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Tim-3 NK cell

Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W Overwijk, Jason Roszik, Francesco M Marincola, Patrick Hwu, Elizabeth A Grimm, Laszlo G Radvanyi
Clinical responses to high-dose IL-2 therapy are limited due to selective expansion of CD4+CD25+oxp3+ T-regulatory cells (Tregs) especially ICOS+Tregs, rather than NK cells and effector T cells. These ICOS+Tregs are highly suppressive and constitutively express high levels of IL-2Ralpha (CD25) and CD39. Here, we characterized the effect of a mutant form of IL-2 (F42K), which preferentially binds to the lower affinity IL-2Rbetagamma with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets...
October 3, 2016: Cancer Immunology Research
Isabel Gonçalves Silva, Laura Rüegg, Bernhard F Gibbs, Marco Bardelli, Alexander Fruehwirth, Luca Varani, Steffen M Berger, Elizaveta Fasler-Kan, Vadim V Sumbayev
The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells...
July 2016: Oncoimmunology
Ranferi Ocaña-Guzman, Luis Torre-Bouscoulet, Isabel Sada-Ovalle
The transmembrane protein TIM-3 is a type I protein expressed by sub-types of lymphoid cells, such as lymphocytes Th1, Th17, Tc1, NK, as well as in myeloid cells. Scientific evidence indicates that this molecule acts as a negative regulator of T lymphocyte activation and that its expression is modified in viral infections or autoimmune diseases. In addition to evidence from lymphoid cells, the function of TIM-3 has been investigated in myeloid cells, such as monocytes, macrophages, and dendritic cells (DC), where studies have demonstrated that it can regulate cytokine production, cell activation, and the capture of apoptotic bodies...
2016: Frontiers in Immunology
Elena Gonzalez-Gugel, Mansi Saxena, Nina Bhardwaj
A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses...
October 2016: Cancer Immunology, Immunotherapy: CII
Su Li Poh, Yeh Ching Linn
We studied whether blockade of inhibitory receptors on cytokine-induced killer (CIK) cells by immune checkpoint inhibitors could increase its anti-tumour potency against haematological malignancies. CIK cultures were generated from seven normal donors and nine patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or multiple myeloma (MM). The inhibitory receptors B and T lymphocyte attenuator, CD200 receptor, lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3) were present at variable percentages in most CIK cultures, while cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1) and killer cell immunoglobulin-like receptors (KIR2DL1/2/3) were expressed at low level in most cultures...
May 2016: Cancer Immunology, Immunotherapy: CII
Qi-wen WU, Xiang ZHU, Xia FU, Jin-sun YANG, Zhi-guo CAO, Chun PU
OBJECTIVE: To explore the expression of T cell immunoglobulin and mucin domain protein 3 (Tim-3) on CD56(+) NK cells in peripheral blood and its correlation with liver fibrosis indicators in patients with advanced schistosomiasis. METHODS: Tim-3 expression on CD6(+) NK cells from 28 patients with advanced schistosomiasis and 30 healthy controls was determined by flow cytometry. The serum levels of IFN-y and IL-4 were detected by enzyme-linked immunosorbent assay (ELISA)...
October 2015: chinese Journal of Parasitology & Parasitic Diseases
Jintang Sun, Meixiang Yang, Yanli Ban, Wenjuan Gao, Bingfeng Song, Yang Wang, Yun Zhang, Qianqian Shao, Beihua Kong, Xun Qu
NK cells accumulate at the maternal-fetal interface (MFI) and play essential roles in maintaining immune tolerance during pregnancy. The mechanisms that facilitate NK cells tolerance to fetal tissue are largely unknown. T cell Ig and mucin domain-containing protein 3 (Tim-3) is a newly defined molecule with essential immunological function in many physiological and pathological processes. Recent study showed that Tim-3 was involved in the regulation of immune tolerance at MFI. However, whether Tim-3 regulates NK cells cytotoxicity toward trophoblasts is unclear...
2016: PloS One
Binh L Phong, Lyndsay Avery, Tina L Sumpter, Jacob V Gorman, Simon C Watkins, John D Colgan, Lawrence P Kane
T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells...
December 14, 2015: Journal of Experimental Medicine
Matyas Meggyes, Adrienn Lajko, Tamas Palkovics, Anett Totsimon, Zsolt Illes, Laszlo Szereday, Eva Miko
INTRODUCTION: Immunoregulation implies the activation of negative pathways leading to the modulation of specific immune responses. Co-inhibitory receptors (such as PD-1 and TIM-3) represent possible tools for this purpose. PD-1 and TIM-3 have been demonstrated to be present on immune cells suggesting general involvement in immunosuppression such as fetomaternal tolerance. The aim of our study was to investigate the expression pattern of PD-1, TIM-3, and its ligand Gal-9 on different immune cell subsets in the peripheral blood and at the fetomaternal interface in pregnant mice...
October 2015: Placenta
Hideo Komita, Shigeo Koido, Kazumi Hayashi, Shin Kan, Masaki Ito, Yuko Kamata, Masafumi Suzuki, Sadamu Homma
Monoclonal antibody therapy for immune checkpoint blockade has achieved promising results for several types of malignant tumors. For the future treatment of gastrointestinal stromal tumors (GISTs) by immune checkpoint blockade, expression of immune checkpoint-related molecules that suppress antitumor immunity in GISTs was examined. Infiltration of immune cell types into 19 GIST tissues was analyzed by immunohistochemistry, and expression of T cell immunoglobulin and mucin protein 3 (Tim-3) and programmed cell death-1 (PD-1) in the infiltrated immune cells was examined by immunofluorescence microscopy...
October 2015: Oncology Reports
Zhixin Yang, Yu Lei, Chunbo Chen, Hong Ren, Tongdong Shi
One of the main responses of invariant natural killer T (iNKT) cells to antigen stimulation is the rapid production of interleukin (IL)-4 and interferon (IFN)-γ cytokines. There is a decline in the function of iNKT cells in chronic hepatitis B (CHB) patients. In this study, we explored the impact of programmed cell death 1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3), and cluster of differentiation 28 (CD28) expression on iNKT cell functions in CHB patients. Flow cytometry was used to test iNKT frequencies and levels of PD-1, Tim-3, CD28, IL-4, and IFN-γ secreted by iNKT cells...
October 2015: Archives of Virology
Zhenxin Wang, Jinlian Zhu, Haidi Gu, Yuan Yuan, Bin Zhang, Dongming Zhu, Jian Zhou, Yibei Zhu, Weichang Chen
AIM: To investigate the clinical significance of Tim-3 (T-cell immunoglobulin- and mucin-domain-containing molecule 3) expression in natural killer (NK) cells from patients with gastric cancer. MATERIALS AND METHODS: Sixty-two patients with gastric cancer and 32 healthy controls were recruited for this study. Tim-3 expression in peripheral blood samples was analyzed using flow cytometry. The expression pattern of Tim-3 on NK cells was also confirmed using a gastric cancer-bearing mouse model...
2015: Immunological Investigations
Lin Cheng, Zhihua Ruan
Both Tim-3 and Tim-4 belong to the T-cell immunoglobulin and mucin domain (Tim) gene family, which plays a critical role in immunoregulation. Tim-3 has been suggested as a negative regulator of anti-tumor immunity due to its function on inducing T cells exhaustion in cancer. In addition to its expression on exhausted T cells, Tim-3 also has been reported to up-regulate on nature killer (NK) cells and promote NK cells functionally exhausted in cancer. While Tim-3 selectively expression on most types of leukemia stem cells, it promotes the progression of acute myeloid leukemia...
2015: Human Vaccines & Immunotherapeutics
Feng Wang, Hongyan Hou, Shiji Wu, Qing Tang, Min Huang, Botao Yin, Jing Huang, Weiyong Liu, Lie Mao, Yanfang Lu, Ziyong Sun
Active tuberculosis (TB) patients show impaired NK cell function, and the underlying mechanism remains largely unknown. In this study, we confirmed the decrease in activation, cytokine secretion, and degranulation potential of NK cells in active TB patients. We further investigated whether coinhibitory receptor Tim-3 was involved with impairment of NK cells. Our results revealed that the expression of Tim-3 on NK cells was increased in active TB patients. Tim-3 expression was inversely correlated with IL-12-stimualted IFN-γ production...
December 2015: Cytokine
Nan Hou, Xianyu Piao, Shuai Liu, Chuang Wu, Qijun Chen
T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected with Schistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response against S. japonicum infection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4(+) and CD8(+) T cells, NK1...
August 2015: Infection and Immunity
Veronika Bachanova, Linda J Burns, Kwang Woo Ahn, Ginna G Laport, Görgün Akpek, Mohamed A Kharfan-Dabaja, Taiga Nishihori, Edward Agura, Philippe Armand, Samantha M Jaglowski, Mitchell S Cairo, Amanda F Cashen, Jonathon B Cohen, Anita D'Souza, César O Freytes, Robert Peter Gale, Siddhartha Ganguly, Nilanjan Ghosh, Leona A Holmberg, David J Inwards, Abraham S Kanate, Hillard M Lazarus, Adriana K Malone, Reinhold Munker, Alberto Mussetti, Maxim Norkin, Tim D Prestidge, Jacob M Rowe, Prakash Satwani, Tanya Siddiqi, Patrick J Stiff, Basem M William, Baldeep Wirk, David G Maloney, Sonali M Smith, Anna M Sureda, Jeanette Carreras, Mehdi Hamadani
Assessment with (18)F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non-Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males...
September 2015: Biology of Blood and Marrow Transplantation
Anne Gallois, Ines Silva, Iman Osman, Nina Bhardwaj
Natural killer (NK) cells are innate immune cells that become progressively exhausted in advanced stage cancer, crippling their ability to execute antitumor functions. We previously characterized the nature of NK cell exhaustion in metastatic melanoma patients, reporting a correlation with high expression of TIM-3. Blockade of this immune checkpoint molecule reversed the exhausted phenotype and improved NK cell function.
December 2014: Oncoimmunology
Jamie L Schafer, Haiying Li, Tristan I Evans, Jacob D Estes, R Keith Reeves
UNLABELLED: Recent evidence suggests that even in treated infections, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication may continue in lymph nodes (LN), serving as a potential virus reservoir. Here we investigated the effects of lentivirus infection on natural killer (NK) cell frequencies, phenotypes, and functions in naive and acutely or chronically SIVmac239-infected rhesus macaques. Compared to that in naive animals, we observed a 3-fold-greater frequency of cytotoxic CD16(+) CD56(-) NK cells in LN of chronically infected macaques...
July 2015: Journal of Virology
Sudipta Tripathi, Lola Chabtini, Pranal J Dakle, Brian Smith, Hisaya Akiba, Hideo Yagita, Indira Guleria
NK cells are the most abundant lymphocyte population in the feto-maternal interface during gestation. The uterine NK cells (uNK) are transient, have a unique immunophenotype and produce a number of cytokines. These cytokines play an important role in establishment and maintenance of vascular remodeling and tolerance associated with successful pregnancy. The uNK cells also express TIM-3 during gestation and blockade of TIM-3 expression results in fetal loss in mice. In this study we determined the effect of TIM-3 blockade on uNK cells...
2015: PloS One
Valentina Folgiero, Loredana Cifaldi, Giuseppina Li Pira, Bianca Maria Goffredo, Luciana Vinti, Franco Locatelli
NK cells expressing TIM-3 show a marked increase in IFNγ production in response to acute myeloid leukemia (AML) blast cells that endogenously express Gal-9. Herein, we demonstrate that NK cell-mediated production of IFNγ, induced by TIM-3/Gal-9 interaction and released in bone marrow microenvironment, is responsible for IDO1 expression in AML blasts. IDO1-expressing AML blasts consequently down-regulate NK cell degranulation activity, by sustaining leukemia immune escape. Furthermore, the blocking of TIM-3/Gal-9 interaction strongly down-regulates IFNγ-dependent IDO1 activity...
April 16, 2015: Journal of Hematology & Oncology
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