2020
|
Donnadieu, Emmanuel ; Dupré, Loïc ; Pinho, Lia Gonçalves ; Cotta-de-Almeida, Vinicius Surmounting the obstacles that impede effective CAR Ŧ cell trafficking to solid tumors Article de journal Journal of Leukocyte Biology, 2020, ISSN: 1938-3673. Résumé | Liens | BibTeX @article{donnadieu_surmounting_2020,
title = {Surmounting the obstacles that impede effective CAR Ŧ cell trafficking to solid tumors},
author = {Donnadieu, Emmanuel and Dupré, Loïc and Pinho, Lia Gonçalves and Cotta-de-Almeida, Vinicius},
doi = {10.1002/JLB.1MR0520-746R},
issn = {1938-3673},
year = {2020},
date = {2020-07-01},
journal = {Journal of Leukocyte Biology},
abstract = {Innovative immunotherapies based on immune checkpoint targeting antibodies and engineered T cells are transforming the way we approach cancer treatment. However, although these T cell centered strategies result in marked and durable responses in patients across many different tumor types, they provide therapeutic efficacy only in a proportion of patients. A major challenge of immuno-oncology is thereby to identify mechanisms responsible for resistance to cancer immunotherapy in order to overcome them via adapted strategies that will ultimately improve intrinsic efficacy and response rates. Here, we focus on the barriers that restrain the trafficking of chimeric antigen receptor (CAR)-expressing T cells to solid tumors. Upon infusion, CAR T cells need to home into malignant sites, navigate within complex tumor environments, form productive interactions with cancer cells, deliver their cytotoxic activities, and finally persist. We review the accumulating evidence that the microenvironment of solid tumors contains multiple obstacles that hinder CAR T cells in the dynamic steps underlying their trafficking. We focus on how these hurdles may in part account for the failure of CAR T cell clinical trials in human carcinomas. Given the engineered nature of CAR T cells and possibilities to modify the tumor environment, there are ample opportunities to augment CAR T cell ability to efficiently find and combat tumors. We present some of these strategies, which represent a dynamic field of research with high potential for clinical applicability.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Innovative immunotherapies based on immune checkpoint targeting antibodies and engineered T cells are transforming the way we approach cancer treatment. However, although these T cell centered strategies result in marked and durable responses in patients across many different tumor types, they provide therapeutic efficacy only in a proportion of patients. A major challenge of immuno-oncology is thereby to identify mechanisms responsible for resistance to cancer immunotherapy in order to overcome them via adapted strategies that will ultimately improve intrinsic efficacy and response rates. Here, we focus on the barriers that restrain the trafficking of chimeric antigen receptor (CAR)-expressing T cells to solid tumors. Upon infusion, CAR T cells need to home into malignant sites, navigate within complex tumor environments, form productive interactions with cancer cells, deliver their cytotoxic activities, and finally persist. We review the accumulating evidence that the microenvironment of solid tumors contains multiple obstacles that hinder CAR T cells in the dynamic steps underlying their trafficking. We focus on how these hurdles may in part account for the failure of CAR T cell clinical trials in human carcinomas. Given the engineered nature of CAR T cells and possibilities to modify the tumor environment, there are ample opportunities to augment CAR T cell ability to efficiently find and combat tumors. We present some of these strategies, which represent a dynamic field of research with high potential for clinical applicability. |
German, Yolla ; Vulliard, Loan ; Rubio, Aude ; Boztug, Kaan ; Ferrand, Audrey ; Menche, Jörg ; Dupré, Loïc Morphological profiling of human Ŧ and NK lymphocytes identifies actin-mediated control of the immunological synapse Article de journal bioRxiv, p. 2020.01.17.910091, 2020. Résumé | Liens | BibTeX @article{german_morphological_2020b,
title = {Morphological profiling of human Ŧ and NK lymphocytes identifies actin-mediated control of the immunological synapse},
author = {German, Yolla and Vulliard, Loan and Rubio, Aude and Boztug, Kaan and Ferrand, Audrey and Menche, Jörg and Dupré, Loïc},
url = {https://www.biorxiv.org/content/10.1101/2020.01.17.910091v1},
doi = {10.1101/2020.01.17.910091},
year = {2020},
date = {2020-01-01},
urldate = {2020-05-13},
journal = {bioRxiv},
pages = {2020.01.17.910091},
abstract = {textlessh3textgreaterAbstracttextless/h3textgreater textlessptextgreaterThe detection and neutralization of infected cells and tumors by cytotoxic lymphocytes is a vital immune defense mechanism. The immunological synapse orchestrates the target recognition process and the subsequent cytotoxic activity. Here, we present an integrated experimental and computational strategy to systematically characterize the morphological properties of the immunological synapse of human cytotoxic lymphocytes. Our approach combines high-content imaging with an unbiased, data-driven identification of high-resolution morphological profiles. Such profiling discriminates with high accuracy immunological synapse perturbations induced by an array of actin drugs in both model cell lines and primary lymphocytes. It reveals inter-individual heterogeneity in lymphocyte morphological traits. Furthermore, it uncovers immunological synapse alterations in functionally defective CD8$^textrm+$ T cells from immunodeficient patients carrying textitARPC1B mutations. Our study thus provides a foundation for the application of morphological profiling as a powerful and scalable approach to monitor lymphocyte activation status in experimental and disease settings.textless/ptextgreater},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
textlessh3textgreaterAbstracttextless/h3textgreater textlessptextgreaterThe detection and neutralization of infected cells and tumors by cytotoxic lymphocytes is a vital immune defense mechanism. The immunological synapse orchestrates the target recognition process and the subsequent cytotoxic activity. Here, we present an integrated experimental and computational strategy to systematically characterize the morphological properties of the immunological synapse of human cytotoxic lymphocytes. Our approach combines high-content imaging with an unbiased, data-driven identification of high-resolution morphological profiles. Such profiling discriminates with high accuracy immunological synapse perturbations induced by an array of actin drugs in both model cell lines and primary lymphocytes. It reveals inter-individual heterogeneity in lymphocyte morphological traits. Furthermore, it uncovers immunological synapse alterations in functionally defective CD8$^textrm+$ T cells from immunodeficient patients carrying textitARPC1B mutations. Our study thus provides a foundation for the application of morphological profiling as a powerful and scalable approach to monitor lymphocyte activation status in experimental and disease settings.textless/ptextgreater |
Gallais, Fanny ; Ysebaert, Loïc ; Despas, Fabien ; De Barros, Sandra ; Dupré, Loïc ; Quillet-Mary, Anne ; Protin, Caroline ; Thomas, Fabienne ; Obéric, Lucie ; Allal, Ben ; Chatelut, Etienne ; White-Koning, Mélanie Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies Article de journal Clinical Pharmacokinetics, 2020, ISSN: 1179-1926. Résumé | Liens | BibTeX @article{gallais_population_2020b,
title = {Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies},
author = {Gallais, Fanny and Ysebaert, Loïc and Despas, Fabien and De Barros, Sandra and Dupré, Loïc and Quillet-Mary, Anne and Protin, Caroline and Thomas, Fabienne and Obéric, Lucie and Allal, Ben and Chatelut, Etienne and White-Koning, Mélanie},
doi = {10.1007/s40262-020-00884-0},
issn = {1179-1926},
year = {2020},
date = {2020-01-01},
journal = {Clinical Pharmacokinetics},
abstract = {BACKGROUND AND OBJECTIVE: Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome.
METHODS: Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4. RESULTS: A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND AND OBJECTIVE: Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome.
METHODS: Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4. RESULTS: A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively |
Thian, Marini ; Hoeger, Birgit ; Kamnev, Anton ; Poyer, Fiona ; Köstel Bal, Sevgi ; Caldera, Michael ; Jiménez-Heredia, Raúl ; Huemer, Jakob ; Pickl, Winfried F; Groß, Miriam ; Ehl, Stephan ; Lucas, Carrie L; Menche, Jörg ; Hutter, Caroline ; Attarbaschi, Andishe ; Dupré, Loïc ; Boztug, Kaan Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation Article de journal Haematologica, 2020, ISSN: 1592-8721. Liens | BibTeX @article{thian_germline_2020b,
title = {Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation},
author = {Thian, Marini and Hoeger, Birgit and Kamnev, Anton and Poyer, Fiona and Köstel Bal, Sevgi and Caldera, Michael and Jiménez-Heredia, Raúl and Huemer, Jakob and Pickl, Winfried F. and Groß, Miriam and Ehl, Stephan and Lucas, Carrie L. and Menche, Jörg and Hutter, Caroline and Attarbaschi, Andishe and Dupré, Loïc and Boztug, Kaan},
doi = {10.3324/haematol.2019.231399},
issn = {1592-8721},
year = {2020},
date = {2020-01-01},
journal = {Haematologica},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Blaize, Gaëtan ; Daniels-Treffandier, Hélène ; Aloulou, Meryem ; Rouquié, Nelly ; Yang, Cui ; Marcellin, Marlène ; Gador, Mylène ; Benamar, Mehdi ; Ducatez, Mariette ; Song, Ki-Duk ; Burlet-Schiltz, Odile ; Saoudi, Abdelhadi ; Love, Paul E; Fazilleau, Nicolas ; Gonzalez de Peredo, Anne ; Lesourne, Renaud CD5 signalosome coordinates antagonist TCR signals to control the generation of Treg cells induced by foreign antigens Article de journal Proceedings of the National Academy of Sciences of the United States of America, 2020, ISSN: 1091-6490. Résumé | Liens | BibTeX @article{blaize_cd5_2020,
title = {CD5 signalosome coordinates antagonist TCR signals to control the generation of Treg cells induced by foreign antigens},
author = {Blaize, Gaëtan and Daniels-Treffandier, Hélène and Aloulou, Meryem and Rouquié, Nelly and Yang, Cui and Marcellin, Marlène and Gador, Mylène and Benamar, Mehdi and Ducatez, Mariette and Song, Ki-Duk and Burlet-Schiltz, Odile and Saoudi, Abdelhadi and Love, Paul E. and Fazilleau, Nicolas and Gonzalez de Peredo, Anne and Lesourne, Renaud},
doi = {10.1073/pnas.1917182117},
issn = {1091-6490},
year = {2020},
date = {2020-01-01},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
abstract = {CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes. |
Salzer, Elisabeth ; Zoghi, Samaneh ; Kiss, Máté G; Kage, Frieda ; Rashkova, Christina ; Stahnke, Stephanie ; Haimel, Matthias ; Platzer, René ; Caldera, Michael ; Ardy, Rico Chandra ; Hoeger, Birgit ; Block, Jana ; Medgyesi, David ; Sin, Celine ; Shahkarami, Sepideh ; Kain, Renate ; Ziaee, Vahid ; Hammerl, Peter ; Bock, Christoph ; Menche, Jörg ; Dupré, Loïc ; Huppa, Johannes B; Sixt, Michael ; Lomakin, Alexis ; Rottner, Klemens ; Binder, Christoph J; Stradal, Theresia E B; Rezaei, Nima ; Boztug, Kaan The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity Article de journal Science Immunology, 5 (49), 2020, ISSN: 2470-9468. Résumé | Liens | BibTeX @article{salzer_cytoskeletal_2020,
title = {The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity},
author = {Salzer, Elisabeth and Zoghi, Samaneh and Kiss, Máté G. and Kage, Frieda and Rashkova, Christina and Stahnke, Stephanie and Haimel, Matthias and Platzer, René and Caldera, Michael and Ardy, Rico Chandra and Hoeger, Birgit and Block, Jana and Medgyesi, David and Sin, Celine and Shahkarami, Sepideh and Kain, Renate and Ziaee, Vahid and Hammerl, Peter and Bock, Christoph and Menche, Jörg and Dupré, Loïc and Huppa, Johannes B. and Sixt, Michael and Lomakin, Alexis and Rottner, Klemens and Binder, Christoph J. and Stradal, Theresia E. B. and Rezaei, Nima and Boztug, Kaan},
doi = {10.1126/sciimmunol.abc3979},
issn = {2470-9468},
year = {2020},
date = {2020-01-01},
journal = {Science Immunology},
volume = {5},
number = {49},
abstract = {The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1-/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1-/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity. |
Yamak, Abir ; Hu, Dongjian ; Mittal, Nikhil ; Buikema, Jan W; Ditta, Sheraz ; Lutz, Pierre G; Moog-Lutz, Christel ; Ellinor, Patrick T; Domian, Ibrahim J Loss of Asb2 Impairs Cardiomyocyte Differentiation and Leads to Congenital Double Outlet Right Ventricle Article de journal iScience, 23 (3), p. 100959, 2020, ISSN: 2589-0042. Résumé | Liens | BibTeX @article{yamak_loss_2020,
title = {Loss of Asb2 Impairs Cardiomyocyte Differentiation and Leads to Congenital Double Outlet Right Ventricle},
author = {Yamak, Abir and Hu, Dongjian and Mittal, Nikhil and Buikema, Jan W. and Ditta, Sheraz and Lutz, Pierre G. and Moog-Lutz, Christel and Ellinor, Patrick T. and Domian, Ibrahim J.},
doi = {10.1016/j.isci.2020.100959},
issn = {2589-0042},
year = {2020},
date = {2020-01-01},
journal = {iScience},
volume = {23},
number = {3},
pages = {100959},
abstract = {Defining the pathways that control cardiac development facilitates understanding the pathogenesis of congenital heart disease. Herein, we identify enrichment of a Cullin5 Ub ligase key subunit, Asb2, in myocardial progenitors and differentiated cardiomyocytes. Using two conditional murine knockouts, Nkx+/Cre.Asb2fl/fl and AHF-Cre.Asb2fl/fl, and tissue clarifying technique, we reveal Asb2 requirement for embryonic survival and complete heart looping. Deletion of Asb2 results in upregulation of its target Filamin A (Flna), and concurrent Flna deletion partially rescues embryonic lethality. Conditional AHF-Cre.Asb2 knockouts harboring one Flna allele have double outlet right ventricle (DORV), which is rescued by biallelic Flna excision. Transcriptomic and immunofluorescence analyses identify Tgfβ/Smad as downstream targets of Asb2/Flna. Finally, using CRISPR/Cas9 genome editing, we demonstrate Asb2 requirement for human cardiomyocyte differentiation suggesting a conserved mechanism between mice and humans. Collectively, our study provides deeper mechanistic understanding of the role of the ubiquitin proteasome system in cardiac development and suggests a previously unidentified murine model for DORV.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Defining the pathways that control cardiac development facilitates understanding the pathogenesis of congenital heart disease. Herein, we identify enrichment of a Cullin5 Ub ligase key subunit, Asb2, in myocardial progenitors and differentiated cardiomyocytes. Using two conditional murine knockouts, Nkx+/Cre.Asb2fl/fl and AHF-Cre.Asb2fl/fl, and tissue clarifying technique, we reveal Asb2 requirement for embryonic survival and complete heart looping. Deletion of Asb2 results in upregulation of its target Filamin A (Flna), and concurrent Flna deletion partially rescues embryonic lethality. Conditional AHF-Cre.Asb2 knockouts harboring one Flna allele have double outlet right ventricle (DORV), which is rescued by biallelic Flna excision. Transcriptomic and immunofluorescence analyses identify Tgfβ/Smad as downstream targets of Asb2/Flna. Finally, using CRISPR/Cas9 genome editing, we demonstrate Asb2 requirement for human cardiomyocyte differentiation suggesting a conserved mechanism between mice and humans. Collectively, our study provides deeper mechanistic understanding of the role of the ubiquitin proteasome system in cardiac development and suggests a previously unidentified murine model for DORV. |
Lamsoul, Isabelle ; Dupré, Loïc ; Lutz, Pierre G Molecular Tuning of Filamin A Activities in the Context of Adhesion and Migration Article de journal Front Cell Dev Biol, 8 , p. 591323, 2020, ISSN: 2296-634X. Résumé | Liens | BibTeX @article{lamsoul_molecular_2020,
title = {Molecular Tuning of Filamin A Activities in the Context of Adhesion and Migration},
author = {Lamsoul, Isabelle and Dupré, Loïc and Lutz, Pierre G.},
doi = {10.3389/fcell.2020.591323},
issn = {2296-634X},
year = {2020},
date = {2020-01-01},
journal = {Front Cell Dev Biol},
volume = {8},
pages = {591323},
abstract = {The dynamic organization of actin cytoskeleton meshworks relies on multiple actin-binding proteins endowed with distinct actin-remodeling activities. Filamin A is a large multi-domain scaffolding protein that cross-links actin filaments with orthogonal orientation in response to various stimuli. As such it plays key roles in the modulation of cell shape, cell motility, and differentiation throughout development and adult life. The essentiality and complexity of Filamin A is highlighted by mutations that lead to a variety of severe human disorders affecting multiple organs. One of the most conserved activity of Filamin A is to bridge the actin cytoskeleton to integrins, thereby maintaining the later in an inactive state. We here review the numerous mechanisms cells have developed to adjust Filamin A content and activity and focus on the function of Filamin A as a gatekeeper to integrin activation and associated adhesion and motility.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The dynamic organization of actin cytoskeleton meshworks relies on multiple actin-binding proteins endowed with distinct actin-remodeling activities. Filamin A is a large multi-domain scaffolding protein that cross-links actin filaments with orthogonal orientation in response to various stimuli. As such it plays key roles in the modulation of cell shape, cell motility, and differentiation throughout development and adult life. The essentiality and complexity of Filamin A is highlighted by mutations that lead to a variety of severe human disorders affecting multiple organs. One of the most conserved activity of Filamin A is to bridge the actin cytoskeleton to integrins, thereby maintaining the later in an inactive state. We here review the numerous mechanisms cells have developed to adjust Filamin A content and activity and focus on the function of Filamin A as a gatekeeper to integrin activation and associated adhesion and motility. |
2019
|
Guipouy, Delphine ; Gertner-Dardenne, Julie ; Pfajfer, Laurène ; German, Yolla ; Belmonte, Nathalie ; Dupré, Loïc Granulysin- and granzyme-dependent elimination of myeloid cells by therapeutic ova-specific type 1 regulatory Ŧ cells Article de journal International Immunology, 31 (4), p. 239–250, 2019, ISSN: 1460-2377. Résumé | Liens | BibTeX @article{guipouy_granulysin-_2019,
title = {Granulysin- and granzyme-dependent elimination of myeloid cells by therapeutic ova-specific type 1 regulatory Ŧ cells},
author = {Guipouy, Delphine and Gertner-Dardenne, Julie and Pfajfer, Laurène and German, Yolla and Belmonte, Nathalie and Dupré, Loïc},
doi = {10.1093/intimm/dxy083},
issn = {1460-2377},
year = {2019},
date = {2019-01-01},
journal = {International Immunology},
volume = {31},
number = {4},
pages = {239--250},
abstract = {The intrinsic immunosuppressive properties of regulatory T (Treg) cells can be harnessed for therapeutic approaches aiming at down-modulating harmful immune reactions. In this context, expanded type 1 Treg cells (Tr1 cells) specific for ovalbumin (ova-Tr1 cells) have been tested for clinical efficacy in the treatment of autoimmune disorders such as refractory Crohn's disease (CD). The clinical use of these therapeutic products warrants exploration of their mechanism of action. Here, we identified a relationship between the CD activity index and the expression of lytic molecules by the ova-Tr1 cells administered in the previously reported First-in-Man study [Crohn's And Treg cells Study 1 (CATS1) study]. Accordingly, ova-Tr1 cells were found to carry granules containing high levels of lytic molecules, including multiple granzymes and granulysin. These cells displayed a T-cell receptor (TCR)-independent cytotoxic activity, which was preferentially directed toward myeloid cell lines and monocyte-derived dendritic cells. Upon contact with myeloid cells, ova-Tr1 cells induced their apoptosis via a perforin-independent and a granulysin/granzyme-dependent mechanism. As compared to CD8+ cytotoxic T cells, ova-Tr1 cells required more time to lyse target cells and displayed a more gradual lytic activity over time. Notably, this activity was sustained over days resulting in the control of myeloid cell populations at a relatively low ratio. Our study reveals that ova-Tr1 cells are endowed with a sustained cytotoxic activity that relies on a unique combination of granulysin and granzymes and that preferentially eliminates myeloid target cells in a TCR-independent manner.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The intrinsic immunosuppressive properties of regulatory T (Treg) cells can be harnessed for therapeutic approaches aiming at down-modulating harmful immune reactions. In this context, expanded type 1 Treg cells (Tr1 cells) specific for ovalbumin (ova-Tr1 cells) have been tested for clinical efficacy in the treatment of autoimmune disorders such as refractory Crohn's disease (CD). The clinical use of these therapeutic products warrants exploration of their mechanism of action. Here, we identified a relationship between the CD activity index and the expression of lytic molecules by the ova-Tr1 cells administered in the previously reported First-in-Man study [Crohn's And Treg cells Study 1 (CATS1) study]. Accordingly, ova-Tr1 cells were found to carry granules containing high levels of lytic molecules, including multiple granzymes and granulysin. These cells displayed a T-cell receptor (TCR)-independent cytotoxic activity, which was preferentially directed toward myeloid cell lines and monocyte-derived dendritic cells. Upon contact with myeloid cells, ova-Tr1 cells induced their apoptosis via a perforin-independent and a granulysin/granzyme-dependent mechanism. As compared to CD8+ cytotoxic T cells, ova-Tr1 cells required more time to lyse target cells and displayed a more gradual lytic activity over time. Notably, this activity was sustained over days resulting in the control of myeloid cell populations at a relatively low ratio. Our study reveals that ova-Tr1 cells are endowed with a sustained cytotoxic activity that relies on a unique combination of granulysin and granzymes and that preferentially eliminates myeloid target cells in a TCR-independent manner. |
Cheminant, Morgane ; Mahlaoui, Nizar ; Desconclois, Céline ; Canioni, Danielle ; Ysebaert, Loïc ; Dupré, Loïc ; Vasconcelos, Zilton ; Malphettes, Marion ; Moshous, Despina ; Neven, Bénédicte ; Rohrlich, Pierre-Simon ; Bernard, Marc ; Bertrand, Yves ; Fischer, Alain ; Suarez, Felipe Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies Article de journal The Journal of Allergy and Clinical Immunology, 143 (6), p. 2311–2315.e7, 2019, ISSN: 1097-6825. Liens | BibTeX @article{cheminant_lymphoproliferative_2019b,
title = {Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies},
author = {Cheminant, Morgane and Mahlaoui, Nizar and Desconclois, Céline and Canioni, Danielle and Ysebaert, Loïc and Dupré, Loïc and Vasconcelos, Zilton and Malphettes, Marion and Moshous, Despina and Neven, Bénédicte and Rohrlich, Pierre-Simon and Bernard, Marc and Bertrand, Yves and Fischer, Alain and Suarez, Felipe},
doi = {10.1016/j.jaci.2019.01.046},
issn = {1097-6825},
year = {2019},
date = {2019-01-01},
journal = {The Journal of Allergy and Clinical Immunology},
volume = {143},
number = {6},
pages = {2311--2315.e7},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Spinner, Camille A; Lamsoul, Isabelle ; Métais, Arnaud ; Febrissy, Chanaëlle ; Moog-Lutz, Christel ; Lutz, Pierre G The E3 Ubiquitin Ligase Asb2α in Ŧ Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer Article de journal Cancer Immunol Res, 7 (8), p. 1332–1344, 2019, ISSN: 2326-6074. Résumé | Liens | BibTeX @article{spinner_e3_2019,
title = {The E3 Ubiquitin Ligase Asb2α in Ŧ Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer},
author = {Spinner, Camille A. and Lamsoul, Isabelle and Métais, Arnaud and Febrissy, Chanaëlle and Moog-Lutz, Christel and Lutz, Pierre G.},
doi = {10.1158/2326-6066.CIR-18-0562},
issn = {2326-6074},
year = {2019},
date = {2019-01-01},
journal = {Cancer Immunol Res},
volume = {7},
number = {8},
pages = {1332--1344},
abstract = {The escape of cancer cells from host immunosurveillance involves a shift in immune responses, including an imbalance in Th1 and Th2 cells. A Th1-dominated immune response predicts positive outcomes in colorectal cancer. The E3 ubiquitin ligase, Asb2α, is expressed in Th2 cells, but its roles in T-cell maturation and cancer are unclear. We provide evidence that the Th2 master regulator, Gata3, induces Asb2 Loss of Asb2 did not affect Th differentiation ex vivo, but reduced IL4 production from Th2 cells. We found that high ASB2 expression was associated with poor outcome in colorectal cancer. Loss of Asb2 from hematopoietic cells promoted a Th1 response and attenuated colitis-associated tumorigenesis in mice. Diminished Th2 function correlated with increased IFNγ production and an enhanced type 1 antitumor immune response in Asb2-deficient mice. Our work suggests that Asb2α promotes a Th2 phenotype in vivo, which in turn is associated with tumor progression in a mouse model of colitis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The escape of cancer cells from host immunosurveillance involves a shift in immune responses, including an imbalance in Th1 and Th2 cells. A Th1-dominated immune response predicts positive outcomes in colorectal cancer. The E3 ubiquitin ligase, Asb2α, is expressed in Th2 cells, but its roles in T-cell maturation and cancer are unclear. We provide evidence that the Th2 master regulator, Gata3, induces Asb2 Loss of Asb2 did not affect Th differentiation ex vivo, but reduced IL4 production from Th2 cells. We found that high ASB2 expression was associated with poor outcome in colorectal cancer. Loss of Asb2 from hematopoietic cells promoted a Th1 response and attenuated colitis-associated tumorigenesis in mice. Diminished Th2 function correlated with increased IFNγ production and an enhanced type 1 antitumor immune response in Asb2-deficient mice. Our work suggests that Asb2α promotes a Th2 phenotype in vivo, which in turn is associated with tumor progression in a mouse model of colitis. |
2018
|
Houmadi, R; Guipouy, D; Rey-Barroso, J; Vasconcelos, Z; Cornet, J; Manghi, M; Destainville, N; Valitutti, S; Allart, S; Dupre, L The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse Article de journal Cell Rep, 22 (4), p. 979-991, 2018, ISSN: 2211-1247 (Electronic). Liens | BibTeX @article{RN3b,
title = {The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse},
author = {Houmadi, R. and Guipouy, D. and Rey-Barroso, J. and Vasconcelos, Z. and Cornet, J. and Manghi, M. and Destainville, N. and Valitutti, S. and Allart, S. and Dupre, L.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29386139},
doi = {10.1016/j.celrep.2017.12.088},
issn = {2211-1247 (Electronic)},
year = {2018},
date = {2018-01-01},
journal = {Cell Rep},
volume = {22},
number = {4},
pages = {979-991},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Gaud, G; Lesourne, R; Love, P E Regulatory mechanisms in T cell receptor signalling Article de journal Nat Rev Immunol, 2018, ISSN: 1474-1741 (Electronic)
1474-1733 (Linking). Liens | BibTeX @article{RN1b,
title = {Regulatory mechanisms in T cell receptor signalling},
author = {Gaud, G. and Lesourne, R. and Love, P. E.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29789755},
doi = {10.1038/s41577-018-0020-8},
issn = {1474-1741 (Electronic)
1474-1733 (Linking)},
year = {2018},
date = {2018-01-01},
journal = {Nat Rev Immunol},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Rey-Barroso, Javier; Calovi, Daniel S; Combe, Maud; German, Yolla; Moreau, Mathieu; Canivet, Astrid; Wang, Xiaobo; Sire, Clément; Theraulaz, Guy; Dupré, Loïc Switching between individual and collective motility in B lymphocytes is controlled by cell-matrix adhesion and inter-cellular interactions Article de journal Scientific Reports, 8 (1), p. 5800, 2018, ISSN: 2045-2322. Résumé | Liens | BibTeX @article{rey-barroso_switching_2018,
title = {Switching between individual and collective motility in B lymphocytes is controlled by cell-matrix adhesion and inter-cellular interactions},
author = { Javier Rey-Barroso and Daniel S. Calovi and Maud Combe and Yolla German and Mathieu Moreau and Astrid Canivet and Xiaobo Wang and Clément Sire and Guy Theraulaz and Loïc Dupré},
doi = {10.1038/s41598-018-24222-4},
issn = {2045-2322},
year = {2018},
date = {2018-01-01},
journal = {Scientific Reports},
volume = {8},
number = {1},
pages = {5800},
abstract = {Lymphocytes alternate between phases of individual migration across tissues and phases of clustering during activation and function. The range of lymphocyte motility behaviors and the identity of the factors that govern them remain elusive. To explore this point, we here collected unprecedented statistics pertaining to cell displacements, cell:matrix and cell:cell interactions using a model B cell line as well as primary human B lymphocytes. At low cell density, individual B lymphocytes displayed a high heterogeneity in their speed and diffusivity. Beyond this intrinsic variability, B lymphocytes adapted their motility to the composition of extra-cellular matrix, adopting slow persistent walks over collagen IV and quick Brownian walks over fibronectin. At high cell density, collagen IV favored the self-assembly of B lymphocytes into clusters endowed with collective coordination, while fibronectin stimulated individual motility. We show that this behavioral plasticity is controlled by acto-myosin dependent adhesive and Arp2/3-dependent protrusive actin pools, respectively. Our study reveals the adaptive nature of B lymphocyte motility and group dynamics, which are shaped by an interplay between and cell:matrix and cell:cell interactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lymphocytes alternate between phases of individual migration across tissues and phases of clustering during activation and function. The range of lymphocyte motility behaviors and the identity of the factors that govern them remain elusive. To explore this point, we here collected unprecedented statistics pertaining to cell displacements, cell:matrix and cell:cell interactions using a model B cell line as well as primary human B lymphocytes. At low cell density, individual B lymphocytes displayed a high heterogeneity in their speed and diffusivity. Beyond this intrinsic variability, B lymphocytes adapted their motility to the composition of extra-cellular matrix, adopting slow persistent walks over collagen IV and quick Brownian walks over fibronectin. At high cell density, collagen IV favored the self-assembly of B lymphocytes into clusters endowed with collective coordination, while fibronectin stimulated individual motility. We show that this behavioral plasticity is controlled by acto-myosin dependent adhesive and Arp2/3-dependent protrusive actin pools, respectively. Our study reveals the adaptive nature of B lymphocyte motility and group dynamics, which are shaped by an interplay between and cell:matrix and cell:cell interactions. |
Sarkar, Koustav ; Han, Seong-Su ; Wen, Kuo-Kuang ; Ochs, Hans D; Dupré, Loïc ; Seidman, Michael M; Vyas, Yatin M R-loops cause genomic instability in Ŧ helper lymphocytes from patients with Wiskott-Aldrich syndrome Article de journal The Journal of Allergy and Clinical Immunology, 142 (1), p. 219–234, 2018, ISSN: 1097-6825. Résumé | Liens | BibTeX @article{sarkar_r-loops_2018,
title = {R-loops cause genomic instability in Ŧ helper lymphocytes from patients with Wiskott-Aldrich syndrome},
author = {Sarkar, Koustav and Han, Seong-Su and Wen, Kuo-Kuang and Ochs, Hans D. and Dupré, Loïc and Seidman, Michael M. and Vyas, Yatin M.},
doi = {10.1016/j.jaci.2017.11.023},
issn = {1097-6825},
year = {2018},
date = {2018-01-01},
journal = {The Journal of Allergy and Clinical Immunology},
volume = {142},
number = {1},
pages = {219--234},
abstract = {BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined.
OBJECTIVE: We sought to define how dysfunctional gene transcription is causally linked to the degree of TH cell deficiency and genomic instability in the XLT/WAS clinical spectrum.
METHODS: In human TH1- or TH2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp.
RESULTS: WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative to TH2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (TH1 genes) in TH1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (TH2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores.
CONCLUSION: Transcriptional R-loop imbalance is a novel molecular defect causative in TH1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined.
OBJECTIVE: We sought to define how dysfunctional gene transcription is causally linked to the degree of TH cell deficiency and genomic instability in the XLT/WAS clinical spectrum.
METHODS: In human TH1- or TH2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp.
RESULTS: WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative to TH2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (TH1 genes) in TH1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (TH2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores.
CONCLUSION: Transcriptional R-loop imbalance is a novel molecular defect causative in TH1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically. |
Pfajfer, Laurène ; Mair, Nina K; Jiménez-Heredia, Raúl ; Genel, Ferah ; Gulez, Nesrin ; Ardeniz, Ömür; Hoeger, Birgit ; Bal, Sevgi Köstel ; Madritsch, Christoph ; Kalinichenko, Artem ; Chandra Ardy, Rico ; Gerçeker, Bengü ; Rey-Barroso, Javier ; Ijspeert, Hanna ; Tangye, Stuart G; Simonitsch-Klupp, Ingrid ; Huppa, Johannes B; van der Burg, Mirjam ; Dupré, Loïc ; Boztug, Kaan Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity Article de journal The Journal of Allergy and Clinical Immunology, 142 (5), p. 1589–1604.e11, 2018, ISSN: 1097-6825. Résumé | Liens | BibTeX @article{pfajfer_mutations_2018,
title = {Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity},
author = {Pfajfer, Laurène and Mair, Nina K. and Jiménez-Heredia, Raúl and Genel, Ferah and Gulez, Nesrin and Ardeniz, Ömür and Hoeger, Birgit and Bal, Sevgi Köstel and Madritsch, Christoph and Kalinichenko, Artem and Chandra Ardy, Rico and Gerçeker, Bengü and Rey-Barroso, Javier and Ijspeert, Hanna and Tangye, Stuart G. and Simonitsch-Klupp, Ingrid and Huppa, Johannes B. and van der Burg, Mirjam and Dupré, Loïc and Boztug, Kaan},
doi = {10.1016/j.jaci.2018.04.023},
issn = {1097-6825},
year = {2018},
date = {2018-01-01},
journal = {The Journal of Allergy and Clinical Immunology},
volume = {142},
number = {5},
pages = {1589--1604.e11},
abstract = {BACKGROUND: The actin-interacting protein WD repeat-containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells.
OBJECTIVE: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects.
METHODS: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes.
RESULTS: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation.
CONCLUSION: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The actin-interacting protein WD repeat-containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells.
OBJECTIVE: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects.
METHODS: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes.
RESULTS: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation.
CONCLUSION: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses. |
Brigida, Immacolata ; Zoccolillo, Matteo ; Cicalese, Maria Pia ; Pfajfer, Laurène ; Barzaghi, Federica ; Scala, Serena ; Oleaga-Quintas, Carmen ; Álvarez-Álvarez, Jesus A; Sereni, Lucia ; Giannelli, Stefania ; Sartirana, Claudia ; Dionisio, Francesca ; Pavesi, Luca ; Benavides-Nieto, Marta ; Basso-Ricci, Luca ; Capasso, Paola ; Mazzi, Benedetta ; Rosain, Jeremie ; Marcus, Nufar ; Lee, Yu Nee ; Somech, Raz ; Degano, Massimo ; Raiola, Giuseppe ; Caorsi, Roberta ; Picco, Paolo ; Moncada Velez, Marcela ; Khourieh, Joelle ; Arias, Andrés Augusto ; Bousfiha, Aziz ; Issekutz, Thomas ; Issekutz, Andrew ; Boisson, Bertrand ; Dobbs, Kerry ; Villa, Anna ; Lombardo, Angelo ; Neven, Benedicte ; Moshous, Despina ; Casanova, Jean-Laurent ; Franco, José Luis ; Notarangelo, Luigi D; Scielzo, Cristina ; Volpi, Stefano ; Dupré, Loïc ; Bustamante, Jacinta ; Gattorno, Marco ; Aiuti, Alessandro T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency Article de journal Blood, 132 (22), p. 2362–2374, 2018, ISSN: 1528-0020. Résumé | Liens | BibTeX @article{brigida_t-cell_2018,
title = {T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency},
author = {Brigida, Immacolata and Zoccolillo, Matteo and Cicalese, Maria Pia and Pfajfer, Laurène and Barzaghi, Federica and Scala, Serena and Oleaga-Quintas, Carmen and Álvarez-Álvarez, Jesus A. and Sereni, Lucia and Giannelli, Stefania and Sartirana, Claudia and Dionisio, Francesca and Pavesi, Luca and Benavides-Nieto, Marta and Basso-Ricci, Luca and Capasso, Paola and Mazzi, Benedetta and Rosain, Jeremie and Marcus, Nufar and Lee, Yu Nee and Somech, Raz and Degano, Massimo and Raiola, Giuseppe and Caorsi, Roberta and Picco, Paolo and Moncada Velez, Marcela and Khourieh, Joelle and Arias, Andrés Augusto and Bousfiha, Aziz and Issekutz, Thomas and Issekutz, Andrew and Boisson, Bertrand and Dobbs, Kerry and Villa, Anna and Lombardo, Angelo and Neven, Benedicte and Moshous, Despina and Casanova, Jean-Laurent and Franco, José Luis and Notarangelo, Luigi D. and Scielzo, Cristina and Volpi, Stefano and Dupré, Loïc and Bustamante, Jacinta and Gattorno, Marco and Aiuti, Alessandro},
doi = {10.1182/blood-2018-07-863431},
issn = {1528-0020},
year = {2018},
date = {2018-01-01},
journal = {Blood},
volume = {132},
number = {22},
pages = {2362--2374},
abstract = {ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID. |
Métais, Arnaud ; Lamsoul, Isabelle ; Melet, Armelle ; Uttenweiler-Joseph, Sandrine ; Poincloux, Renaud ; Stefanovic, Sonia ; Valière, Amélie ; Gonzalez de Peredo, Anne ; Stella, Alexandre ; Burlet-Schiltz, Odile ; Zaffran, Stéphane ; Lutz, Pierre G; Moog-Lutz, Christel Asb2α-Filamin A Axis Is Essential for Actin Cytoskeleton Remodeling During Heart Development Article de journal Circ. Res., 122 (6), p. e34–e48, 2018, ISSN: 1524-4571. Résumé | Liens | BibTeX @article{metais_asb2-filamin_2018,
title = {Asb2α-Filamin A Axis Is Essential for Actin Cytoskeleton Remodeling During Heart Development},
author = {Métais, Arnaud and Lamsoul, Isabelle and Melet, Armelle and Uttenweiler-Joseph, Sandrine and Poincloux, Renaud and Stefanovic, Sonia and Valière, Amélie and Gonzalez de Peredo, Anne and Stella, Alexandre and Burlet-Schiltz, Odile and Zaffran, Stéphane and Lutz, Pierre G. and Moog-Lutz, Christel},
doi = {10.1161/CIRCRESAHA.117.312015},
issn = {1524-4571},
year = {2018},
date = {2018-01-01},
journal = {Circ. Res.},
volume = {122},
number = {6},
pages = {e34--e48},
abstract = {RATIONALE: Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that regulate actin cytoskeleton remodeling during cardiac cell differentiation.
OBJECTIVE: The Asb2α (Ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2) CRL5 (cullin 5 RING E3 ubiquitin ligase) triggers polyubiquitylation and subsequent degradation by the proteasome of FLNs (filamins). Here, we investigate the role of Asb2α in heart development and its mechanisms of action.
METHODS AND RESULTS: Using Asb2 knockout embryos, we show that Asb2 is an essential gene, critical to heart morphogenesis and function, although its loss does not interfere with the overall patterning of the embryonic heart tube. We show that the Asb2α E3 ubiquitin ligase controls Flna stability in immature cardiomyocytes. Importantly, Asb2α-mediated degradation of the actin-binding protein Flna marks a previously unrecognized intermediate step in cardiac cell differentiation characterized by cell shape changes and actin cytoskeleton remodeling. We further establish that in the absence of Asb2α, myofibrils are disorganized and that heartbeats are inefficient, leading to embryonic lethality in mice.
CONCLUSIONS: These findings identify Asb2α as an unsuspected key regulator of cardiac cell differentiation and shed light on the molecular and cellular mechanisms determining the onset of myocardial cell architecture and its link with early cardiac function. Although Flna is known to play roles in cytoskeleton organization and to be required for heart function, this study now reveals that its degradation mediated by Asb2α ensures essential functions in differentiating cardiac progenitors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RATIONALE: Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that regulate actin cytoskeleton remodeling during cardiac cell differentiation.
OBJECTIVE: The Asb2α (Ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2) CRL5 (cullin 5 RING E3 ubiquitin ligase) triggers polyubiquitylation and subsequent degradation by the proteasome of FLNs (filamins). Here, we investigate the role of Asb2α in heart development and its mechanisms of action.
METHODS AND RESULTS: Using Asb2 knockout embryos, we show that Asb2 is an essential gene, critical to heart morphogenesis and function, although its loss does not interfere with the overall patterning of the embryonic heart tube. We show that the Asb2α E3 ubiquitin ligase controls Flna stability in immature cardiomyocytes. Importantly, Asb2α-mediated degradation of the actin-binding protein Flna marks a previously unrecognized intermediate step in cardiac cell differentiation characterized by cell shape changes and actin cytoskeleton remodeling. We further establish that in the absence of Asb2α, myofibrils are disorganized and that heartbeats are inefficient, leading to embryonic lethality in mice.
CONCLUSIONS: These findings identify Asb2α as an unsuspected key regulator of cardiac cell differentiation and shed light on the molecular and cellular mechanisms determining the onset of myocardial cell architecture and its link with early cardiac function. Although Flna is known to play roles in cytoskeleton organization and to be required for heart function, this study now reveals that its degradation mediated by Asb2α ensures essential functions in differentiating cardiac progenitors. |
2017
|
Duguet, F; Locard-Paulet, M; Marcellin, M; Chaoui, K; Bernard, I; Andreoletti, O; Lesourne, R; Burlet-Schiltz, O; Gonzalez de Peredo, A; Saoudi, A Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function Article de journal Mol Cell Proteomics, 16 (8), p. 1416-1432, 2017, ISSN: 1535-9484 (Electronic) 1535-9476 (Linking). Liens | BibTeX @article{RN4b,
title = {Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function},
author = {Duguet, F. and Locard-Paulet, M. and Marcellin, M. and Chaoui, K. and Bernard, I. and Andreoletti, O. and Lesourne, R. and Burlet-Schiltz, O. and Gonzalez de Peredo, A. and Saoudi, A.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/28373295},
doi = {10.1074/mcp.M116.062745},
issn = {1535-9484 (Electronic) 1535-9476 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Mol Cell Proteomics},
volume = {16},
number = {8},
pages = {1416-1432},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Cheng, D; Deobagkar-Lele, M; Zvezdova, E; Choi, S; Uehara, S; Baup, D; Bennett, S C; Bull, K R; Crockford, T L; Ferry, H; Warzecha, C; Marcellin, M; de Peredo, A G; Lesourne, R; Anzilotti, C; Love, P E; Cornall, R J Themis2 lowers the threshold for B cell activation during positive selection Article de journal Nat Immunol, 18 (2), p. 205-213, 2017, ISSN: 1529-2916 (Electronic)
1529-2908 (Linking). Liens | BibTeX @article{RN6b,
title = {Themis2 lowers the threshold for B cell activation during positive selection},
author = {Cheng, D. and Deobagkar-Lele, M. and Zvezdova, E. and Choi, S. and Uehara, S. and Baup, D. and Bennett, S. C. and Bull, K. R. and Crockford, T. L. and Ferry, H. and Warzecha, C. and Marcellin, M. and de Peredo, A. G. and Lesourne, R. and Anzilotti, C. and Love, P. E. and Cornall, R. J.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/27992403},
doi = {10.1038/ni.3642},
issn = {1529-2916 (Electronic)
1529-2908 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Nat Immunol},
volume = {18},
number = {2},
pages = {205-213},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Choi, S; Cornall, R; Lesourne, R; Love, P E THEMIS: Two Models, Different Thresholds Article de journal Trends Immunol, 38 (9), p. 622-632, 2017, ISSN: 1471-4981 (Electronic)
1471-4906 (Linking). Liens | BibTeX @article{RN2b,
title = {THEMIS: Two Models, Different Thresholds},
author = {Choi, S. and Cornall, R. and Lesourne, R. and Love, P. E.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/28697966},
doi = {10.1016/j.it.2017.06.006},
issn = {1471-4981 (Electronic)
1471-4906 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Trends Immunol},
volume = {38},
number = {9},
pages = {622-632},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Choi, S; Warzecha, C; Zvezdova, E; Lee, J; Argenty, J; Lesourne, R; Aravind, L; Love, P E THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1 Article de journal Nat Immunol, 18 (4), p. 433-441, 2017, ISSN: 1529-2916 (Electronic)
1529-2908 (Linking). Liens | BibTeX @article{RN5b,
title = {THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1},
author = {Choi, S. and Warzecha, C. and Zvezdova, E. and Lee, J. and Argenty, J. and Lesourne, R. and Aravind, L. and Love, P. E.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/28250424},
doi = {10.1038/ni.3692},
issn = {1529-2916 (Electronic)
1529-2908 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Nat Immunol},
volume = {18},
number = {4},
pages = {433-441},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Combedazou, A; Choesmel-Cadamuro, V; Gay, G; Liu, J; Dupre, L; Ramel, D; Wang, X Myosin II governs collective cell migration behaviour downstream of guidance receptor signalling Article de journal J Cell Sci, 130 (1), p. 97-103, 2017, ISSN: 1477-9137 (Electronic)
0021-9533 (Linking). Liens | BibTeX @article{RN10b,
title = {Myosin II governs collective cell migration behaviour downstream of guidance receptor signalling},
author = {Combedazou, A. and Choesmel-Cadamuro, V. and Gay, G. and Liu, J. and Dupre, L. and Ramel, D. and Wang, X.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/27034137},
doi = {10.1242/jcs.179952},
issn = {1477-9137 (Electronic)
0021-9533 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {J Cell Sci},
volume = {130},
number = {1},
pages = {97-103},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Cotta-de-Almeida, V; Dupre, L; Savino, W Editorial: T-Cell Migration in Health and Disease Article de journal Front Immunol, 8 , p. 132, 2017, ISSN: 1664-3224 (Print)
1664-3224 (Linking). Liens | BibTeX @article{RN11b,
title = {Editorial: T-Cell Migration in Health and Disease},
author = {Cotta-de-Almeida, V. and Dupre, L. and Savino, W.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/28243238},
doi = {10.3389/fimmu.2017.00132},
issn = {1664-3224 (Print)
1664-3224 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Front Immunol},
volume = {8},
pages = {132},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Garreau, A; Blaize, G; Argenty, J; Rouquie, N; Tourdes, A; Wood, S A; Saoudi, A; Lesourne, R Grb2-Mediated Recruitment of USP9X to LAT Enhances Themis Stability following Thymic Selection Article de journal J Immunol, 2017, ISSN: 1550-6606 (Electronic)
0022-1767 (Linking). Liens | BibTeX @article{RN1b,
title = {Grb2-Mediated Recruitment of USP9X to LAT Enhances Themis Stability following Thymic Selection},
author = {Garreau, A. and Blaize, G. and Argenty, J. and Rouquie, N. and Tourdes, A. and Wood, S. A. and Saoudi, A. and Lesourne, R.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/28877990},
doi = {10.4049/jimmunol.1700566},
issn = {1550-6606 (Electronic)
0022-1767 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {J Immunol},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Pfajfer, L; Seidel, M G; Houmadi, R; Rey-Barroso, J; Hirschmugl, T; Salzer, E; Anton, I M; Urban, C; Schwinger, W; Boztug, K; Dupre, L WIP deficiency severely affects human lymphocyte architecture during migration and synapse assembly Article de journal Blood, 130 (17), p. 1949-1953, 2017, ISSN: 1528-0020 (Electronic)
0006-4971 (Linking). Liens | BibTeX @article{RN12b,
title = {WIP deficiency severely affects human lymphocyte architecture during migration and synapse assembly},
author = {Pfajfer, L. and Seidel, M. G. and Houmadi, R. and Rey-Barroso, J. and Hirschmugl, T. and Salzer, E. and Anton, I. M. and Urban, C. and Schwinger, W. and Boztug, K. and Dupre, L.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/28903942},
doi = {10.1182/blood-2017-04-777383},
issn = {1528-0020 (Electronic)
0006-4971 (Linking)},
year = {2017},
date = {2017-01-01},
journal = {Blood},
volume = {130},
number = {17},
pages = {1949-1953},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2016
|
Lamsoul, Isabelle ; Uttenweiler-Joseph, Sandrine ; Moog-Lutz, Christel ; Lutz, Pierre G Cullin 5-RING E3 ubiquitin ligases, new therapeutic targets? Article de journal Biochimie, 122 , p. 339–347, 2016, ISSN: 1638-6183. Résumé | Liens | BibTeX @article{lamsoul_cullin_2016,
title = {Cullin 5-RING E3 ubiquitin ligases, new therapeutic targets?},
author = {Lamsoul, Isabelle and Uttenweiler-Joseph, Sandrine and Moog-Lutz, Christel and Lutz, Pierre G.},
doi = {10.1016/j.biochi.2015.08.003},
issn = {1638-6183},
year = {2016},
date = {2016-03-01},
journal = {Biochimie},
volume = {122},
pages = {339--347},
abstract = {Ubiquitylation is a reversible post-translational modification of proteins that controls a myriad of functions and cellular processes. It occurs through the sequential action of three distinct enzymes. E3 ubiquitin ligases (E3s) play the role of conductors of the ubiquitylation pathway making them attractive therapeutic targets. This review is dedicated to the largest family of multimeric E3s, the Cullin-RING E3 (CRL) family and more specifically to cullin 5 based CRLs that remains poorly characterized.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ubiquitylation is a reversible post-translational modification of proteins that controls a myriad of functions and cellular processes. It occurs through the sequential action of three distinct enzymes. E3 ubiquitin ligases (E3s) play the role of conductors of the ubiquitylation pathway making them attractive therapeutic targets. This review is dedicated to the largest family of multimeric E3s, the Cullin-RING E3 (CRL) family and more specifically to cullin 5 based CRLs that remains poorly characterized. |
Salzer, E; Cagdas, D; Hons, M; Mace, E M; Garncarz, W; Petronczki, O Y; Platzer, R; Pfajfer, L; Bilic, I; Ban, S A; Willmann, K L; Mukherjee, M; Supper, V; Hsu, H T; Banerjee, P P; Sinha, P; McClanahan, F; Zlabinger, G J; Pickl, W F; Gribben, J G; Stockinger, H; Bennett, K L; Huppa, J B; Dupre, L; Sanal, O; Jager, U; Sixt, M; Tezcan, I; Orange, J S; Boztug, K RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics Article de journal Nat Immunol, 17 (12), p. 1352-1360, 2016, ISSN: 1529-2916 (Electronic)
1529-2908 (Linking). Liens | BibTeX @article{RN14,
title = {RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics},
author = {Salzer, E. and Cagdas, D. and Hons, M. and Mace, E. M. and Garncarz, W. and Petronczki, O. Y. and Platzer, R. and Pfajfer, L. and Bilic, I. and Ban, S. A. and Willmann, K. L. and Mukherjee, M. and Supper, V. and Hsu, H. T. and Banerjee, P. P. and Sinha, P. and McClanahan, F. and Zlabinger, G. J. and Pickl, W. F. and Gribben, J. G. and Stockinger, H. and Bennett, K. L. and Huppa, J. B. and Dupre, L. and Sanal, O. and Jager, U. and Sixt, M. and Tezcan, I. and Orange, J. S. and Boztug, K.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/27776107},
doi = {10.1038/ni.3575},
issn = {1529-2916 (Electronic)
1529-2908 (Linking)},
year = {2016},
date = {2016-01-01},
journal = {Nat Immunol},
volume = {17},
number = {12},
pages = {1352-1360},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Zvezdova, E; Mikolajczak, J; Garreau, A; Marcellin, M; Rigal, L; Lee, J; Choi, S; Blaize, G; Argenty, J; Familiades, J; Li, L; Gonzalez de Peredo, A; Burlet-Schiltz, O; Love, P E; Lesourne, R Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability Article de journal Sci Signal, 9 (428), p. ra51, 2016, ISSN: 1937-9145 (Electronic)
1945-0877 (Linking). Liens | BibTeX @article{RN7b,
title = {Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability},
author = {Zvezdova, E. and Mikolajczak, J. and Garreau, A. and Marcellin, M. and Rigal, L. and Lee, J. and Choi, S. and Blaize, G. and Argenty, J. and Familiades, J. and Li, L. and Gonzalez de Peredo, A. and Burlet-Schiltz, O. and Love, P. E. and Lesourne, R.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/27188442},
doi = {10.1126/scisignal.aad1576},
issn = {1937-9145 (Electronic)
1945-0877 (Linking)},
year = {2016},
date = {2016-01-01},
journal = {Sci Signal},
volume = {9},
number = {428},
pages = {ra51},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2015
|
Amin, R; Mourcin, F; Uhel, F; Pangault, C; Ruminy, P; Dupre, L; Guirriec, M; Marchand, T; Fest, T; Lamy, T; Tarte, K DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma Article de journal Blood, 126 (16), p. 1911-20, 2015, ISSN: 1528-0020 (Electronic)
0006-4971 (Linking). Liens | BibTeX @article{RN15b,
title = {DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma},
author = {Amin, R. and Mourcin, F. and Uhel, F. and Pangault, C. and Ruminy, P. and Dupre, L. and Guirriec, M. and Marchand, T. and Fest, T. and Lamy, T. and Tarte, K.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/26272216},
doi = {10.1182/blood-2015-04-640912},
issn = {1528-0020 (Electronic)
0006-4971 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {Blood},
volume = {126},
number = {16},
pages = {1911-20},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Christophe, C; Muller, S; Rodrigues, M; Petit, A E; Cattiaux, P; Dupre, L; Gadat, S; Valitutti, S A biased competition theory of cytotoxic T lymphocyte interaction with tumor nodules Article de journal PLoS One, 10 (3), p. e0120053, 2015, ISSN: 1932-6203 (Electronic)
1932-6203 (Linking). Liens | BibTeX @article{RN16b,
title = {A biased competition theory of cytotoxic T lymphocyte interaction with tumor nodules},
author = {Christophe, C. and Muller, S. and Rodrigues, M. and Petit, A. E. and Cattiaux, P. and Dupre, L. and Gadat, S. and Valitutti, S.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/25815811},
doi = {10.1371/journal.pone.0120053},
issn = {1932-6203 (Electronic)
1932-6203 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {PLoS One},
volume = {10},
number = {3},
pages = {e0120053},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Cotta-de-Almeida, V; Dupre, L; Guipouy, D; Vasconcelos, Z Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome Article de journal Front Immunol, 6 , p. 47, 2015, ISSN: 1664-3224 (Print)
1664-3224 (Linking). Liens | BibTeX @article{RN17b,
title = {Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome},
author = {Cotta-de-Almeida, V. and Dupre, L. and Guipouy, D. and Vasconcelos, Z.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/25709608},
doi = {10.3389/fimmu.2015.00047},
issn = {1664-3224 (Print)
1664-3224 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {Front Immunol},
volume = {6},
pages = {47},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Dupre, L; Houmadi, R; Tang, C; Rey-Barroso, J T Lymphocyte Migration: An Action Movie Starring the Actin and Associated Actors Article de journal Front Immunol, 6 , p. 586, 2015, ISSN: 1664-3224 (Print)
1664-3224 (Linking). Liens | BibTeX @article{RN18b,
title = {T Lymphocyte Migration: An Action Movie Starring the Actin and Associated Actors},
author = {Dupre, L. and Houmadi, R. and Tang, C. and Rey-Barroso, J.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/26635800},
doi = {10.3389/fimmu.2015.00586},
issn = {1664-3224 (Print)
1664-3224 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {Front Immunol},
volume = {6},
pages = {586},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Malet-Engra, G; Yu, W; Oldani, A; Rey-Barroso, J; Gov, N S; Scita, G; Dupre, L Collective cell motility promotes chemotactic prowess and resistance to chemorepulsion Article de journal Curr Biol, 25 (2), p. 242-50, 2015, ISSN: 1879-0445 (Electronic)
0960-9822 (Linking). Liens | BibTeX @article{RN19b,
title = {Collective cell motility promotes chemotactic prowess and resistance to chemorepulsion},
author = {Malet-Engra, G. and Yu, W. and Oldani, A. and Rey-Barroso, J. and Gov, N. S. and Scita, G. and Dupre, L.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/25578904},
doi = {10.1016/j.cub.2014.11.030},
issn = {1879-0445 (Electronic)
0960-9822 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {Curr Biol},
volume = {25},
number = {2},
pages = {242-50},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Pedros, C; Gaud, G; Bernard, I; Kassem, S; Chabod, M; Lagrange, D; Andreoletti, O; Dejean, A S; Lesourne, R; Fournie, G J; Saoudi, A An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development Article de journal J Immunol, 195 (4), p. 1608-16, 2015, ISSN: 1550-6606 (Electronic)
0022-1767 (Linking). Liens | BibTeX @article{RN8,
title = {An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development},
author = {Pedros, C. and Gaud, G. and Bernard, I. and Kassem, S. and Chabod, M. and Lagrange, D. and Andreoletti, O. and Dejean, A. S. and Lesourne, R. and Fournie, G. J. and Saoudi, A.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/26163585},
doi = {10.4049/jimmunol.1402562},
issn = {1550-6606 (Electronic)
0022-1767 (Linking)},
year = {2015},
date = {2015-01-01},
journal = {J Immunol},
volume = {195},
number = {4},
pages = {1608-16},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Vasconcelos, Z; Muller, S; Guipouy, D; Yu, W; Christophe, C; Gadat, S; Valitutti, S; Dupre, L Individual Human Cytotoxic T Lymphocytes Exhibit Intraclonal Heterogeneity during Sustained Killing Article de journal Cell Rep, 11 (9), p. 1474-85, 2015, ISSN: 2211-1247 (Electronic). Liens | BibTeX @article{RN20b,
title = {Individual Human Cytotoxic T Lymphocytes Exhibit Intraclonal Heterogeneity during Sustained Killing},
author = {Vasconcelos, Z. and Muller, S. and Guipouy, D. and Yu, W. and Christophe, C. and Gadat, S. and Valitutti, S. and Dupre, L.},
url = {http://www.ncbi.nlm.nih.gov/pubmed/26027932},
doi = {10.1016/j.celrep.2015.05.002},
issn = {2211-1247 (Electronic)},
year = {2015},
date = {2015-01-01},
journal = {Cell Rep},
volume = {11},
number = {9},
pages = {1474-85},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Spinner, Camille A; Uttenweiler-Joseph, Sandrine ; Metais, Arnaud ; Stella, Alexandre ; Burlet-Schiltz, Odile ; Moog-Lutz, Christel ; Lamsoul, Isabelle ; Lutz, Pierre G Substrates of the ASB2α E3 ubiquitin ligase in dendritic cells Article de journal Scientific Reports, 5 (1), p. 16269, 2015, ISSN: 2045-2322, (Number: 1
Publisher: Nature Publishing Group). Résumé | Liens | BibTeX @article{spinner_substrates_2015,
title = {Substrates of the ASB2α E3 ubiquitin ligase in dendritic cells},
author = {Spinner, Camille A. and Uttenweiler-Joseph, Sandrine and Metais, Arnaud and Stella, Alexandre and Burlet-Schiltz, Odile and Moog-Lutz, Christel and Lamsoul, Isabelle and Lutz, Pierre G.},
url = {http://www.nature.com/articles/srep16269},
doi = {10.1038/srep16269},
issn = {2045-2322},
year = {2015},
date = {2015-01-01},
urldate = {2020-09-30},
journal = {Scientific Reports},
volume = {5},
number = {1},
pages = {16269},
abstract = {Conventional dendritic cells (cDCs) comprise distinct populations with specialized immune functions that are mediators of innate and adaptive immune responses. Transcriptomic and proteomic approaches have been used so far to identify transcripts and proteins that are differentially expressed in these subsets to understand the respective functions of cDCs subsets. Here, we showed that the Cullin 5-RING E3 ubiquitin ligase (E3) ASB2α, by driving degradation of filamin A (FLNa) and filamin B (FLNb), is responsible for the difference in FLNa and FLNb abundance in the different spleen cDC subsets. Importantly, the ability of these cDC subsets to migrate correlates with the level of FLNa. Furthermore, our results strongly point to CD4 positive and double negative cDCs as distinct populations. Finally, we develop quantitative global proteomic approaches to identify ASB2α substrates in DCs using ASB2 conditional knockout mice. As component of the ubiquitin-proteasome system (UPS) are amenable to pharmacological manipulation, these approaches aimed to the identification of E3 substrates in physiological relevant settings could potentially lead to novel targets for therapeutic strategies.},
note = {Number: 1
Publisher: Nature Publishing Group},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Conventional dendritic cells (cDCs) comprise distinct populations with specialized immune functions that are mediators of innate and adaptive immune responses. Transcriptomic and proteomic approaches have been used so far to identify transcripts and proteins that are differentially expressed in these subsets to understand the respective functions of cDCs subsets. Here, we showed that the Cullin 5-RING E3 ubiquitin ligase (E3) ASB2α, by driving degradation of filamin A (FLNa) and filamin B (FLNb), is responsible for the difference in FLNa and FLNb abundance in the different spleen cDC subsets. Importantly, the ability of these cDC subsets to migrate correlates with the level of FLNa. Furthermore, our results strongly point to CD4 positive and double negative cDCs as distinct populations. Finally, we develop quantitative global proteomic approaches to identify ASB2α substrates in DCs using ASB2 conditional knockout mice. As component of the ubiquitin-proteasome system (UPS) are amenable to pharmacological manipulation, these approaches aimed to the identification of E3 substrates in physiological relevant settings could potentially lead to novel targets for therapeutic strategies. |
