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https://www.readbyqxmd.com/read/29118758/combining-v%C3%AE-9v%C3%AE-2-t-cells-with-a-lipophilic-bisphosphonate-efficiently-kills-activated-hepatic-stellate-cells
#1
Xiaoying Zhou, Yanzheng Gu, Hongying Xiao, Ning Kang, Yonghua Xie, Guangbo Zhang, Yan Shi, Xiaoyu Hu, Eric Oldfield, Xueguang Zhang, Yonghui Zhang
Activated hepatic stellate cells (aHSCs) are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vγ9Vδ2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vγ9Vδ2 T cells and aHSCs. We find that Vγ9Vδ2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29075255/il-17-production-from-t-helper-17-mucosal-associated-invariant-t-and-%C3%AE-%C3%AE-cells-in-tuberculosis-infection-and-disease
#2
Felicity Coulter, Amy Parrish, Declan Manning, Beate Kampmann, Joseph Mendy, Mathieu Garand, David M Lewinsohn, Eleanor M Riley, Jayne S Sutherland
IL-17-producing cells have been shown to be important in the early stages of Mycobacterium tuberculosis (Mtb) infection in animal models. However, there are very little data on the role of IL-17 in human studies of tuberculosis (TB). We recruited TB patients and their highly exposed contacts who were further categorized based on results from an IFN-γ-release assay (IGRA): (1) IGRA positive (IGRA(+)) at recruitment (latently TB infected), (2) IGRA negative (IGRA(-)) at recruitment and 6 months [non-converters (NC)], and (3) IGRA(-) at recruitment and IGRA(+) at 6 months (converters)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29055564/the-effects-of-systemic-treatment-with-aminobisphosphonates-and-statins-on-circulating-v%C3%AE-9v%C3%AE-2-t-cells-in-patients-with-advanced-cancer
#3
Famke L Schneiders, Charlotte M Huijts, Martine Reijm, Hetty J Bontkes, Henk M W Verheul, Tanja D de Gruijl, Hans J van der Vliet
Aminobisphosphonates (NBP) are used for treatment of metastatic bone disease. Frequently, patients undergoing NBP-treatment experience side-effects, known as acute phase response (APR), resulting from cytokine production by Vγ9Vδ2-T cells. As opposed to NBP, statins reduce intracellular phosphoantigen levels and prevent NBP-induced Vγ9Vδ2-T cell activation in vitro. We conducted a pilot study in patients with (bone-)metastasized malignancies receiving NBP-treatment and evaluated the phenotype and function of circulating Vγ9Vδ2-T cells in vivo and the effects of statins on Vγ9Vδ2-T cell responses and the associated APR...
October 16, 2017: Immunobiology
https://www.readbyqxmd.com/read/29029951/intrahepatic-v%C3%AE-9v%C3%AE-2-t-cells-from-hcv-infected-patients-show-an-exhausted-phenotype-but-can-inhibit-hcv-replication
#4
E Cimini, V Bordoni, A Sacchi, U Visco-Comandini, M Montalbano, C Taibi, R Casetti, E Lalle, G D'Offizi, M R Capobianchi, C Agrati
Hepatitis C virus (HCV) persistence results from inefficiencies of both innate and adaptive immune responses to eradicate the infection. A functional impairment of circulating Vγ9Vδ2 T-cells was described but few data are available on Vγ9Vδ2 T-cells in the liver that, however, represents the battlefield in the HCV/host interaction. Aim of this work was to compare circulating and intrahepatic Vγ9Vδ2 T-cells in chronic HCV-infected patients (HCV(pos)) and in HCV-negative (HCV(neg)) subjects. Phenotypic and functional analysis was performed by flow cytometry...
October 10, 2017: Virus Research
https://www.readbyqxmd.com/read/28972090/il-17-secreting-%C3%AE-%C3%AE-t-cells-are-completely-dependent-upon-ccr6-for-homing-to-inflamed-skin
#5
James J Campbell, Karen Ebsworth, Linda S Ertl, Jeffrey P McMahon, Dale Newland, Yu Wang, Shirley Liu, Zhenhua Miao, Ton Dang, Penglie Zhang, Israel F Charo, Rajinder Singh, Thomas J Schall
mAbs that neutralize IL-17 or its receptor have proven efficacious in treating moderate-to-severe psoriasis, confirming IL-17 as an important driver of this disease. In mice, a rare population of T cells, γδT17 cells, appears to be a dominant source of IL-17 in experimental psoriasis. These cells traffic between lymph nodes and the skin, and are identified by their coexpression of the TCR variable regions γ4 and δ4. These cells are homologous to the Vγ9Vδ2 T cell population identified in human psoriatic plaques...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28894450/dual-face-of-v%C3%AE-9v%C3%AE-2-t-cells-in-tumor-immunology-anti-versus-pro-tumoral-activities
#6
REVIEW
Zheng Xiang, Wenwei Tu
Vγ9Vδ2-T cells are considered as potent effector cells for tumor immunotherapy through directly killing tumor cells and indirectly regulating other innate and adaptive immune cells to establish antitumoral immunity. The antitumoral activity of Vγ9Vδ2-T cells is governed by a complicated set of activating and inhibitory cell receptors. In addition, cytokine milieu in tumor microenvironment can also induce the pro-tumoral activities and functional plasticity of Vγ9Vδ2-T cells. Here, we review the anti- versus pro-tumoral activities of Vγ9Vδ2-T cells and discuss the mechanisms underlying the recognition, activation, differentiation and regulation of Vγ9Vδ2-T cells in tumor immunosurveillance...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28807997/phosphoantigen-induced-conformational-change-of-butyrophilin-3a1-btn3a1-and-its-implication-on-v%C3%AE-9v%C3%AE-2-t-cell-activation
#7
Siyi Gu, Joseph R Sachleben, Christopher T Boughter, Wioletta I Nawrocka, Marta T Borowska, Jeffrey T Tarrasch, Georgios Skiniotis, Benoît Roux, Erin J Adams
Human Vγ9Vδ2 T cells respond to microbial infections as well as certain types of tumors. The key initiators of Vγ9Vδ2 activation are small, pyrophosphate-containing molecules called phosphoantigens (pAgs) that are present in infected cells or accumulate intracellularly in certain tumor cells. Recent studies demonstrate that initiation of the Vγ9Vδ2 T cell response begins with sensing of pAg via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule. However, it is unknown how downstream events can ultimately lead to T cell activation...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28741710/il-33-expanded-human-v%C3%AE-9v%C3%AE-2-t%C3%A2-cells-have-anti-lymphoma-effect-in-a-mouse-tumor-model
#8
Caroline Duault, Delphine Betous, Christine Bezombes, Stéphane Roga, Corinne Cayrol, Jean-Philippe Girard, Jean-Jacques Fournié, Mary Poupot
From several years, the anticancer effects of Vγ9 T lymphocytes make these cells good candidates for cancer immunotherapies. However, the proved efficacy of γδ Τ cell-based cancer immunotherapies in some clinical trials was minimized due to the inherent toxicity of IL-2, which is essential for the combination therapy with Phosphoantigen (PAg). Recently, we showed that IL-33, a γ chain receptor-independent cytokine, was able to induce the in vitro proliferation of PAg-activated Vγ9 T cells, which were fully functional expressing IFN-γ and TNF-α and showing in vitro anti-tumor cytotoxicity...
July 25, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28705810/the-butyrophilin-3a1-intracellular-domain-undergoes-a-conformational-change-involving-the-juxtamembrane-region
#9
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
#10
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
#11
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
#12
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...
December 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
#13
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
#14
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-photo-crosslinkable-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
#15
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 but further contributing proteins, a biotinylated, photo-crosslinkable 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
#16
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
#17
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
#18
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
#19
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...
June 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
#20
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
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