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Vγ9Vδ2

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https://www.readbyqxmd.com/read/28705810/the-butyrophilin-3a1-intracellular-domain-undergoes-a-conformational-change-involving-the-juxtamembrane-region
#1
Khiem Nguyen, Jin Li, Robbins Puthenveetil, Xiaochen Lin, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, Andrew J Wiemer
Small isoprenoid diphosphates, such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), are ligands of the internal domain of BTN3A1. Ligand binding in target cells promotes activation of Vγ9Vδ2 T cells. We demonstrate by small-angle X-ray scattering (SAXS) that HMBPP binding to the internal domain of BTN3A1 induces a conformational change in the position of the B30.2 domain relative to the juxtamembrane (JM) region. To better understand the molecular details of this conformational rearrangement, NMR spectroscopy was used to discover that the JM region interacts with HMBPP, specifically at the diphosphate...
July 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28690614/what-else-can-cd39-tell-us
#2
REVIEW
Hai Zhao, Cong Bo, Yan Kang, Hong Li
As the rate-limiting enzyme in ATP/ADP-AMP-adenosine pathway, CD39 would be a novel checkpoint inhibitor target in preventing adenosine-triggered immune-suppressive effect. In addition, CD39(hi) Tregs, but not CD25(hi) Tregs, exhibit sustained Foxp3 levels and functional abilities, indicating it could represent a new specific marker of Tregs. Similarly, inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Far from conclusive, present research revealed that CD39 also dephosphorylated and thus inactivated self- and pathogen-associated phosphoantigens of Vγ9Vδ2 T cells, which may be the most promising subpopulation for cellular vaccine...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28679955/adoptively-transferred-v%C3%AE-9v%C3%AE-2-t-cells-show-potent-antitumor-effects-in-a-preclinical-b-cell-lymphomagenesis-model
#3
Nicholas A Zumwalde, Akshat Sharma, Xuequn Xu, Shidong Ma, Christine L Schneider, James C Romero-Masters, Amy W Hudson, Annette Gendron-Fitzpatrick, Shannon C Kenney, Jenny E Gumperz
A central issue for adoptive cellular immunotherapy is overcoming immunosuppressive signals to achieve tumor clearance. While γδ T cells are known to be potent cytolytic effectors that can kill a variety of cancers, it is not clear whether they are inhibited by suppressive ligands expressed in tumor microenvironments. Here, we have used a powerful preclinical model where EBV infection drives the de novo generation of human B cell lymphomas in vivo, and autologous T lymphocytes are held in check by PD-1/CTLA-4-mediated inhibition...
July 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28669030/v%C3%AE-9v%C3%AE-2-t-cell-activation-by-strongly-agonistic-nucleotidic-phosphoantigens
#4
Morgane Moulin, Javier Alguacil, Siyi Gu, Asmaa Mehtougui, Erin J Adams, Suzanne Peyrottes, Eric Champagne
Human Vγ9Vδ2 T cells can sense through their TCR tumor cells producing the weak endogenous phosphorylated antigen isopentenyl pyrophosphate (IPP), or bacterially infected cells producing the strong agonist hydroxyl dimethylallyl pyrophosphate (HDMAPP). The recognition of the phosphoantigen is dependent on its binding to the intracellular B30.2 domain of butyrophilin BTN3A1. Most studies have focused on pyrophosphate phosphoantigens. As triphosphate nucleotide derivatives are naturally co-produced with IPP and HDMAPP, we analyzed their specific properties using synthetic nucleotides derived from HDMAPP...
July 1, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28653491/the-role-of-%C3%AE-%C3%AE-t-cells-during-human-pregnancy
#5
Chunyu Huang, Yong Zeng, Wenwei Tu
Pregnancy is an evolutionarily important and mysterious process. The placenta, as the nutrient and gas exchange organ, plays an essential role during this process. In addition, the interaction between trophoblast and maternal immune cells at the maternal-fetal interface is also associated with successful pregnancy. Human leukocyte antigen (HLA) molecules on trophoblast cells are involved in protecting the fetus from maternal rejection. Trophoblast cells comprise three subpopulations, including syncytiotrophoblast cells, cytotrophoblast cells, and extravillous trophoblast cells, and these cells express different HLA molecules...
June 27, 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/28649243/distinct-blood-and-visceral-adipose-tissue-regulatory-t-cell-and-innate-lymphocyte-profiles-characterize-obesity-and-colorectal-cancer
#6
Gloria Donninelli, Manuela Del Cornò, Marina Pierdominici, Beatrice Scazzocchio, Rosaria Varì, Barbara Varano, Ilenia Pacella, Silvia Piconese, Vincenzo Barnaba, Massimo D'Archivio, Roberta Masella, Lucia Conti, Sandra Gessani
Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this association remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (Treg) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28631855/a-photocrosslinkable-biotin-derivative-of-the-phosphoantigen-e-4-hydroxy-3-methylbut-2-enyl-diphosphate-hmbpp-activates-v%C3%AE-9v%C3%AE-2-t-cells-and-binds-to-the-hmbpp-site-of-btn3a1
#7
Andrea Mattarei, Monika Enzinger, Siyi Gu, Mohindar Murugesh Karunakaran, Brigitte Kimmel, Nicole Berner, Erin J Adams, Thomas Herrmann, Sabine Amslinger
Vγ9Vδ2 T cells play an important role in the cross talk of the innate and adaptive immune system. For their activation by phosphoantigens (PAgs) both cell surface receptors the eponymous Vγ9Vδ2 T cell antigen receptors (Vγ9Vδ2 TCRs) on Vγ9Vδ2 T cells and butyrophilin 3A1 (BTN3A1) on the phosphoantigen-"presenting" cell are mandatory. To find yet undetected further contributing proteins a biotinylated, photocrosslinkable benzophenone probe BioBP-HMBPP (2) was synthesized from a known allyl alcohol in nine steps and overall 16% yield...
June 20, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28584241/e-coli-promotes-human-v%C3%AE-9v%C3%AE-2%C3%A2-t-cell-transition-from-cytokine-producing-bactericidal-effectors-to-professional-phagocytic-killers-in-a-tcr-dependent-manner
#8
M Barisa, A M Kramer, Y Majani, D Moulding, L Saraiva, M Bajaj-Elliott, J Anderson, K Gustafsson
γδT cells provide immune-surveillance and host defense against infection and cancer. Surprisingly, functional details of γδT cell antimicrobial immunity to infection remain largely unexplored. Limited data suggests that γδT cells can phagocytose particles and act as professional antigen-presenting cells (pAPC). These potential functions, however, remain controversial. To better understand γδT cell-bacterial interactions, an ex vivo co-culture model of human peripheral blood mononuclear cell (PBMC) responses to Escherichia coli was employed...
June 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28580927/the-atp-binding-cassette-transporter-a1-regulates-phosphoantigen-release-and-v%C3%AE-9v%C3%AE-2-t-cell-activation-by-dendritic-cells
#9
Barbara Castella, Joanna Kopecka, Patrizia Sciancalepore, Giorgia Mandili, Myriam Foglietta, Nico Mitro, Donatella Caruso, Francesco Novelli, Chiara Riganti, Massimo Massaia
Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA)...
June 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28521284/cytokine-mediated-activation-of-human-ex-vivo-expanded-v%C3%AE-9v%C3%AE-2-t-cells
#10
Eisuke Domae, Yuya Hirai, Takashi Ikeo, Seiji Goda, Yoji Shimizu
Vγ9Vδ2 T cells, the major subset of the human peripheral blood γδ T-cell, respond to microbial infection and stressed cells through the recognition of phosphoantigens. In contrast to the growing knowledge of antigen-mediated activation mechanisms, the antigen-independent and cytokine-mediated activation mechanisms of Vγ9Vδ2 T cells are poorly understood. Here, we show that interleukin (IL) -12 and IL-18 synergize to activate human ex vivo-expanded Vγ9Vδ2 T cells. Vγ9Vδ2 T cells treated with IL-12 and IL-18 enhanced effector functions, including the expression of IFN-γ and granzyme B, and cytotoxicity...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28461569/the-juxtamembrane-domain-of-butyrophilin-btn3a1-controls-phosphoantigen-mediated-activation-of-human-v%C3%AE-9v%C3%AE-2-t-cells
#11
Cassie-Marie Peigné, Alexandra Léger, Marie-Claude Gesnel, Fabienne Konczak, Daniel Olive, Marc Bonneville, Richard Breathnach, Emmanuel Scotet
Vγ9Vδ2 T lymphocytes are the major human peripheral γδ T cell subset, with broad reactivity against stressed human cells, including tumor cells. Vγ9Vδ2 T cells are specifically activated by small phosphorylated metabolites called phosphoantigens (PAg). Stress-induced changes in target cell PAg levels are specifically detected by butyrophilin (BTN)3A1, using its intracellular B30.2 domain. This leads to the activation of Vγ9Vδ2 T cells. In this study, we show that changes in the juxtamembrane domain of BTN3A1, but not its transmembrane domain, induce a markedly enhanced or reduced γδ T cell reactivity...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28432037/investigating-in-vitro-and-in-vivo-%C3%AE-v%C3%AE-6-integrin-receptor-targeting-liposomal-alendronate-for-combinatory-%C3%AE-%C3%AE-t-cell-immunotherapy
#12
Naomi O Hodgins, Wafa' T Al-Jamal, Julie T-W Wang, Rebecca Klippstein, Pedro M Costa, Jane K Sosabowski, John F Marshall, John Maher, Khuloud T Al-Jamal
The αvβ6 integrin receptor has been shown to be overexpressed on many types of cancer cells, resulting in a more pro-invasive and aggressive phenotype, this makes it an attractive target for selective drug delivery. In tumours that over-express the αvβ6 receptor, cellular uptake of liposomes can be enhanced using ligand-targeted liposomes. It has previously been shown in both in vitro and in vivo studies that liposomal alendronate (L-ALD) can sensitise cancer cells to destruction by Vγ9Vδ2 T cells. It is hypothesised that by using the αvβ6-specific peptide A20FMDV2 as a targeting moiety for L-ALD, the therapeutic efficacy of this therapy can be increased in αvβ6 positive tumours...
June 28, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28416722/correction-prevention-of-v%C3%AE-9v%C3%AE-2-t-cell-activation-by-a-v%C3%AE-9v%C3%AE-2-tcr-nanobody
#13
Renée C G de Bruin, Anita G M Stam, Anna Vangone, Paul M P van Bergen En Henegouwen, Henk M W Verheul, Zsolt Sebestyén, Jürgen Kuball, Alexandre M J J Bonvin, Tanja D de Gruijl, Hans J van der Vliet
No abstract text is available yet for this article.
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28405500/zoledronate-can-induce-colorectal-cancer-microenvironment-expressing-btn3a1-to-stimulate-effector-%C3%AE-%C3%AE-t-cells-with-antitumor-activity
#14
Maria Raffaella Zocchi, Delfina Costa, Roberta Venè, Francesca Tosetti, Nicoletta Ferrari, Simona Minghelli, Roberto Benelli, Stefano Scabini, Emanuele Romairone, Silvia Catellani, Aldo Profumo, Alessandro Poggi
Amino-bis-phosphonates (N-BPs) such as zoledronate (Zol) have been used in anticancer clinical trials due to their ability to upregulate pyrophosphate accumulation promoting antitumor Vγ9Vδ2 T cells. The butyrophilin 3A (BTN3A, CD277) family, mainly the BTN3A1 isoform, has emerged as an important structure contributing to Vγ9Vδ2 T cells stimulation. It has been demonstrated that the B30.2 domain of BTN3A1 can bind phosphoantigens (PAg) and drive the activation of Vγ9Vδ2 T cells through conformational changes of the extracellular domains...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28386905/butyrophilin-3a-btn3a-cd277-specific-antibody-20-1-differentially-activates-v%C3%AE-9v%C3%AE-2-tcr-clonotypes-and-interferes-with-phosphoantigen-activation
#15
Lisa Starick, Felipe Riano, Mohindar M Karunakaran, Volker Kunzmann, Jianqiang Li, Matthias Kreiss, Sabine Amslinger, Emmanuel Scotet, Daniel Olive, Gennaro De Libero, Thomas Herrmann
Phosphoantigens (PAgs)-like HMBPP ((E)-4-hydroxy-3-methyl-but-2-enyl diphosphate) and butyrophilin 3 (BTN3A, CD277)-specific monoclonal antibody 20.1 induce TCR-mediated activation of Vγ9Vδ2 T cells. Here, we compared murine reporter cells transduced with Vγ9Vδ2 TCRs G115, D1C55, and MOP for the activation in culture with human RAJI cells and PAgs or mAb 20.1 and its single-chain (sc) derivative. All transductants responded readily to PAg but only TCR MOP γ-chain-expressing cells responded to mAb/sc 20...
April 6, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28368498/the-antigen-presenting-potential-of-v%C3%AE-9v%C3%AE-2-t-cells-during-plasmodium-falciparum-blood-stage-infection
#16
Jennifer Howard, Séverine Loizon, Christopher J Tyler, Dorothée Duluc, Bernhard Moser, Matthieu Mechain, Alexandre Duvignaud, Denis Malvy, Marita Troye-Blomberg, Jean-Francois Moreau, Matthias Eberl, Odile Mercereau-Puijalon, Julie Déchanet-Merville, Charlotte Behr, Maria Mamani-Matsuda
During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function, compromising effective antimalarial adaptive immunity. Human Vγ9Vδ2 T cells can act in vitro as antigen-presenting cells (APCs) and induce αβ T-cell activation. However, the relevance of this activity in vivo has remained elusive. Because Vγ9Vδ2 T cells are activated during the early immune response against P. falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites...
May 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28341563/avoidance-of-on-target-off-tumor-activation-using-a-co-stimulation-only-chimeric-antigen-receptor
#17
Jonathan Fisher, Pierre Abramowski, Nisansala Dilrukshi Wisidagamage Don, Barry Flutter, Anna Capsomidis, Gordon Weng-Kit Cheung, Kenth Gustafsson, John Anderson
Chimeric antigen receptors (CARs) combine T cell activation with antibody-mediated tumor antigen specificity, bypassing the need for T cell receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target antigen expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized by using T cells expressing Vγ9Vδ2 TCR, which recognizes transformed cells in a major histocompatibility complex (MHC)-unrestricted manner, in combination with a co-stimulatory CAR that would function independently of the TCR...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28339029/hydroxychloroquine-sensitizes-chronic-myeloid-leukemia-cells-to-v%C3%AE-9v%C3%AE-2-t-cell-mediated-lysis-independent-of-autophagy
#18
Biqing Han, Yanmin Zhao, Yu Lin, Shan Fu, Limengmeng Wang, Mingming Zhang, Ruxiu Tie, Binsheng Wang, Yi Luo, Lizhen Liu, Jian Yu, He Huang
Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vγ9Vδ2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7...
May 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28218845/phosphinophosphonates-and-their-tris-pivaloyloxymethyl-prodrugs-reveal-a-negatively-cooperative-butyrophilin-activation-mechanism
#19
Rebekah R Shippy, Xiaochen Lin, Sherry S Agabiti, Jin Li, Brendan M Zangari, Benjamin J Foust, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, David F Wiemer, Andrew J Wiemer
Butyrophilin 3A1 (BTN3A1) binds small phosphorus-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl (tris-POM) prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone...
March 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28076364/ifn%C3%AE-regulates-activated-v%C3%AE-2-t-cells-through-a-feedback-mechanism-mediated-by-mesenchymal-stem-cells
#20
Karoline Fechter, Akaitz Dorronsoro, Emma Jakobsson, Izaskun Ferrin, Valérie Lang, Pilar Sepulveda, Daniel J Pennington, César Trigueros
γδ T cells play a role in a wide range of diseases such as autoimmunity and cancer. The majority of circulating human γδ T lymphocytes express a Vγ9Vδ2+ (Vδ2+) T cell receptor (TCR) and following activation release pro-inflammatory cytokines. In this study, we show that IFNγ, produced by Vδ2+ cells, activates mesenchymal stem cell (MSC)-mediated immunosupression, which in turn exerts a negative feedback mechanism on γδ T cell function ranging from cytokine production to proliferation. Importantly, this modulatory effect is limited to a short period of time (<24 hours) post-T cell activation, after which MSCs can no longer exert their immunoregulatory capacity...
2017: PloS One
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