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Alina Suzann Fichtner, Mohindar Murugesh Karunakaran, Lisa Starick, Richard W Truman, Thomas Herrmann
1-5% of human blood T cells are Vγ9Vδ2 T cells whose T cell receptor (TCR) contain a TRGV9/TRGJP rearrangement and a TRDV2 comprising Vδ2-chain. They respond to phosphoantigens (PAgs) like isopentenyl pyrophosphate or (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) in a butyrophilin 3 (BTN3)-dependent manner and may contribute to the control of mycobacterial infections. These cells were thought to be restricted to primates, but we demonstrated by analysis of genomic databases that TRGV9, TRDV2 , and BTN3 genes coevolved and emerged together with placental mammals...
2018: Frontiers in Immunology
Siyi Gu, Marta Borowska, Christopher T Boughter, Erin J Adams
Despite playing critical roles in the immune response and having significant potential in immunotherapy, γδ T cells have garnered little of the limelight. One major reason for this paradox is that their antigen recognition mechanisms are largely unknown, limiting our understanding of their biology and our potential to modulate their activity. One of the best-studied γδ subsets is the human Vγ9Vδ2 T cell population, which predominates in peripheral blood and can combat both microbial infections and cancers...
February 19, 2018: Seminars in Cell & Developmental Biology
Lin Xiao, Can Chen, Zhendong Li, Sumin Zhu, Johan Ck Tay, Xi Zhang, Shijun Zha, Jieming Zeng, Wee Kiat Tan, Xin Liu, Wee Joo Chng, Shu Wang
Vγ9Vδ2 T cells are a minor subset of lymphocytes in the peripheral blood that has been extensively investigated for their tolerability, safety and anticancer efficacy. A hindrance to the broad application of these cells for adoptive cellular immunotherapy has been attaining clinically appropriate numbers of Vγ9Vδ2 T cells. Furthermore, Vγ9Vδ2 T cells exist at low frequencies among cancer patients. We, therefore, sought to conceive an economical method that allows for a quick and robust large-scale expansion of Vγ9Vδ2 T cells...
March 2018: Cytotherapy
Pierre Vantourout, Adam Laing, Martin J Woodward, Iva Zlatareva, Luis Apolonia, Andrew W Jones, Ambrosius P Snijders, Michael H Malim, Adrian C Hayday
The long-held view that gamma delta (γδ) T cells in mice and humans are fundamentally dissimilar, as are γδ cells in blood and peripheral tissues, has been challenged by emerging evidence of the cells' regulation by butyrophilin (BTN) and butyrophilin-like (BTNL) molecules. Thus, murine Btnl1 and the related gene, Skint1, mediate T cell receptor (TCR)-dependent selection of murine intraepithelial γδ T cell repertoires in gut and skin, respectively; BTNL3 and BTNL8 are TCR-dependent regulators of human gut γδ cells; and BTN3A1 is essential for TCR-dependent activation of human peripheral blood Vγ9Vδ2+ T cells...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yoshimasa Tanaka, Kaoru Murata-Hirai, Masashi Iwasaki, Kenji Matsumoto, Kosuke Hayashi, Asuka Kumagai, Mohanad H Nada, Hong Wang, Hirohito Kobayashi, Hiroshi Kamitakahara, Haruki Okamura, Tomoharu Sugie, Nagahiro Minato, Masakazu Toi, Craig T Morita
Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in an MHC-unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA)...
December 30, 2017: Cancer Science
Elena Lo Presti, Gabriele Pizzolato, Eliana Gulotta, Gianfranco Cocorullo, Gaspare Gulotta, Francesco Dieli, Serena Meraviglia
γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells...
2017: Frontiers in Immunology
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
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
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
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
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
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
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
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...
December 2017: European Journal of Immunology
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...
November 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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
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
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
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
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
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