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Lymphocyte exhaustion

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https://www.readbyqxmd.com/read/28337208/natural-killer-cell-development-and-maturation-revisited-possible-implications-of-a-novel-distinct-lin-cd34-dnam-1-bright-cxcr4-cell-progenitor
#1
Federica Bozzano, Francesco Marras, Andrea De Maria
Since the first description of natural killer (NK) cells, the view on their role in innate immunity has evolved considerably. In addition to first-line defense against transformed and pathogen-infected autologous cells, NK cells contribute to modulate adaptive immune responses and in some cases acquire specialized functions, including exhausted, adaptive, and decidual NK cells. NK cells derive from CD34(+) progenitors, in vivo and in vitro; however, it is unclear whether the high phenotype diversity in vivo may be generated from these precursors alone...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28306177/frequency-and-functional-characterization-of-exhausted-cd8-t-cells-in-chronic-lymphocytic-leukemia
#2
Saeid Taghiloo, Esmaeil Allahmoradi, Mohsen Tehrani, Hadi Hossein-Nataj, Ramin Shekarriz, Ghasem Janbabaei, Saeid Abediankenari, Hossein Asgarian-Omran
OBJECTIVES: The phenotypic and functional properties of Tim-3+/PD-1+/CD8+ cells as exhausted T-cells were investigated in chronic lymphocytic leukemia (CLL). METHODS: Frequency of CD8+/Tim-3+/PD-1+ exhausted cells was determined by flow cytometry. For functional analysis, magnetic beads isolated CD8+ T-cells were stimulated with PHA and PMA/ionocymin to assess their proliferative responses and cytokine production by MTT and ELISA, respectively. Cytotoxic activity of isolated CD8+ T-cells was determined using CD107a degranulation assay...
March 17, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28292435/obstacles-posed-by-the-tumor-microenvironment-to-t%C3%A2-cell-activity-a-case-for-synergistic-therapies
#3
REVIEW
Kristin G Anderson, Ingunn M Stromnes, Philip D Greenberg
T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28289860/the-pd-l1-pd-1-pathway-promotes-dysfunction-but-not-exhaustion-in-tumor-responding-t-cells-from-pleural-effusions-in-lung-cancer-patients
#4
Heriberto Prado-Garcia, Susana Romero-Garcia, Alejandra Puerto-Aquino, Uriel Rumbo-Nava
Malignant pleural effusions are frequent in patients with advanced stages of lung cancer and are commonly infiltrated by lymphocytes and tumor cells. CD8+ T cells from these effusions have reduced effector functions. The programmed death receptor 1(PD-1)/programmed death ligand 1 (PD-L1) pathway is involved in T-cell exhaustion, and it might be responsible for T-cell dysfunction in lung cancer patients. Here, we show that PD-L1 is expressed on tumor cell samples from malignant effusions, on lung cancer cell lines, and, interestingly, on MRC-5 lung fibroblasts...
March 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28287115/efficient-control-of-chronic-lcmv-infection-by-a-cd4-t-cell-epitope-based-heterologous-prime-boost-vaccination-in-a-murine-model
#5
Ran He, Xinxin Yang, Cheng Liu, Xiangyu Chen, Lin Wang, Minglu Xiao, Jianqiang Ye, Yuzhang Wu, Lilin Ye
CD4(+) T cells are essential for sustaining CD8(+) T cell responses during a chronic infection. The adoptive transfer of virus-specific CD4(+) T cells has been shown to efficiently rescue exhausted CD8(+) T cells. However, the question of whether endogenous virus-specific CD4(+) T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8(+) T cells remains unexplored. In this study, we developed a CD4(+) T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection...
March 13, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28283662/exhaustion-associated-regulatory-regions-in-cd8-tumor-infiltrating-t-cells
#6
Giuliana P Mognol, Roberto Spreafico, Victor Wong, James P Scott-Browne, Susan Togher, Alexander Hoffmann, Patrick G Hogan, Anjana Rao, Sara Trifari
T-cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8(+) tumor-infiltrating lymphocytes (TILs) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, nonexhausted TILs and in acutely restimulated CD8(+) T cells, we define a pattern of chromatin accessibility specific for T-cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors...
March 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28258692/lag3-cd223-as-a-cancer-immunotherapy-target
#7
REVIEW
Lawrence P Andrews, Ariel E Marciscano, Charles G Drake, Dario A A Vignali
Despite the impressive impact of CTLA4 and PD1-PDL1-targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene-3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity...
March 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28255718/studying-immunoreceptor-signaling-in-human-t-cells-using-electroporation-of-in-vitro-transcribed-mrna
#8
Omkar Kawalekar, Carl H June, Michael C Milone
The recognition bestowed upon T lymphocytes as key mediators of cellular immunity has been further attested by recent successful clinical studies using genetically modified T cells. With an ever-growing interest in the application of T cells to treat human malignancies, studying the molecular mechanisms of T cell activation, signaling, and function has become imperative. This, therefore, calls for the development of new easy-to-use and accurate models to investigate the biological phenomena that begin at the synaptic levels of T cell and antigen interactions to the ultimate exhaustion and death of the T cell...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28250797/changes-in-peripheral-immune-cell-numbers-and-functions-in-octogenarian-walkers-an-acute-exercise-study
#9
Kornelis S M van der Geest, Qi Wang, Thijs M H Eijsvogels, Hans J P Koenen, Irma Joosten, Elisabeth Brouwer, Maria T E Hopman, Joannes F M Jacobs, Annemieke M H Boots
BACKGROUND: Age-related changes of the immune system, termed immunosenescence, may underlie the increased risk of infections and morbidity in the elderly. Little is known about the effects of acute exercise on peripheral immune parameters in octogenarians. Therefore, we investigated acute exercise-induced changes in phenotype and function of the immune system in octogenarians participating in the 2013 edition of the Nijmegen Four Days Marches. Blood sampling was performed at baseline and immediately after 4 days of the walking exercise (30 km/day)...
2017: Immunity & Ageing: I & A
https://www.readbyqxmd.com/read/28247187/development-of-novel-immunopet-tracers-to-image-human-pd-1-checkpoint-expression-on-tumor-infiltrating-lymphocytes-in-a-humanized-mouse-model
#10
Arutselvan Natarajan, Aaron T Mayer, Robert E Reeves, Claude M Nagamine, Sanjiv Sam Gambhir
PURPOSE: It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and its ligand (PD-L1)) to evade anti-tumor immune responses. Although immune checkpoint (IC) blockade is a promising approach, not all patients respond. Hence, imaging of tumor-infiltrating lymphocytes (TILs) is of high specific interest, as they are known to express PD-1 during activation and subsequent exhaustion in the tumor microenvironment and are thought to be potentially predictive of therapeutic responses to IC blockade...
February 28, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/28217593/validity-of-tuberculous-pleuritis-diagnosed-in-a-resource-constrained-setting-in-dindigul-district-of-tamil-nadu
#11
Baranidharan Chennaiyan, Arun N Bhatt, Roopa Kancherla, Cijoy K Kuriakose, Anand Vimal Dev, George A Philip
CONTEXT: Majority of the Indians live in rural areas where resource constrained settings depend on cheaper and less invasive tests to diagnose extrapulmonary tuberculosis (TB). The decline in prevalence of TB in the country could affect the validity of the diagnosis. The aim was to measure validity of the pleural fluid study of proteins, lactate dehydrogenase (LDH), and cell counts in diagnosis of tuberculous pleuritis. MATERIALS AND METHODS: This was a cross-sectional study conducted in a 300 bedded secondary care hospital in rural Tamil Nadu...
July 2016: Journal of Family Medicine and Primary Care
https://www.readbyqxmd.com/read/28214859/farnesoid-x-receptor-in-mice-prevents-severe-liver-immunopathology-during-lymphocytic-choriomeningitis-virus-infection
#12
Nadine Honke, Namir Shaabani, Cornelia Hardt, Caroline Krings, Dieter Häussinger, Philipp A Lang, Karl S Lang, Verena Keitel
BACKGROUND: Bile acids (BAs) are steroid molecules that are synthesized in the liver. In addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. The role of BAs and their receptor farnesoid X receptor (FXR) during viral infection has not been studied in detail. METHODS: By using FXR-deficient mice, we investigated the role of bile acid receptor FXR during infection with lymphocytic choriomeningitis virus (LCMV)...
January 25, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28197391/high-nkg2a-expression-contributes-to-nk-cell-exhaustion-and-predicts-a-poor-prognosis-of-patients-with-liver-cancer
#13
Cheng Sun, Jing Xu, Qiang Huang, Mei Huang, Hao Wen, Chuanshan Zhang, Jinyu Wang, Jiaxi Song, Meijuan Zheng, Haoyu Sun, Haiming Wei, Weihua Xiao, Rui Sun, Zhigang Tian
Background and Aims: As the predominant lymphocyte subset in the liver, natural killer (NK) cells have been shown to be highly associated with the outcomes of patients with chronic hepatitis B virus infection (CHB) and hepatocellular carcinoma (HCC). Previously, we reported that NKG2A, a checkpoint candidate, mediates human and murine NK cell dysfunction in CHB. However, NK cell exhaustion and, particularly, the level of NKG2A expression within liver tumors have not been reported. Methods: In this study, we analyzed NKG2A expression and the related dysfunction of NK cells located in intra- or peritumor regions of liver tissue samples from 207 HCC patients, in addition to analyzing disease outcomes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28197389/adaptive-resistance-to-anti-pd1-therapy-by-tim-3-upregulation-is-mediated-by-the-pi3k-akt-pathway-in-head-and-neck-cancer
#14
Gulidanna Shayan, Raghvendra Srivastava, Jing Li, Nicole Schmitt, Lawrence P Kane, Robert L Ferris
Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28179496/cutting-edge-chromatin-accessibility-programs-cd8-t-cell-memory
#15
Christopher D Scharer, Alexander P R Bally, Bhanu Gandham, Jeremy M Boss
CD8 T cell memory is characterized by rapid recall of effector function, increased proliferation, and reduced activation requirements. Despite the extensive functional characterization, the molecular mechanisms that facilitate these enhanced properties are not well characterized. In this study, the assay for transposase-accessible chromatin sequencing was employed to map the cis-regulatory elements in CD8 T cells responding to acute and chronic lymphocytic choriomeningitis virus infections. Integration of chromatin accessibility profiles with gene expression data identified unique regulatory modules that were enriched for distinct combinations of transcription factor-binding motifs...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28154084/lymphocyte-activation-gene-3-a-novel-therapeutic-target-in-chronic-lymphocytic-leukemia
#16
Mika Shapiro, Yair Herishanu, Ben-Zion Katz, Nili Dezorella, Clare Sun, Sigi Kay, Aaron Polliack, Irit Avivi, Adrian Wiestner, Chava Perry
A novel therapeutic approach in cancer, attempting to stimulate host anti-tumor immunity, involves blocking of immune checkpoints. LAG3 is an immune checkpoint receptor expressed on activated/exhausted T-cells. When engaged by MHC class II molecules, LAG3 negatively regulates T-cell function thereby contributing to tumor escape. Intriguingly, a soluble LAG3 variant activates both immune and malignant MHC class II-presenting cells. In this study, we examined the role of LAG3 in the pathogenesis of chronic lymphocytic leukemia, an MHC class II-presenting malignancy, and show that chronic lymphocytic leukemia cells express and secrete LAG3...
February 2, 2017: Haematologica
https://www.readbyqxmd.com/read/28153727/cd40-agonist-converting-ctl-exhaustion-via-the-activation-of-the-mtorc1-pathway-enhances-pd-1-antagonist-action-in-rescuing-exhausted-ctls-in-chronic-infection
#17
Aizhang Xu, Rong Wang, Andrew Freywald, Kristoffor Stewart, Suresh Tikoo, Jianqing Xu, Changyu Zheng, Jim Xiang
Expansion of PD-1-expressing CD8(+) cytotoxic T lymphocytes (CTLs) and associated CTL exhaustion are chief issues for ineffective virus-elimination in chronic infectious diseases. PD-1 blockade using antagonistic anti-PD-L1 antibodies results in a moderate conversion of CTL exhaustion. We previously demonstrated that CD40L signaling of ovalbumin (OVA)-specific vaccine, OVA-Texo, converts CTL exhaustion via the activation of the mTORC1 pathway in OVA-expressing adenovirus (AdVova)-infected B6 mice showing CTL inflation and exhaustion...
March 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28142150/camel-whey-protein-protects-b-and-t-cells-from-apoptosis-by-suppressing-activating-transcription-factor-3-atf-3-mediated-oxidative-stress-and-enhancing-phosphorylation-of-akt-and-i%C3%AE%C2%BAb-%C3%AE-in-type-i-diabetic-mice
#18
Gamal Badr, Leila H Sayed, Hossam El-Din M Omar, Ali M Abd El-Rahim, Emad A Ahmed, Mohamed H Mahmoud
BACKGROUND: Diabetes mellitus (DM) is associated with severe immune system complications. Camel whey protein (CWP) decreases free radicals (ROS) and modulates immune functions, but its effect on DM-impaired immune systems has not been studied. We investigated the impact of CWP on the immune system in a Type 1 diabetes mouse model. METHODS: Three experimental groups were used: (1) non-diabetic control; (2) diabetic; and (3) CWP-treated diabetic mice. RESULTS: Induction of diabetes by streptozotocin was associated with reduction of body weight and insulin level, increase in glucose level and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and reduction in IL-2 and IL-4 levels...
January 17, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28114604/topical-imiquimod-plus-nab-paclitaxel-for-breast-cancer-cutaneous-metastases-a-phase-2-clinical-trial
#19
Lupe G Salazar, Hailing Lu, Jessica L Reichow, Jennifer S Childs, Andrew L Coveler, Doreen M Higgins, James Waisman, Kimberly H Allison, Yushe Dang, Mary L Disis
Importance: Salvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod. Objective: To evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall...
January 19, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28110884/tumor-antigen-specific-cd8-t-cells-are-negatively-regulated-by-pd-1-and-tim-3-in-human-gastric-cancer
#20
Xu Lu, Lin Yang, Daxing Yao, Xuan Wu, Jingpo Li, Xuesong Liu, Lijuan Deng, Caiting Huang, Yue Wang, Dan Li, Jingwei Liu
Cytotoxic CD8 T lymphocytes that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally important in eliciting tumor rejection. NY-ESO-1 is a major target of CD8(+) T cell recognition in gastric cancer (GC) and is among the most immunogenic tumor antigens defined to date. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8(+) T cell dysfunction may reveal effective strategies for immunotherapy. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs) and tumor-associated lymphocytes (TALs) of GC patients...
March 2017: Cellular Immunology
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