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T cell exhaustion

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https://www.readbyqxmd.com/read/28632753/mait-cells-launch-a-rapid-robust-and-distinct-hyperinflammatory-response-to-bacterial-superantigens-and-quickly-acquire-an-anergic-phenotype-that-impedes-their-cognate-antimicrobial-function-defining-a-novel-mechanism-of-superantigen-induced-immunopathology
#1
Christopher R Shaler, Joshua Choi, Patrick T Rudak, Arash Memarnejadian, Peter A Szabo, Mauro E Tun-Abraham, Jamie Rossjohn, Alexandra J Corbett, James McCluskey, John K McCormick, Olivier Lantz, Roberto Hernandez-Alejandro, S M Mansour Haeryfar
Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28630092/characterization-of-high-avidity-cytomegalovirus-specific-t-cells-with-differential-tetramer-binding-coappearing-after-allogeneic-stem-cell-transplantation
#2
Justyna Ogonek, Kriti Verma, Christian Schultze-Florey, Pavankumar Varanasi, Susanne Luther, Patrick Schweier, Wolfgang Kühnau, Gudrun Göhring, Elke Dammann, Michael Stadler, Arnold Ganser, Ulrike Koehl, Christian Koenecke, Eva M Weissinger, Lothar Hambach
CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tet(low) CTLs) and high tetramer binding (CMV tet(high) CTLs) in 53/115 CMV IgG(+) patients stem cell transplanted from CMV IgG(+) donors. However, the relevance of these coappearing differentially tetramer binding ("dual") CMV-CTLs was unclear...
June 19, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28630062/the-transcription-factor-nfat1-participates-in-the-induction-of-cd4-t-cell-functional-exhaustion-during-plasmodium-yoelii-infection
#3
Rachel Y Ames, Li-Min Ting, Inessa Gendlina, Kami Kim, Fernando Macian
Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and up-regulate cell-surface inhibitory molecules such as PD-1 and LAG-3...
June 19, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28629373/blimp-1-impairs-t-cell-function-via-upregulation-of-tigit-and-pd-1-in-patients-with-acute-myeloid-leukemia
#4
Liuluan Zhu, Yaxian Kong, Jianhong Zhang, David F Claxton, W Christopher Ehmann, Witold B Rybka, Neil D Palmisiano, Ming Wang, Bei Jia, Michael Bayerl, Todd D Schell, Raymond J Hohl, Hui Zeng, Hong Zheng
BACKGROUND: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML...
June 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28627729/the-immune-deficiency-of-chromosome-22q11-2-deletion-syndrome
#5
Megan Morsheimer, Terri F Brown Whitehorn, Jennifer Heimall, Kathleen E Sullivan
The syndrome originally described by Dr. Angelo DiGeorge had immunodeficiency as a central component. When a 22q11.2 deletion was identified as the cause in the majority of patients with DiGeorge syndrome, the clinical features of 22q11.2 deletion syndrome became so expansive that the immunodeficiency became less prominent in our thinking about the syndrome. This review will focus on the immune system and the changes in our understanding over the past 50 years. Initially characterized as a pure defect in T cell development, we now appreciate that many of the clinical features related to the immunodeficiency are well downstream of the limitation imposed by a small thymus...
June 19, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28625352/rna-seq-and-metabolic-flux-analysis-of-tetraselmis-sp-m8-during-nitrogen-starvation-reveals-a-two-stage-lipid-accumulation-mechanism
#6
David K Y Lim, Holger Schuhmann, Skye R Thomas-Hall, Kenneth C K Chan, Taylor J Wass, Felipe Aguilera, T Catalina Adarme-Vega, Cristiana G O Dal'Molin, Glen J Thorpe, Jacqueline Batley, David Edwards, Peer M Schenk
To map out key lipid-related pathways that lead to rapid triacylglyceride accumulation in oleaginous microalgae, RNA-Seq was performed with Tetraselmis sp. M8 at 24h after exhaustion of exogenous nitrogen to reveal molecular changes during early stationary phase. Further gene expression profiling by quantitative real-time PCR at 16-72h revealed a distinct shift in expression of the fatty acid/triacylglyceride biosynthesis and β-oxidation pathways, when cells transitioned from log-phase into early-stationary and stationary phase...
June 6, 2017: Bioresource Technology
https://www.readbyqxmd.com/read/28624577/identification-of-an-immune-specific-class-of-hepatocellular-carcinoma-based-on-molecular-features
#7
Daniela Sia, Yang Jiao, Iris Martinez-Quetglas, Olga Kuchuk, Carlos Villacorta-Martin, Manuel Castro de Moura, Juan Putra, Genis Camprecios, Laia Bassaganyas, Nicholas Akers, Bojan Losic, Samuel Waxman, Swan N Thung, Vincenzo Mazzaferro, Manel Esteller, Scott L Friedman, Myron Schwartz, Augusto Villanueva, Josep M Llovet
BACKGROUND AND AIMS: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors. METHODS: We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm...
June 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28622514/landscape-of-infiltrating-t-cells-in-liver-cancer-revealed-by-single-cell-sequencing
#8
Chunhong Zheng, Liangtao Zheng, Jae-Kwang Yoo, Huahu Guo, Yuanyuan Zhang, Xinyi Guo, Boxi Kang, Ruozhen Hu, Julie Y Huang, Qiming Zhang, Zhouzerui Liu, Minghui Dong, Xueda Hu, Wenjun Ouyang, Jirun Peng, Zemin Zhang
Systematic interrogation of tumor-infiltrating lymphocytes is key to the development of immunotherapies and the prediction of their clinical responses in cancers. Here, we perform deep single-cell RNA sequencing on 5,063 single T cells isolated from peripheral blood, tumor, and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional profiles of these individual cells, coupled with assembled T cell receptor (TCR) sequences, enable us to identify 11 T cell subsets based on their molecular and functional properties and delineate their developmental trajectory...
June 15, 2017: Cell
https://www.readbyqxmd.com/read/28621034/depletion-of-foxp3-tregs-improves-control-of-larval-echinococcus-multilocularis-infection-by-promoting-co-stimulation-and-th1-17-immunity
#9
Junhua Wang, Stephan Müller, Renyong Lin, Myriam Siffert, Dominique A Vuitton, Hao Wen, Bruno Gottstein
INTRODUCTION: The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. Previous studies had shown that regulatory T cells (Tregs) become gradually up-regulated in the course of both chronic human and murine AE. Thus we now tackled the role of FoxP3(+) Tregs and FoxP3(+) -Treg-regulated immune response in contributing to the control of this helminthic infection...
June 16, 2017: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/28619747/successful-immune-checkpoint-blockade-in-a-patient-with-advanced-stage-microsatellite-unstable-biliary-tract-cancer
#10
Elena Czink, Matthias Kloor, Benjamin Goeppert, Stefan Froehling, Sebastian Uhrig, Tim F Weber, Joern Meinel, Christian Sutter, Karl Heinz Weiss, Peter Schirmacher, Magnus von Knebel Doeberitz, Dirk Jaeger, Christoph Springfeld
Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy...
June 15, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28618268/antigen-availability-shapes-t-cell-differentiation-and-function-during-tuberculosis
#11
Albanus O Moguche, Munyaradzi Musvosvi, Adam Penn-Nicholson, Courtney R Plumlee, Helen Mearns, Hennie Geldenhuys, Erica Smit, Deborah Abrahams, Virginie Rozot, One Dintwe, Søren T Hoff, Ingrid Kromann, Morten Ruhwald, Peter Bang, Ryan P Larson, Shahin Shafiani, Shuyi Ma, David R Sherman, Alessandro Sette, Cecilia S Lindestam Arlehamn, Denise M McKinney, Holden Maecker, Willem A Hanekom, Mark Hatherill, Peter Andersen, Thomas J Scriba, Kevin B Urdahl
CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28615538/expression-of-lag-3-defines-exhaustion-of-intratumoral-pd-1-t-cells-and-correlates-with-poor-outcome-in-follicular-lymphoma
#12
Zhi-Zhang Yang, Hyo Jin Kim, Jose C Villasboas, Ya-Ping Chen, Tammy Price-Troska, Shahrzad Jalali, Mara Wilson, Anne J Novak, Stephen M Ansell
Exhausted T-cells in follicular lymphoma (FL) typically express PD-1, but expression of PD-1 is not limited to exhausted cells. Although expected to be functionally suppressed, we found that the population of intratumoral PD-1+ T cells were predominantly responsible for production of cytokines and granules. This surprising finding prompted us to explore the involvement of LAG-3 to specifically identify functionally exhausted T cells. We found that LAG-3 was expressed on a subset of intratumoral T cells from FL and LAG-3+ T cells almost exclusively came from PD-1+ population...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28608730/novel-therapy-for-childhood-acute-lymphoblastic-leukemia
#13
Raoul Santiago, Stéphanie Vairy, Daniel Sinnett, Maja Krajinovic, Henrique Bittencourt
During recent decades, the prognosis of childhood acute lymphoblastic leukemia (ALL) has improved dramatically, nowadays, reaching a cure rate of almost 90%. These results are due to a better management and combination of old therapies, refined risk-group stratification and emergence of minimal residual disease (MRD) combined with treatment's intensification for high-risk subgroups. However, the subgroup of patients with refractory/relapsed ALL still presents a dismal prognosis indicating necessity for innovative therapeutic approaches...
June 13, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28607114/varicella-zoster-virus-specific-cellular-immune-responses-to-the-live-attenuated-zoster-vaccine-in-young-and-older-adults
#14
Adriana Weinberg, Jennifer Canniff, Nadine Rouphael, Aneesh Mehta, Mark Mulligan, Jennifer A Whitaker, Myron J Levin
The incidence and severity of herpes zoster (HZ) increases with age. The live attenuated zoster vaccine generates immune responses similar to HZ. We compared the immune responses to zoster vaccine in young and older to adults to increase our understanding of the immune characteristics that may contribute to the increased susceptibility to HZ in older adults. Young (25-40 y; n = 25) and older (60-80 y; n = 33) adults had similar magnitude memory responses to varicella-zoster virus (VZV) ex vivo restimulation measured by responder cell-frequency and flow cytometry, but the responses were delayed in older compared with young adults...
June 12, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28606939/transcriptional-and-epigenetic-regulation-of-t-cell-hyporesponsiveness
#15
REVIEW
Renata M Pereira, Patrick G Hogan, Anjana Rao, Gustavo J Martinez
Naive CD8(+) T cells differentiate into effector and memory cytolytic T cells (CTLs) during an acute infection. In contrast, in scenarios of persistent antigen stimulation, such as chronic infections and cancer, antigen-specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8(+) T cell "exhaustion" or "dysfunction." Another hyporesponsive state, termed anergy, is observed when T cells are activated in the absence of positive costimulatory signals. Among the many negative regulators induced in hyporesponsive T cells are inhibitory cell-surface receptors, such as PD-1, LAG-3, CTLA-4, and TIM-3; "checkpoint blockade" therapies that involve treatment of patients with cancer with blocking antibodies to those receptors show considerable promise in the clinic because the blocking antibodies can mitigate hyporesponsiveness and promote tumor rejection...
June 12, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28606013/decrease-of-cd69-levels-on-tcr-v%C3%AE-7-2-cd4-innate-like-lymphocytes-is-associated-with-impaired-cytotoxic-functions-in-chronic-hepatitis-b-virus-infected-patients
#16
Yean K Yong, Hong Y Tan, Alireza Saeidi, Mohamed Rosmawati, Nadia Atiya, Abdul W Ansari, Jayakumar Rajarajeswaran, Jamuna Vadivelu, Vijayakumar Velu, Marie Larsson, Esaki M Shankar
Hepatitis B virus (HBV) infection is a major cause of chronic liver disease that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses represent the key determinants of HBV clearance or persistence. Here, we investigated the role of the early activation marker, CD69 and effector cytokines, granzyme B (GrB) and IFN-γ in the exhaustion of innate-like TCR Vα7.2(+)CD4(+)T cells, in 15 individuals with chronic HBV (CHB) infection where six were HBV DNA(+) and nine were HBV DNA(-)...
January 1, 2017: Innate Immunity
https://www.readbyqxmd.com/read/28600479/trabectedin-overrides-osteosarcoma-differentiative-block-and-reprograms-the-tumor-immune-environment-enabling-effective-combination-with-immune-checkpoint-inhibitors
#17
Chiara Ratti, Laura Botti, Valeria Cancila, Silvia Galvan, Ilaria Torselli, Cecilia Garofalo, Maria Cristina Manara, Lucia Bongiovanni, Cesare F Valenti, Alessia Burocchi, Mariella Parenza, Barbara Cappetti, Sabina Sangaletti, Claudio Tripodo, Katia Scotlandi, Mario P Colombo, Claudia Chiodoni
Purpose: Osteosarcoma (OS), the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. <p>Experimental Design: We have developed immuno-competent OS models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human OS...
June 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28585539/il-21-mediated-reversal-of-nk-cell-exhaustion-facilitates-anti-tumour-immunity-in-mhc-class-i-deficient-tumours
#18
Hyungseok Seo, Insu Jeon, Byung-Seok Kim, Myunghwan Park, Eun-Ah Bae, Boyeong Song, Choong-Hyun Koh, Kwang-Soo Shin, Il-Kyu Kim, Kiyoung Choi, Taegwon Oh, Jiyoun Min, Byung Soh Min, Yoon Dae Han, Suk-Jo Kang, Sang Joon Shin, Yeonseok Chung, Chang-Yuil Kang
During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours...
June 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28582466/aberrant-plasma-il-7-and-soluble-il-7-receptor-levels-indicate-impaired-t-cell-response-to-il-7-in-human-tuberculosis
#19
Christian Lundtoft, Anthony Afum-Adjei Awuah, Jens Rimpler, Kirstin Harling, Norman Nausch, Malte Kohns, Ernest Adankwah, Franziska Lang, Laura Olbrich, Ertan Mayatepek, Ellis Owusu-Dabo, Marc Jacobsen
T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7-modulated T-cell functions. Aberrant expression of soluble (s) and membrane-associated (m) IL-7R molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis...
June 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28579805/bisdemethoxycurcumin-in-combination-with-%C3%AE-pd-l1-antibody-boosts-immune-response-against-bladder-cancer
#20
Yiqun Shao, Wenjing Zhu, Jun Da, Mingxi Xu, Yiwei Wang, Juan Zhou, Zhong Wang
Curcumin was recently discovered to strengthen immune response through multiple mechanisms. Cytotoxic CD8(+) T-cells play a critical role in modulating anticancer immune response, but is severely restricted by T-cell exhaustion. Bladder carcinomas express PD-L1 and can abrogate CD8(+) T-cell response. Thus, we hypothesized that bisdemethoxycurcumin, a natural dimethoxy derivative of curcumin, may provide a favorable environment for T-cell response against bladder cancer when used in combination with α-PD-L1 antibody...
2017: OncoTargets and Therapy
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