40 results on '"Astier, Anne"'
Search Results
2. Editorial: Dysregulation of Th17 and Treg cells in autoimmune diseases
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Astier, Anne L., primary and Kofler, David M., additional
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- 2023
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3. Full spectrum of vitamin D immunomodulation in multiple sclerosis
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Galoppin, Manon, Kari, Saniya, Soldati, Sasha, Pal, Arindam, Rival, Manon, Engelhardt, Britta, Astier, Anne Laurence, Thouvenot, Eric, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), University of Bern, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), ANR-19-CE14-0043,VITADIMS,Rôle de la vitamine D dans la SEP(2019), Astier, Anne, and Rôle de la vitamine D dans la SEP - - VITADIMS2019 - ANR-19-CE14-0043 - AAPG2019 - VALID
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lymphocytes ,[SDV] Life Sciences [q-bio] ,CITE-seq = Cellular Indexing of Transcriptomes and Epitopes by sequencing ,[SDV]Life Sciences [q-bio] ,immunomodulation Abbreviations: BBB = blood-brain barrier ,vitamin D ,multiple sclerosis ,cytokines - Abstract
International audience; Vitamin D deficiency has been associated with the risk of multiple sclerosis, disease activity and progression. Results from in vitro experiments, animal models and analysis of human samples from randomized controlled trials provide comprehensive data illustrating the pleiotropic actions of Vitamin D on the immune system. They globally result in immunomodulation by decreasing differentiation of effector T and B cells while promoting regulatory subsets. Vitamin D also modulates innate immune cells such as macrophages, monocytes and dendritic cells, and acts at the level of the blood-brain barrier reducing immune cell trafficking. Vitamin D exerts additional activity within the central nervous system reducing microglial and astrocytic activation. The immunomodulatory role of Vitamin D detected in animal models of multiple sclerosis has suggested its potential therapeutic use for treating multiple sclerosis. In this review, we focus on recent published data describing the biological effects of Vitamin D in animal models of multiple sclerosis on immune cells, blood-brain barrier function, activation of glial cells and its potential neuroprotective effects. Based on the current knowledge, we also discuss optimization of therapeutic interventions with Vitamin D in patients with multiple sclerosis, as well as new technologies allowing in-depth analysis of immune cell regulations by vitamin D.
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- 2022
4. HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33
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Osbourn, Megan, Soares, Dinesh C., Vacca, Francesco, Cohen, Suzanne E., Scott, Ian C., Gregory, William F., Smyth, Danielle J., Toivakka, Matilda, Kemter, Andrea M., le Bihan, Thierry, Wear, Martin, Hoving, Dennis, Filbey, Kara J., Hewitson, James P., Henderson, Holly, Gonzàlez-Cìscar, Andrea, Errington, Claire, Vermeren, Sonja, Astier, Anne L., Wallace, William A., Schwarze, Jürgen, Ivens, Alasdair C., Maizels, Rick M., and McSorley, Henry J.
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- 2017
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5. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis
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Astier, Anne L., Meiffren, Gregory, Freeman, Samuel, and Hafler, David A.
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Multiple sclerosis -- Research ,Multiple sclerosis -- Development and progression ,T cells -- Genetic aspects ,T cells -- Physiological aspects - Abstract
Loss of Treg function appears to be a critical factor in the pathogenesis of human autoimmune diseases. Attention has focused on defects of CD[4.sup.+]CD[25.sup.high] Tregs, and techniques have been developed [...]
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- 2006
6. Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis
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Killick, Justin, primary, Hay, Joanne, additional, Morandi, Elena, additional, Vermeren, Sonja, additional, Kari, Saniya, additional, Angles, Thibault, additional, Williams, Anna, additional, Damoiseaux, Jan, additional, and Astier, Anne L., additional
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- 2020
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7. T-cell regulation by CD46 and its relevance in multiple sclerosis
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Astier, Anne L.
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- 2008
8. Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival
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Astier, Anne Laurence, Xu, Ronghui, Svoboda, Marek, Hinds, Esther, Munoz, Olivier, de Beaumont, Rosalie, Crean, Colin Daniel, Gabig, Theodore, and Freedman, Arnold Stephen
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- 2003
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9. Nitric oxide induces functional human CLA+CD25+Foxp3+ regulatory T cells with skin homing potential
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Yu, Cunjing, Fitzpatrick, Amanda, Cong, Duanduan, Yao, Chengcan, Yoo, Jinah, Turnbull, Andrew, Schwarze, Jürgen, Norval, Mary, Howie, Sarah, Weller, Richard B., and Astier, Anne
- Abstract
Phototherapy releases nitric oxide and can reduce symptoms in Atopic Dermatitis (AD). Nitric oxide induced suppressive regulatory T cells and, post-phototherapy, a clinical improvement in AD correlated with an increased ratio of Tregulatory:Teffector cells.
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- 2017
10. Preclinical safety, pharmacokinetics, pharmacodynamics and biodistribution studies with Ad35K++ protein, a novel rituximab co‐therapeutic in mice and non‐human primates
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Richter, Maximilian, Yumul, Roma, Saydaminova, Kamola, Wang, Hongjie, Gough, Michael, Baldessari, Audrey, Lee, Frank, Wang, Chung-Huei Katherine, Jang, Haishan, Astier, Anne, Gopal, Ajay, Carter, Darrick, and Lieber, Andre
- Abstract
Rituximab is a mouse/human chimeric monoclonal antibody targeted towards CD20. It is efficient as first line therapy of CD20‐positive B‐cell malignancies. However, a large fraction of treated patients relapse with rituximab‐resistant disease. So far, only modest progress has been made in treatment options forrituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells tocomplement‐dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 • histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab mediated killing of CD20‐positive target cells in mice and non‐human primates. The presence of the tag, while allowing for easy purification by Ni‐NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His‐tag. In the present study we performed preclinical studies in two animal species with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used asa pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an Investigational New Drug (IND) application for the use of Ad35K++ in combination with rituximab in the treatment of patients with B‐cell malignancies.
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- 2016
11. Nitric oxide induces human CLA + CD25 + Foxp3 + regulatory T cells with skin-homing potential
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Yu, Cunjing, Fitzpatrick, Amanda, Cong, Duanduan, Yao, Chengcan, Yoo, Jinah, Turnbull, Andrew, Schwarze, Jürgen, Norval, Mary, Howie, Sarah E.M., Weller, Richard, Hafler, David, Astier, Anne, University of Edinburgh, Yale University School of Medicine, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,business.industry ,Immunology ,FOXP3 ,Ultraviolet therapy ,3. Good health ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Forkhead Transcription Factors ,chemistry ,Skin homing ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Immunology and Allergy ,Medicine ,IL-2 receptor ,business ,ComputingMilieux_MISCELLANEOUS ,030215 immunology - Abstract
International audience
- Published
- 2017
12. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic
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Richter, Maximilian, primary, Yumul, Roma, additional, Saydaminova, Kamola, additional, Wang, Hongjie, additional, Gough, Michael, additional, Baldessari, Audrey, additional, Cattaneo, Roberto, additional, Lee, Frank, additional, Wang, Chung-Huei Katherine, additional, Jang, Haishan, additional, Astier, Anne, additional, Gopal, Ajay, additional, Carter, Darrick, additional, and Lieber, André, additional
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- 2016
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13. Editorial: T Cell Regulation by the Environment
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Hafler, David A., primary and Astier, Anne L., additional
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- 2015
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14. Recombinant Ad35 adenoviral proteins as potent modulators of human T-cell activation
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Hay, Joanne, primary, Carter, Darrick, additional, Lieber, André, additional, and Astier, Anne L., additional
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- 2014
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15. Calcitriol Modulates the CD46 Pathway in T Cells
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Kickler, Karoline, primary, Ni Choileain, Siobhan, additional, Williams, Anna, additional, Richards, Anna, additional, and Astier, Anne L., additional
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- 2012
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16. The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation
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Ni Choileain, Siobhan, primary, Weyand, Nathan J., additional, Neumann, Christian, additional, Thomas, Joelle, additional, So, Magdalene, additional, and Astier, Anne L., additional
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- 2011
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17. Recombinant Ad35 adenoviral proteins as potent modulators of human T-cell activation.
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Hay, Joanne, Carter, Darrick, Lieber, André, and Astier, Anne L.
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ADENOVIRUSES ,T cells ,RECOMBINANT proteins ,IMMUNOLOGICAL adjuvants ,CD46 antigen ,COMPLEMENT (Immunology) - Abstract
The protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD46 also regulates the adaptive immune response by controlling T-cell activation and differentiation. Co-engagement of the T-cell receptor and CD46 notably drives T-cell differentiation by switching production of interferon-γ to secretion of anti-inflammatory interleukin-10. This regulatory pathway is altered in several chronic inflammatory diseases, highlighting its key role for immune homeostasis. The manipulation of the CD46 pathway may therefore provide a powerful means to regulate immune responses. Herein, we investigated the effect of recombinant proteins derived from the fibre knob of the adenovirus serotype 35 (Ad35) that uses CD46 as its entry receptor, on human T-cell activation. We compared the effects of Ad35K++, engineered to exhibit enhanced affinity to CD46, and of Ad35K-, mutated in the binding site for CD46. Ad35K++ profoundly affects T-cell activation by decreasing the levels of CD46 at the surface of primary T cells, and impairing T-cell coactivation, shown by decreased CD25 expression, reduced proliferation and lower secretion of interleukin-10 and interferon-γ. In contrast, Ad35K- acts a potent co-activator of T cells, enhancing T-cell proliferation and cytokine production. These data show that recombinant Ad35 proteins are potent modulators of human T-cell activation, and support their further development as potential drugs targeting T-cell responses. [ABSTRACT FROM AUTHOR]
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- 2015
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18. Measles Virus Induces Functional TRAIL Production by Human Dendritic Cells
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Vidalain, Pierre-Olivier, primary, Azocar, Olga, additional, Lamouille, Barbara, additional, Astier, Anne, additional, Rabourdin-Combe, Chantal, additional, and Servet-Delprat, Christine, additional
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- 2000
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19. The Related Adhesion Focal Tyrosine Kinase Differentially Phosphorylates p130Cas and the Cas-like Protein, p105HEF1
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Astier, Anne, primary, Manié, Serge N., additional, Avraham, Hava, additional, Hirai, Hisamaru, additional, Law, Susan F., additional, Zhang, Yuzhu, additional, Golemis, Erica A., additional, Fu, Yigong, additional, Druker, Brian J., additional, Haghayeghi, Nilou, additional, Freedman, Arnold S., additional, and Avraham, Shalom, additional
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- 1997
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20. Regulation of Integrin-mediated p130Cas Tyrosine Phosphorylation in Human B Cells
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Manié, Serge N., primary, Astier, Anne, additional, Haghayeghi, Nilou, additional, Canty, Timothy, additional, Druker, Brian J., additional, Hirai, Hisamaru, additional, and Freedman, Arnold S., additional
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- 1997
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21. Involvement of p130Cas and p105HEF1, a Novel Cas-like Docking Protein, in a Cytoskeleton-dependent Signaling Pathway Initiated by Ligation of Integrin or Antigen Receptor on Human B Cells
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Manié, Serge N., primary, Beck, Andreas R.P., additional, Astier, Anne, additional, Law, Susan F., additional, Canty, Tim, additional, Hirai, Hisamaru, additional, Druker, Brian J., additional, Avraham, Hava, additional, Haghayeghi, Nilou, additional, Sattler, Martin, additional, Salgia, Ravi, additional, Griffin, James D., additional, Golemis, Erica A., additional, and Freedman, Arnold S., additional
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- 1997
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22. The Related Adhesion Focal Tyrosine Kinase Is Tyrosine-phosphorylated after β1-Integrin Stimulation in B Cells and Binds to p130cas
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Astier, Anne, primary, Avraham, Hava, additional, Manie, Serge N., additional, Groopman, Jerome, additional, Canty, Timothy, additional, Avraham, Shalom, additional, and Freedman, Arnold S., additional
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- 1997
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23. Soluble FCγ receptors
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Fridman, Wolf H, primary, Teillaud, Jean-Luc, additional, Bouchard, Caroline, additional, Teillaud, Christophe, additional, Astier, Anne, additional, Tartour, Eric, additional, Galon, Jerome, additional, Mathiot, Claire, additional, and Sautes, Catherine, additional
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- 1993
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24. The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation.
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Choileain, Siobhan Ni, Weyand, Nathan J., Neumann, Christian, Thomas, Joelle, So, Magdalene, and Astier, Anne L.
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IMMUNE response ,RHEUMATOID arthritis ,CELL physiology ,GENOTYPE-environment interaction ,CELLULAR immunity ,BLOOD hyperviscosity syndrome ,ANTIASTHMATIC agents ,T cells ,PHENOTYPES - Abstract
Background: Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated. Methodology/Principal Findings: Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually. Conclusions/Significance: We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails. [ABSTRACT FROM AUTHOR]
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- 2011
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25. Release of FcγRIIa2 by Activated Platelets and Inhibition of Anti-CD9-Mediated Platelet Aggregation by Recombinant FcγRIIa2
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Gachet, Christian, Astier, Anne, Salle, Henri de la, Salle, Corinne de la, Fridman, Wolf Herman, Cazenave, Jean-Pierre, Hanau, Daniel, and Teillaud, Jean-Luc
- Abstract
Thrombin-activated human platelets and megakaryocyte cell lines release soluble FcγRII (FcγRlla2) containing the extracellular and intracellular regions of FcγRIIal, but lacking the transmembrane domain. Use of polyclonal antibodies directed either against the entire intracytoplasmic tail, or against a peptide located near the C-terminal part of the intracellular region of FcγRlla2, showed the presence of both a complete form of FcγRlla2 and a C-terminal truncated form in supernatants of platelets after release of their α granule contents and in culture supernatants of megakaryocyte cell lines. Furthermore, recombinant FcγRlla2 inhibited in a dose-dependent manner Fc-dependent anti-CD9 antibody-induced platelet aggregation. Thus, release of FcγRlla2 by activated platelets could play an important role in the regulation of platelet activation by immune complexes.
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- 1995
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26. Stimulation of Tyrosine Phosphorylation After Ligation of β7 and β1 Integrins on Human B Cells
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Manie, Serge N., Astier, Anne, Wang, Dakun, Phifer, J.Scott, Chen, Jichun, Lazarovits, Andrew I., Morimoto, Chikao, and Freedman, Arnold S.
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B lymphocytes express several members of the integrin family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. In addition to β1 integrins, predominantly α4β1, mature B cells also express α4β7, which is a receptor for vascular cell adhesion molecule-1 and fibronectin, and is also involved in the homing of B cells to mucosal sites through binding to a third ligand, mucosal addressin cell adhesion molecule-1. Here we describe that crosslinking of α4β7 integrins on B cell lines and normal tonsillar B cells, induces tyrosine phosphorylation of multiple substrates of 105-130 kD, indicating that β7 integrin plays a role as signaling molecule in B cells. This pattern of phosphorylated proteins was very similar to that induced following ligation of α4β1. Interestingly, ligation of α5β1 or α6β1 also stimulated the 105-125 kD group of phosphorylated proteins, whereas ligation of β2 integrins did not. The focal adhesion tyrosine kinase p125FAKwas identified as one of these substrates. 01 or 07 mediated tyrosine phosphorylations were markedly decreased when the microfilament assembly was inhibited by cytochalasin B. These results suggest that intracellular signals initiated by different integrins in B cells may converge, to similar cytoskeleton-dependent tyrosine phosphorylated proteins.
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- 1996
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27. Regulation of Integrin-mediated p130CasTyrosine Phosphorylation in Human B Cells
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Manié, Serge N., Astier, Anne, Haghayeghi, Nilou, Canty, Timothy, Druker, Brian J., Hirai, Hisamaru, and Freedman, Arnold S.
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Engagement of β1 integrins in terminally differentiated human B cell lines, such as ARH-77, leads to prominent tyrosine phosphorylation of the p130 Crk-associated substrate (Cas). Cas regulates the assembly of several SH2 and SH3 domain-containing proteins into signaling complexes, which are potentially involved in the propagation of downstream signals. We demonstrate here that immunoprecipitated Cas from β1 integrin-stimulated ARH-77 cells was associated with tyrosine kinase and phosphatase activities and that integrin ligation led to the recruitment of at least p59Fyntyrosine kinase and SHP2 tyrosine phosphatase in Cas immune complexes. Cotransfection studies in COS-7 cells further indicated that Fyn/Cas physical interaction and Fyn-mediated Cas phosphorylation required amino acids 638–889 in the C-terminal region of Cas. This sequence contains both c-Src SH2 and SH3 domain-binding motifs. In vitrobinding studies using glutathioneS-transferase fusion proteins derived from the SH2 or SH3 domains of Fyn suggested that both Fyn domains can participate in Fyn/Cas interaction. These data implicate Fyn and SHP2 as potential modulators of Cas signaling complexes in B cells.
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- 1997
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28. Involvement of p130Casand p105HEF1, a Novel Cas-like Docking Protein, in a Cytoskeleton-dependent Signaling Pathway Initiated by Ligation of Integrin or Antigen Receptor on Human B Cells*
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Manié, Serge N., Beck, Andreas R.P., Astier, Anne, Law, Susan F., Canty, Tim, Hirai, Hisamaru, Druker, Brian J., Avraham, Hava, Haghayeghi, Nilou, Sattler, Martin, Salgia, Ravi, Griffin, James D., Golemis, Erica A., and Freedman, Arnold S.
- Abstract
The Crk-associated substrate p130Cas(Cas) and the recently described human enhancer of filamentation 1 (HEF1) are two proteins with similar structure (64% amino acid homology), which are thought to act as “docking” molecules in intracellular signaling cascades. Both proteins contain an N-terminal Src homology (SH), three domain and a cluster of SH2 binding motifs. Here we show that ligation of either β1 integrin or B cell antigen receptor (BCR) on human tonsillar B cells and B cell lines promoted tyrosine phosphorylation of HEF1. In contrast, Cas tyrosine phosphorylation was observed in certain B cell lines but not in tonsillar B cells, indicating a more general role for HEF1 in B cell signaling. Interestingly, pretreatment of tonsillar B cells with cytochalasin B dramatically reduced both integrin- and BCR-induced HEF1 phosphorylation, suggesting that some component of the BCR-mediated signaling pathway is closely linked with a cytoskeletal reorganization. Both HEF1 and Cas were found to complex with the related adhesion focal tyrosine kinase (RAFTK), and when tyrosine phosphorylated, with the adapter molecule CrkL. In addition, the two molecules were detected in p53/56Lynimmunoprecipitates, and Lyn kinase was found to specifically bind the C-terminal proline-rich sequence of Cas in an in vitrobinding assay. These associations implicate HEF1 and Cas as important components in a cytoskeleton-linked signaling pathway initiated by ligation of β1 integrin or BCR on human B cells.
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- 1997
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29. The Related Adhesion Focal Tyrosine Kinase Differentially Phosphorylates p130Casand the Cas-like Protein, p105HEF1*
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Astier, Anne, Manié, Serge N., Avraham, Hava, Hirai, Hisamaru, Law, Susan F., Zhang, Yuzhu, Golemis, Erica A., Fu, Yigong, Druker, Brian J., Haghayeghi, Nilou, Freedman, Arnold S., and Avraham, Shalom
- Abstract
The related adhesion focal tyrosine kinase (RAFTK) is tyrosine-phosphorylated following β1 integrin or B cell antigen receptor stimulation in human B cells. Two substrates that are tyrosine-phosphorylated following integrin ligation in B cells are p130Casand the Cas family member human enhancer of filamentation 1 (HEF1), both of which can associate with RAFTK. In this report we observed that RAFTK was involved in the phosphorylation of these two proteins. While a catalytically active RAFTK was required for both p130Casand HEF1, phosphorylation of p130Cas, but not of HEF1, was dependent on an intact autophosphorylation site (Tyr402) on RAFTK. To determine if RAFTK phosphorylated p130Casand HEF1 directly or through an intermediate, we assayed the ability of RAFTK and of a Tyr402mutant to phosphorylate purified HEF1 and p130Casdomains. RAFTK was able to phosphorylate the substrate domains of both p130Casand HEF1, but only the C-terminal domain of p130Cas. Furthermore, Tyr402, which mediates the binding of RAFTK to c-Src kinase, was required for the phosphorylation of the C-terminal domain of p130Cas. These data suggest that RAFTK itself is sufficient for HEF1 phosphorylation, whereas a cooperation between RAFTK and Src kinases is required for the complete phosphorylation of p130Cas.
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- 1997
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30. Syntheses and structural studies on two cycloruthenapentadienyl complexes: [(CO)3RuC4(CH2OH)4]Ru(CO)3·H2O and [(CO)3RuC4(CH2CH2OH)2(C2H5)2]Ru(CO)3
- Author
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Astier, Anne, primary, Daran, Jean-Claude, additional, Jeannin, Yves, additional, and Rigault, Catherine, additional
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- 1983
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31. Syntheses and structural studies on two cycloruthenapentadienyl complexes: [(CO) 3RuC 4(CH 2OH) 4]Ru(CO) 3·H 2O and [(CO) 3RuC 4(CH 2CH 2OH) 2(C 2H 5) 2]Ru(CO) 3
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Astier, Anne, Daran, Jean-Claude, Jeannin, Yves, and Rigault, Catherine
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- 1983
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32. Investigation into the regulation of CD46 function in T cells
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Hay, Joanne, Astier, Anne, Dransfield, Ian, and Howie, Sarah
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CD46 ,T cell activation ,CD46 O-glycosylation ,STP region - Abstract
CD46 is a ubiquitously expressed transmembrane protein in humans with a role in immune homeostasis. Originally identified as a complement regulator, CD46 has since been regarded a receptor for several pathogens and most recently, described as a T cell costimulatory molecule. Its coligation with CD3 and consequent cleavage from the T cell surface serves as a costimulatory stimulus for T cell activation. In addition, in the presence of IL-2, CD46 induces Tr1 cell differentiation which is characterised by low IFN-γ and high IL-10 secretion. CD3/CD46-induced Tr1 differentiation is defective in patients with MS, rheumatoid arthritis and asthma, highlighting the need to investigate the mechanisms involved in the regulation of the CD46 pathway. CD46 is a highly glycosylated protein with three N-glycosylation sites in the short consensus repeats and multiple O-glycosylation sites in the STP region. Previous data from the lab have shown that CD3 activation causes a change in CD46 glycosylation. Herein, I convey that this change is more pronounced in memory than naive CD4+ T cells and is mainly due to changes in CD46 O-glycosylation. Furthermore, these changes are required for the T cell responses triggered by CD46 costimulation including T cell activation and Tr1 differentiation. Interestingly, CD46 is recruited to the immunological synapse formed between a T cell and an antigen presenting cell and I illustrate that the STP region is needed for this also. These data suggest that the glycosylation status of CD46 regulates its function. In MS, vitamin D deficiency is considered to be a significant risk factor and many patients take vitamin D supplement to help manage their condition. Herein, I report that treatment of healthy and MS CD4+ T cells with vitamin D does not prevent T cell activation but it decreases adhesion molecule expression. Moreover, vitamin D supplementation in MS enhances CD46 cleavage. Therefore, vitamin D also plays a role in the regulation of the CD46 pathway and it would be interesting to investigate whether vitamin D affects CD46 glycosylation. During my MSc, I showed that a recombinant protein derived from adenovirus serotype 35 (which naturally binds CD46) known as Ad35K++ controls the CD46 pathway in CD4+ T cells. Lymphoma cells treated with Ad35K++ in combination with monoclonal antibody therapy rituximab have demonstrated increased sensitivity to rituximab and prove that virus-derived recombinant proteins that target CD46 have therapeutic potential. Considering the key role of CD46 as a T cell costimulatory molecule, I have investigated the effects of Ad35K++ on the CD46 pathway following its use in vivo and confirm CD46 is still cleaved from the cell surface and the cells still become activated. Overall these results provide insight into the mechanisms involved in the regulation of the CD46 pathway and highlight how it can be manipulated for therapeutic use.
- Published
- 2017
33. Modulation of immune responses by UV irradiation
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Yu, Cunjing, Astier, Anne, Howie, Sarah, and Weller, Richard
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616.5 ,human regulatory T cells ,Tregs ,nitric oxide ,cis-urocanic acid ,cis-UCA ,UV radiation ,atopic dermatitis - Abstract
Atopic dermatitis (AD) is a common, chronic relapsing inflammatory skin disease associated with cutaneous hyper-reactivity to environmental triggers that are innocuous to normal nonatopic individuals. AD affects 10% to 15% of children and 2% to 10% of adults in industrialized countries. There has been increasing interest in this disease triggered by its increasing prevalence in western societies and its contribution to the increasing health care costs. Yet, the underlying pathophysiologic and genetic mechanisms leading to the manifestation of AD are not clear. AD results from a complex interplay between environmental triggers, susceptibility genes including mutations in the keratinocyte protein filaggrin and altered immune responses resulting in allergic CD4+ T cell (Th2) immunity to epidermally encountered antigens. Regulatory T cells (Tregs) play an important role in controlling responsiveness to self-antigens and preventing autoimmune diseases, as well as in limiting inflammatory responses during inflammation and infection. Currently, studies investigating the number and function of Tregs in patients with AD have shown controversial results. It has been long established that symptoms of AD improve on exposure to sunlight. Narrowband UVB (NB-UVB) phototherapy is a common treatment modality for a variety of skin diseases. Considering the adverse effects for systemic treatment for severe adult AD, phototherapy, especially NB-UVB phototherapy may be a more practical long-term treatment. However, approximately 50% of patients over an 8-week treatment course do not improve after NB-UVB phototherapy. Therefore, it is important to identify characteristics of AD patients to determine whether they will respond to phototherapy and to avoid adverse effects for unresponsive patients. UVB exposure has also been associated with induction of Tregs in mice and increasing their numbers and/or functional capacity may offer benefit to patients with chronic AD. Active vitamin D (1,25(OH)2D3), one of the factors induced by UV-B radiation induces Tregs and is suggested to contribute to the suppressive effect of NB-UVB phototherapy. However, UV radiation could also have beneficial effects through other pathways known to affect immunoregulation. UVB exposure upregulates production of nitric oxide (NO) in the skin which also affects immune cell function. The protein filaggrin is broken down in differentiating keratinocytes to form the natural moisturizer of the skin. The gene encoding filaggrin (FLG) has been shown to be a major predisposing factor for AD. A key breakdown product is urocanic acid (UCA) which also acts as a natural sunscreen and undergoes trans-cis isomerisation on exposure to UV-B. Cis-UCA is known to modulate immune responses, however, the mechanisms of its action remain elusive. The production of all three compounds, vitamin D, cis-UCA and NO might all increase in the circulation of patients undergoing UVB phototherapy. While the immunomodulatory effect of Vitamin D is well described, cis-UCA and NO may also affect the behaviour of T lymphocytes systemically. Therefore, I investigated the effect of NO and cis-UCA on the phenotype and function of CD4+T cells and monocyte-derived dendritic cells (Mo-DCs) derived from peripheral blood mononuclear cells (PBMCs) from healthy volunteers. I also investigated the correlation between plasma concentration of 25(OH) vitamin D and nitrate, FLG genotype, circulating Tregs and clinical efficacy of NB-UVB phototherapy. My results showed that NO did not affect the phenotype of human mo-DCs and directly affected peripheral CD4+ T cells by inducing functional CD25+Foxp3+CD127-Tregs from CD4+CD25lo/- effector T cells. Moreover, NO increased expression of the of skin homing marker CLA on these Tregs, suggesting an increased ability of NO-induced Tregs to migrate to the skin. These NO-induced CD25+Foxp3+CD127-Tregs had immunosuppressive functions and inhibited autologous CD4+ T cell proliferation. Cytokines, at least IL-10, secreted by NO-treated CD4+ T cells were not sufficient for the suppressive function of NOinduced Foxp3+Tregs. The immune regulatory function of NO-induced Fopx3+Tregs required cell-cell contact and was mediated by membrane bound TGFβ and PD-1/PD-L1 but not CTLA-4. Results also showed that cis-UCA might have both pro- and anti-inflammatory effects. Cis- UCA significantly decreased the proportion of CD25hi Foxp3+ cells from activated CD4+ T cells. It also decreased the expression of vitamin D receptor in CD4+ T cells which may interfere with the immune regulatory function of vitamin D. These results suggested that there might be a fine balance between UV-induced anti-inflammatory molecules’ effect on CD4+ T cells. However, Cis-UCA also modulated CD4+ T cell directly by decreasing CD4+ T cell proliferation, decreasing phosphorylation of ERK after TCR activation, enhancing immune suppressive cytokines secretion, and inhibiting the percentage of CLA+CD4+T cells suggesting a decreased ability to migrate to the skin, . Cis-UCA also affected the phenotype and function of antigen presenting cells by decreasing the expression of HLA-DR, CD86 and CD40 on immature mo-DCs, which led to increased proportion of CD25+Foxp3+CD127- T cells when co-cultured with allogenic CD4+ T cells. Results generated from the clinical study in which all 29 patients got better after phototherapy suggested although circulating 25 (OH) vitamin D concentration was significantly increased after NB-UVB phototherapy, the change of circulating 25 (OH) vitamin D concentration did not correlate with disease improvement. This suggests that vitamin D is not the only pathway involved and that other molecules contribute to UVB-induced immune-regulation. The data also show that of the levels of circulating nitrate and the FLG genotype did not correlate with improvement / change with phototherapy. However, the expression of CD69 and CLA on circulating CD4+ T cells was decreased after treatment suggesting that UVB affected T cell activation and migration to the skin, and their importance in determining clinical responses requires further investigation. Taken together, the results from my study provide evidence that vitamin D is not the only molecule responsible for the beneficial effect of NB-UVB phototherapy. NO and cis-UCA may down-regulate immune responses by affecting human peripheral CD4+ T cells and mo- DCs phenotype and function. A further understanding of the effect of NO and cis-UCA on skin resident immune cells will provide more insights for narrowing NB-UVB phototherapy which will help to select patients that most likely to benefit from a mechanism-based treatment.
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- 2016
34. Processing and glycosylation of CD46 regulate : its expression and T cell responses
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Ní Choileáin, Siobhán, Anderton, Stephen, and Astier, Anne
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616.07 ,CD46 ,T cells ,processing ,glycosylation ,multiple sclerosis - Abstract
CD46 is a ubiquitously expressed transmembrane molecule and has an important role in the innate and adaptive immune system. CD46 was originally identified as a complement receptor that protects cells from autologous attack. However, CD46’s immunological profile is ever expanding and more recently it was identified as a T cell costimulatory molecule. Notably, in the presence of IL-2, CD46 can induce a Tr1-like phenotype that is characterized by the secretion of large amounts of the potent anti-inflammatory cytokine, IL-10. Defects in CD46- induced IL-10 secretion have been identified in multiple sclerosis, asthma and rheumatoid arthritis. Despite CD46’s promiscuous nature in immune responses there is little known about its underlying processing and signalling pathways. Herein, I report that CD46 expression and processing are important for regulating T cell anti-inflammatory responses and activation. Cyt1 but not Cyt2 promotes an increased ratio IL-10+ cells compared to cells that secrete both Il-10 and IFNγ. Upon CD46 costimulation, proteolytic cleavage of CD46 occurs at the surface and intracellularly with the subsequent release of a functional intracellular domain (ICD). As a result of alternative splicing, there are two main cytoplasmic isoforms of CD46, both of which release ICDs, Cyt1 and Cyt2. It is shown that the smaller Cyt1 ICD fragment facilitates T cell activation, whereas, Cyt2 promotes T cell activation when expressed in an uncleaved form. As the expression and cleavage of CD46 is important for regulating T cell function, I went on to identify factors that can regulate CD46 cleavage. Herein, it is demonstrated that T cell activation by the T cell receptor (TCR) acts as a major regulator of CD46 cleavage and expression, emphasizing the inherent role of CD46 in T cell activation. TCR stimulation also modulates CD46 glycosylation, which may effect CD46 expression and T cell phenotype. Importantly, I have identified a dysregulated expression of CD46 in a preliminary cohort of RRMS patients. It will be interesting to examine if aberrant CD46 glycosylation or cleavage accounts for its altered expression levels and impaired IL-10 secretion in RRMS patients.
- Published
- 2013
35. Immune complex-induced apoptosis and concurrent immune complex clearance are anti-inflammatory neutrophil functions
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Julia Y. Chu, Sonja Vermeren, Kruthika Sundaram, Ian Dransfield, Hannah Garside, Anne Astier, Utsa Karmakar, Carsten G. Hansen, University of Edinburgh, Centre de Physiopathologie Toulouse Purpan (CPTP), 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), Astier, Anne, Medical Research Council (MR/S008020/1), and Versus Arthritis PhD scholarship (21577)
- Subjects
Cancer Research ,Programmed cell death ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Neutrophils ,[SDV]Life Sciences [q-bio] ,Phagocytosis ,Immunology ,Inflammation ,Apoptosis ,Antigen-Antibody Complex ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Immune system ,Cell death and immune response ,medicine ,Humans ,lcsh:QH573-671 ,MESH: Antigen-Antibody Complex / metabolism ,030304 developmental biology ,MESH: Inflammation / immunology ,chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,MESH: Humans ,Immune complex clearance ,Chemistry ,lcsh:Cytology ,MESH: Apoptosis ,MESH: Neutrophils / immunology ,Cell Biology ,Immune complex ,Endocytosis ,3. Good health ,[SDV] Life Sciences [q-bio] ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,medicine.symptom ,030215 immunology - Abstract
Persistent neutrophilic inflammation drives host damage in autoimmune diseases that are characterized by abundant immune complexes. Insoluble immune complexes (iICs) potently activate pro-inflammatory neutrophil effector functions. We and others have shown that iICs also promote resolution of inflammation via stimulation of neutrophil apoptosis. We demonstrate here that iICs trigger FcγRIIa-dependent neutrophil macropinocytosis, leading to the rapid uptake, and subsequent degradation of iICs. We provide evidence that concurrent iIC-induced neutrophil apoptosis is distinct from phagocytosis-induced cell death. First, uptake of iICs occurs by FcγRII-stimulated macropinocytosis, rather than phagocytosis. Second, production of reactive oxygen species, but not iIC-internalization is a pre-requisite for iIC-induced neutrophil apoptosis. Our findings identify a previously unknown mechanism by which neutrophils can remove pro-inflammatory iICs from the circulation. Together iIC clearance and iIC-induced neutrophil apoptosis may act to prevent the potential escalation of neutrophilic inflammation in response to iICs.
- Published
- 2021
36. Complement as a regulator of adaptive immunity
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Dirk Sieger, Anne Astier, Justin Killick, Gregoire Morisse, Centre for Inflammation Research [Edinburgh, UK], University of Edinburgh-Queen's Medical Researche Institute, University of Edinburgh, Centre for Neuroregeneration [Edinburgh, UK], Centre de Physiopathologie Toulouse Purpan (CPTP), 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), These studies were partly supported by research grants to ALA and DS from the Multiple Sclerosis Society (GB)., Astier, Anne, Queen's Medical Researche Institute, and University of Edinburgh-University of Edinburgh
- Subjects
0301 basic medicine ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,T-Lymphocytes ,Immunology ,Adaptive immunity ,Complement ,T cells ,Antigen-Presenting Cells ,Complement receptor ,Cell Communication ,Review ,Biology ,Lymphocyte Activation ,Immunomodulation ,03 medical and health sciences ,Classical complement pathway ,0302 clinical medicine ,Immunology and Allergy ,Animals ,Humans ,Immunologic Factors ,Molecular Targeted Therapy ,Complement Activation ,CD46 ,Inflammation ,B-Lymphocytes ,B cells ,Complement component 2 ,Pattern recognition receptor ,Complement System Proteins ,Acquired immune system ,Cell biology ,Complement system ,030104 developmental biology ,Alternative complement pathway ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Disease Susceptibility ,Carrier Proteins ,030215 immunology ,Protein Binding ,Signal Transduction - Abstract
International audience; The complement system is an ancient and evolutionarily conserved effector system comprising in mammals over 50 circulating and membrane bound proteins. Complement has long been described as belonging to the innate immune system; however, a number of recent studies have demonstrated its key role in the modulation of the adaptive immune response. This review does not set out to be an exhaustive list of the numerous interactions of the many complement components with adaptive immunity; rather, we will focus more precisely on the role of some complement molecules in the regulation of antigen presenting cells, as well as on their direct effect on the activation of the core adaptive immune cells, B and T lymphocytes. Recent reports on the local production and activation of complement proteins also suggest a major role in the control of effector responses. The crucial role of complement in adaptive immunity is further highlighted by several examples of dysregulation of these pathways in human diseases.
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- 2017
37. Editorial: T Cell Regulation by the Environment
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David A. Hafler, Anne Astier, Astier, Anne, Yale School of Medicine [New Haven, Connecticut] (YSM), Centre de Physiopathologie Toulouse Purpan (CPTP), 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), and Yale University School of Medicine
- Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology ,T cell ,Immunology ,T cells ,microbiome ,vitamin D ,Biology ,Environment ,Major histocompatibility complex ,regulatory T cells ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,IL-2 receptor ,Vitamin D ,Receptor ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,T-cell receptor ,pathogens ,Regulatory T cells ,Editorial ,medicine.anatomical_structure ,Metabolism ,030220 oncology & carcinogenesis ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Microbiome ,Pathogens ,Cell activation ,environment ,metabolism ,CD8 - Abstract
T cell responses are initiated by ligation of their cognate T cell receptor by MHC loaded with antigenic peptide, but their response is carefully controlled by a myriad of environmental cues, including co-activation receptors, cytokines, nutrients, growth factors, local oxygen levels, salt concentrations, and microbiome. The complexity of the integration of signals received by T cells is only beginning to be fully understood (1). This research topic in T cell biology aims at highlighting some of the latest research on intrinsic and extrinsic signals regulating T cell responses. The ebook contains 10 articles that encompass key pathways that modulate T cell function and discuss how T cells coordinate their response to environmental cues. One of the first components regulating T cell activation is the expression and subsequent activation of surface receptors. Notably, T cell activation is governed by the co-activation of the TCR and of co-stimulatory or co-inhibitory molecules (2, 3). Expression and activation of co-inhibitory molecules, such as CTLA-4 and PD1 play a key part in turning off effector responses and the balance of expression of co-stimulatory and co-inhibitory receptors needs to be tightly regulated to ensure a proper level of T cell activation (4, 5). The review by Schneider and Rudd nicely illustrates how expression of the co-inhibitory molecule CTLA-4 is regulated, and how that affects T cell activation (6). In recent years, the importance of cellular metabolism in the activation of immune cells, in particular T cells, has been reported. T cell activation requires a change in cellular metabolism to face increased energetic demand. This is an exciting area of research showing that not only changes in metabolism are necessary for cell activation but that they are also actively involved in regulating T cell function and differentiation. This is discussed in several reviews. Craig Byersdorfer focuses on the role of fatty acid oxidation for T cell functions, and notably on its role in graft versus host disease (7). Ramsay and Cantrell discuss the importance of glucose metabolism for T cell function and highlight the role of hypoxia-inducible factor alpha and mTOR in coordinating the responses to the environmental cues (8). They also summarize the importance of the microbiome in regulating T cells, and the key role of the aryl hydrocarbon receptor in sensing microbes. Clovis Palmer and collaborators review glucose metabolism in T cells and also discuss how HIV infection modulates T cell metabolism (9). One of the central questions is how do T cells integrate the multitude of signals received? In their comprehensive review, Chapman and Chi discuss the central role of mTOR in the integration of the many signals received by the T cells that ultimately shape their response (10). Another related aspect of the topic is the impact of infection on T cells, whereby pathogens control the host response, mostly to their advantage, and are able to switch T cell responses to favor their own survival. A study by the group of Francisca Mutapi describes a novel mechanism by which helminth infection downregulates T cell activation, by lowering the level of CD3zeta chain in infected individuals (11). A review from Zaunders further illustrates how HIV infection affects the balance of the various T cell subsets and promotes regulatory T cells and T helper follicular cells (12). Diet can also influence immune homeostasis, with recent studies showing, for instance, how salt can affect Th differentiation (13). The effects of vitamins and their metabolites on T cells are also well described. Colleen Hayes’ group summarizes the latest data on the effects of Vitamin D on T cell responses, and how this can be modulated in autoimmune diseases (14). A review by Leving’s group focuses more particularly on the environmental factors that affect regulatory T cells. This includes cytokines, vitamin A and vitamin D, metabolism, and microbiome (15). Finally, can we therapeutically manipulate the environmental milieu to modulate T cell responses in humans? The study by the group of David Klatzmann highlights the effects of IL-2 in modulating T cell responses in type 1 diabetes (16). While the functions of regulatory CD4+ Tregs have been described years ago, the characterization of CD8+ Tregs is more recent. The authors notably report how injection of low doses of IL-2 modulates the levels of CD8+ Tregs in vivo, in both mice and in patients with type 1 diabetes, following their numbers and phenotype. This study illustrates how exogenous cytokines can modulate in vivo T cell responses, which may prove beneficial for autoimmune diseases. We hope that this compilation of reviews and research that provides an overview on environmental regulators of T cells will give the readers a flavor on the latest development in T cell biology. We would also like to thank all the contributors to this topic and the reviewers for their time in making this ebook possible.
- Published
- 2015
38. Impact of the Multiple Sclerosis-Associated Genetic Variant CD226 Gly307Ser on Human CD8 T-Cell Functions.
- Author
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Morandi E, Adoue V, Bernard I, Friebel E, Nunez N, Aubert Y, Masson F, Dejean AS, Becher B, Astier A, Martinet L, and Saoudi A
- Subjects
- Humans, Adult, Female, Male, Middle Aged, CD8-Positive T-Lymphocytes immunology, Antigens, Differentiation, T-Lymphocyte genetics, Multiple Sclerosis genetics, Multiple Sclerosis immunology
- Abstract
Background and Objectives: The rs763361 nonsynonymous variant in the CD226 gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined., Methods: To study whether the CD226 risk variant affects human CD8 T-cell functions, we used CD8 T cells isolated from peripheral blood mononuclear cell of 16 age-matched healthy donors homozygous for either the protective or the risk allele of CD226. We characterized these CD8 T cells on T-cell receptor (TCR) stimulation using high-parametric flow cytometry and bulk RNAseq and through characterization of canonical signaling pathways and cytokine production., Results: On TCR engagement, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, the transcriptomic signature of CD8 T cells from the donors carrying the risk allele presented an enrichment in TCR, JAK/STAT, and IFNγ signaling. We next found that the CD226-307Ser risk allele leads to a selective increase in the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) associated with enhanced phosphorylation of STAT4 and increased production of IFNγ., Discussion: Our data suggest that the CD226-307Ser risk variant imposes immune dysregulation by increasing the pathways related to IFNγ signaling in CD8 T cells, thereby contributing to the risk of developing chronic inflammation.
- Published
- 2024
- Full Text
- View/download PDF
39. Full spectrum of vitamin D immunomodulation in multiple sclerosis: mechanisms and therapeutic implications.
- Author
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Galoppin M, Kari S, Soldati S, Pal A, Rival M, Engelhardt B, Astier A, and Thouvenot E
- Abstract
Vitamin D deficiency has been associated with the risk of multiple sclerosis, disease activity and progression. Results from in vitro experiments, animal models and analysis of human samples from randomized controlled trials provide comprehensive data illustrating the pleiotropic actions of Vitamin D on the immune system. They globally result in immunomodulation by decreasing differentiation of effector T and B cells while promoting regulatory subsets. Vitamin D also modulates innate immune cells such as macrophages, monocytes and dendritic cells, and acts at the level of the blood-brain barrier reducing immune cell trafficking. Vitamin D exerts additional activity within the central nervous system reducing microglial and astrocytic activation. The immunomodulatory role of Vitamin D detected in animal models of multiple sclerosis has suggested its potential therapeutic use for treating multiple sclerosis. In this review, we focus on recent published data describing the biological effects of Vitamin D in animal models of multiple sclerosis on immune cells, blood-brain barrier function, activation of glial cells and its potential neuroprotective effects. Based on the current knowledge, we also discuss optimization of therapeutic interventions with Vitamin D in patients with multiple sclerosis, as well as new technologies allowing in-depth analysis of immune cell regulations by vitamin D., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
- Full Text
- View/download PDF
40. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic.
- Author
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Richter M, Yumul R, Saydaminova K, Wang H, Gough M, Baldessari A, Cattaneo R, Lee F, Wang CH, Jang H, Astier A, Gopal A, Carter D, and Lieber A
- Abstract
Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the treatment of patients with B-cell malignancies.
- Published
- 2016
- Full Text
- View/download PDF
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