then captured to form a 12/23 RSSs synapse leading to coupled DNA cleavage. Herein, we probed RSS nicks at the TCRbeta locus and found that nicks were only detectable at Dbeta-associated RSSs. This pattern implies that Dbeta 12RSS and, unexpectedly, Dbeta 23RSS initiate V(D)J recombination and capture their respective Vbeta or Jbeta RSS partner. Using both in vitro and in vivo assays, we further demonstrate that the Dbeta1 23RSS impedes cleavage at the adjacent Dbeta1 12RSS and consequently Vbeta-to-Dbeta1 rearrangement first requires the Dbeta1 23RSS excision. Altogether, our results provide the molecular explanation to the B12/23 constraint and also uncover a 'Dbeta1 23RSS-mediated' restriction operating beyond chromatin accessibility, which directs Dbeta1 ordered rearrangements.

Published
2009
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32. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum

Author

Edgardo Moreno, Don-Marc Franchini, Jean-Pierre Gorvel, Jean Celli, Chantal de Chastellier, and Javier Pizarro-Cerdá

Subjects
Endosome, Calnexin, Virulence Factors, Immunology, Endocytic cycle, Green Fluorescent Proteins, BRUCELLA ABORTUS, Brucella abortus, Brucella, Vacuole, Endosomes, macrophage, TYPE IV SECRETION, Endoplasmic Reticulum, Membrane Fusion, Brucellosis, Article, Microbiology, Mice, Bacterial Proteins, Antigens, CD, trafficking, Immunology and Allergy, Animals, Humans, Secretion, BRUCELLA, Cells, Cultured, biology, Endoplasmic reticulum, Macrophages, Lysosome-Associated Membrane Glycoproteins, Membrane Proteins, biology.organism_classification, type IV secretion, Endocytosis, Vesicular transport protein, Mice, Inbred C57BL, Luminescent Proteins, BRUCELOSIS, MAMMALS, Female, Intracellular, Biomarkers, MAMIFEROS
Abstract

The intracellular pathogen Brucella is the causative agent of brucellosis, a worldwide zoonosis that affects mammals, including humans. Essential to Brucella virulence is its ability to survive and replicate inside host macrophages, yet the underlying mechanisms and the nature of the replica tive compartment remain unclear. Here we show in a model of Brucella abortus infection of mu rine bone marrow–derived macrophages that a fraction of the bacteria that survive an initial macrophage killing proceed to replicate in a compartment segregated from the endocytic path way. The maturation of the Brucella-containing vacuole involves sustained interactions and fusion with the endoplasmic reticulum (ER), which creates a replicative compartment with ER-like properties. The acquisition of ER membranes by replicating Brucella is independent of ER-Golgi COPI-dependent vesicular transport. A mutant of the VirB type IV secretion system, which is necessary for intracellular survival, was unable to sustain interactions and fuse with the ER, and was killed via eventual fusion with lysosomes. Thus, we demonstrate that live intracellular Bru cella evade macrophage killing through VirB-dependent sustained interactions with the ER. Moreover, we assign an intracellular function to the VirB system, as being required for late mat uration events necessary for the biogenesis of an ER-derived replicative organelle. El patógeno intracelular Brucella es el agente causante de la brucelosis, una zoonosis mundial que afecta a los mamíferos, incluidos los humanos. La capacidad de Brucella de sobrevivir y replicarse en los macrófagos del huésped es esencial para su virulencia. replicarse en el interior de los macrófagos del huésped, pero los mecanismos subyacentes y la naturaleza del compartimento replicativo siguen sin estar claros. En este caso, demostramos en un modelo de infección por Brucella abortus de macrófagos murinos derivados de la médula ósea que una fracción de las bacterias que sobreviven a la muerte inicial de los macrófagos se replica. de los macrófagos procede a replicarse en un compartimento segregado de la vía endocítica. La maduración de la vacuola que contiene Brucella implica interacciones sostenidas y fusión con el retículo endoplásmico (RE), lo que crea un compartimento replicativo con propiedades propiedades similares a las del RE. La adquisición de las membranas del RE por parte de la Brucella replicante es independiente del transporte vesicular dependiente del RE-Golgi El transporte vesicular dependiente de COPI. Un mutante del sistema de secreción de tipo IV de VirB, que es necesaria para la supervivencia intracelular, fue incapaz de mantener interacciones y fusionarse con el RE, y se mató a través de una eventual fusión con los lisosomas. Así, demostramos que las Brucellas intracelulares vivas evaden la muerte de los macrófagos a través de interacciones sostenidas dependientes de VirB con el RE. Además, asignamos una función intracelular al sistema VirB, ya que se requiere para los eventos de maduración tardía necesarios para la biogénesis de un orgánulo replicativo derivado del RE Universidad Nacional, Costa Rica Escuela de Medicina Veterinaria

Published
2003

33. BTN3A1-antibodies and phosphoantigens: TCRVγ9Vδ2 'see' the difference.

Author

Franchini, Don‐Marc, Michelas, Marie, Lanvin, Olivia, Poupot, Mary, and Fournié, Jean Jacques

Abstract

Human blood γδ T lymphocytes express TCRVγ9Vδ2 and respond to nonpeptide phosphoantigens (PAgs) by a mysterious mechanism involving the BTN3A1 (CD277) molecule . BTN3A1 is a butyrophilin-like protein related to CD80, PD-L1, and MHC, and is either a presenting or a co-stimulatory molecule for PAgs. Although the precise roles and molecular interactions with the TCRVγ9Vδ2 are currently not determined, it is commonly thought that all TCRVγ9Vδ2 lymphocytes 'see' PAg and BTN3A1 together, presumably in a single molecular recognition event. But whether this recognition event could be reproduced in a simplified model was not addressed in previous studies. In this issue, Starick et al. ( Eur. J. Immunol. 2017. 47: 982-992) compared the response of three TCRVγ9Vδ2 pairs of murine and human cell transfectants to PAg and anti-BTN3A1 antibodies using IL-2 release as a readout. The authors found that although the two murine transfectants responded similarly to either stimuli, one murine TCRVγ9Vδ2 transfectant reacted to PAgs but not to anti-BTN3A1 (mAb 20.1). Human transductants behave in a similar fashion, demonstrating that TCRVγ9Vδ2 lymphocytes differentiate PAg and BTN3A1 signals, while species of the transductants unmask this differential sensitivity. Indeed, understanding the puzzling mode of antigen recognition by γδ T lymphocytes will be essential for developing γδ T-cell-based immunotherapies, and the authors of this study now demonstrate that TCRVγ9Vδ2 lymphocytes are able to differentiate the PAg and BTN3A1 stimuli. [ABSTRACT FROM AUTHOR]

Published
2017
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36. Processive DNA Demethylation via DNA Deaminase-Induced Lesion Resolution.

Author

Franchini, Don-Marc, Chan, Chun-Fung, Morgan, Hugh, Incorvaia, Elisabetta, Rangam, Gopinath, Dean, Wendy, Santos, Fatima, Reik, Wolf, and Petersen-Mahrt, Svend K.

Subjects
DNA demethylation, CYTOSINE deaminase, DNA repair, GENE expression, GENE targeting, BIOCHEMISTRY
Abstract

Base modifications of cytosine are an important aspect of chromatin biology, as they can directly regulate gene expression, while DNA repair ensures that those modifications retain genome integrity. Here we characterize how cytosine DNA deaminase AID can initiate DNA demethylation. In vitro, AID initiated targeted DNA demethylation of methyl CpGs when in combination with DNA repair competent extracts. Mechanistically, this is achieved by inducing base alterations at or near methyl-cytosine, with the lesion being resolved either via single base substitution or a more efficient processive polymerase dependent repair. The biochemical findings are recapitulated in an in vivo transgenic targeting assay, and provide the genetic support of the molecular insight into DNA demethylation. This targeting approach supports the hypothesis that mCpG DNA demethylation can proceed via various pathways and mCpGs do not have to be targeted to be demethylated. [ABSTRACT FROM AUTHOR]

Published
2014
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37. Simultaneous In Vitro Characterisation of DNA Deaminase Function and Associated DNA Repair Pathways.

Author

Franchini, Don-Marc, Incorvaia, Elisabetta, Rangam, Gopinath, Coker, Heather A., and Petersen-Mahrt, Svend K.

Subjects
IN vitro studies, DEAMINASES, DNA repair, IMMUNOGLOBULINS, GENETIC mutation, CYTOSINE, PRECANCEROUS conditions
Abstract

During immunoglobulin (Ig) diversification, activation-induced deaminase (AID) initiates somatic hypermutation and class switch recombination by catalysing the conversion of cytosine to uracil. The synergy between AID and DNA repair pathways is fundamental for the introduction of mutations, however the molecular and biochemical mechanisms underlying this process are not fully elucidated. We describe a novel method to efficiently decipher the composition and activity of DNA repair pathways that are activated by AID-induced lesions. The in vitro resolution (IVR) assay combines AID based deamination and DNA repair activities from a cellular milieu in a single assay, thus avoiding synthetically created DNA-lesions or genetic-based readouts. Recombinant GAL4-AID fusion protein is targeted to a plasmid containing GAL4 binding sites, allowing for controlled cytosine deamination within a substrate plasmid. Subsequently, the Xenopus laevis egg extract provides a source of DNA repair proteins and functional repair pathways. Our results demonstrated that DNA repair pathways which are in vitro activated by AID-induced lesions are reminiscent of those found during AID-induced in vivo Ig diversification. The comparative ease of manipulation of this in vitro systems provides a new approach to dissect the complex DNA repair pathways acting on defined physiologically lesions, can be adapted to use with other DNA damaging proteins (e.g. APOBECs), and provide a means to develop and characterise pharmacological agents to inhibit these potentially oncogenic processes. [ABSTRACT FROM AUTHOR]

Published
2013
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38. 5-Methylcytosine DNA Demethylation: More Than Losing a Methyl Group.

Author

Franchini, Don-Marc, Schmitz, Kerstin-Maike, and Petersen-Mahrt, Svend K.

Subjects
METHYLCYTOSINE, DNA demethylation, METHYL groups, EPIGENETICS, CELL metabolism, CHROMOSOMAL translocation
Abstract

Demethylation of 5-methylcytosine in DNA is integral to the maintenance of an intact epigenome. The balance between the presence or absence of 5-methylcytosine determines many physiological aspects of cell metabolism, with a turnover that can be measured in minutes to years. Biochemically, addition of the methyl group is shared among all living kingdoms and has been well characterized, whereas the removal or reversion of this mark seems diverse and much less understood. Here, we present a summary of how DNA demethylation can be initiated directly, utilizing the ten-eleven translocation (TET) family of proteins, activation-induced deaminase (AID), or other DNA modifying enzymes, or indirectly, via transcription, RNA metabolism, or DNA repair; how intermediates in those pathways are substrates of the DNA repair machinery; and how demethylation pathways are linked and possibly balanced, avoiding mutations. [ABSTRACT FROM AUTHOR]

Published
2012
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39. Acknowledgment to Reviewers of IJMS in 2021.

Subjects
SCHOLARLY publishing
Abstract

Thanks to the great efforts of our reviewers, I IJMS i was able to maintain its standards for the high quality of its published papers. Rigorous peer-reviews are the basis of high-quality academic publishing. Thanks to the contribution of our reviewers, in 2021, the median time to first decision was 16 days and the median time to publication was 34 days. [Extracted from the article]

Published
2022
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41. Dna Deamination And The Immune System: Aid In Health And Disease

Author

Nina Papavasiliou, Sebastian Fugmann, Marilyn Diaz, Nina Papavasiliou, Sebastian Fugmann, and Marilyn Diaz

Subjects
Immunoglobulins, Deamination, Enzymes, Autoimmune diseases--Gene therapy, Autoimmune diseases--Molecular aspects
Abstract

This book covers the current understanding of the role of activation-induced cytidine deaminase (AID) in the generation of antibody response to antigenic challenge. Since the discovery of AID, and the genetic demonstration of its role in somatic hypermutation and class-switch recombination of antibody genes, much has been learned about the biochemistry of this enzyme. However, some key questions remain hotly contested, such as: how does this enzyme get to the antibody locus leaving the rest of the genome intact, and why are DNA repair pathways which normally repair deamination events co-opted into actually fixing mutations into the genome? These questions, among others, will be addressed in this monograph from various perspectives. Being leading experts in their respective fields, the contributors of this highly valued title summarize current research in the field of AID and put forth hypotheses in order to provide a platform for future experiments.

Published
2011

42. Recent Findings from University of Toulouse III Paul Sabatier Provides New Insights into Follicular Lymphoma (Baseline Suvmax Is Related To Tumor Cell Proliferation and Patient Outcome In Follicular Lymphoma)

Subjects
University of Toulouse, Care and treatment, Research, Patient outcomes, Non-Hodgkin lymphomas -- Patient outcomes -- Research -- Care and treatment, Non-Hodgkin's lymphomas -- Patient outcomes -- Research -- Care and treatment
Abstract

2022 NOV 28 (NewsRx) -- By a News Reporter-Staff News Editor at Hematology Week -- Researchers detail new data in Oncology - Follicular Lymphoma. According to news reporting out of [...]

Published
2022

43. Reports Summarize Cancer Research from Centre de Recherches en Cancerologie de Toulouse (Phased differentiation of gd T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers)

Subjects
Research, Reports, Antigens -- Research -- Reports, Cancer -- Reports, Cell differentiation -- Research -- Reports, Cancer research -- Reports, Immunotherapy -- Reports -- Research, T cells -- Reports -- Research, Oncology, Experimental -- Reports, Cancer -- Reports -- Research
Abstract

2021 OCT 6 (NewsRx) -- By a News Reporter-Staff News Editor at Immunotherapy Weekly -- Research findings on cancer are discussed in a new report. According to news reporting originating [...]

Published
2021

44. Studies from French National Institute of Health and Medical Research UMR 1037 Provide New Data on Cell and Developmental Biology (Stress Granules in the Post-transcriptional Regulation of Immune Cells)

Subjects
Genetic aspects, Stress (Physiology) -- Genetic aspects, Transcription (Genetics) -- Genetic aspects, Medical research, Developmental biology -- Genetic aspects, Medicine, Experimental, Genetic transcription -- Genetic aspects
Abstract

2021 FEB 2 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- Investigators discuss new findings in cell and developmental biology. According to news reporting out [...]

Published
2021

45. Reports from University of Toulouse Provide New Insights into Follicular Lymphoma (Baseline SUVmax is related to tumor cell proliferation and patient outcome in follicular lymphoma)

Subjects
University of Toulouse, Care and treatment, Patient outcomes, Non-Hodgkin lymphomas -- Patient outcomes -- Care and treatment, Non-Hodgkin's lymphomas -- Patient outcomes -- Care and treatment
Abstract

2021 JAN 4 (NewsRx) -- By a News Reporter-Staff News Editor at Hematology Week -- Research findings on Oncology - Follicular Lymphoma are discussed in a new report. According to [...]

Published
2021

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