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t cell anergy

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https://www.readbyqxmd.com/read/29140996/childhood-tuberculosis-is-associated-with-decreased-abundance-of-t-cell-gene-transcripts-and-impaired-t-cell-function
#1
Cheryl Hemingway, Maurice Berk, Suzanne T Anderson, Victoria J Wright, Shea Hamilton, Hariklia Eleftherohorinou, Myrsini Kaforou, Greg M Goldgof, Katy Hickman, Beate Kampmann, Johan Schoeman, Brian Eley, David Beatty, Sandra Pienaar, Mark P Nicol, Michael J Griffiths, Simon J Waddell, Sandra M Newton, Lachlan J Coin, David A Relman, Giovanni Montana, Michael Levin
The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB...
2017: PloS One
https://www.readbyqxmd.com/read/29128997/pd-1-pd-l1-immune-checkpoint-blockade-in-malignant-lymphomas
#2
REVIEW
Yi Wang, Ling Wu, Chen Tian, Yizhuo Zhang
Tumor cells can evade immune surveillance through overexpressing the ligands of checkpoint receptors on tumor cells or adjacent cells, leading T cells to anergy or exhaustion. Growing evidence of the interaction between tumor cells and microenvironment promoted the emergence of immune-checkpoint blockade. By targeting programmed cell death-1 (PD-1) pathway, cytotoxic activity of T cell is enhanced significantly and tumor cell lysis is induced subsequently. Currently, various antibodies against PD-1 and programmed death-ligand 1 (PD-L1) are under clinical studies in lymphomas...
November 11, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29122838/soluble-cd80-protein-delays-tumor-growth-and-promotes-tumor-infiltrating-lymphocytes
#3
Lucas A Horn, Tiha M Long, Ryan Atkinson, Virginia Clements, Suzanne Ostrand-Rosenberg
Tumor cells employ various immune suppressive strategies to overcome antitumor immunity. One such method is tumor expression of programmed death ligand-1 (PD-L1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD-1) on T cells. Our previous in vitro cellular studies with human and mouse PD-L1+ tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PD-L1-mediated immune suppression and restored T-cell activation by binding PD-L1 and blocking interaction with PD-1...
November 9, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29111717/discovery-of-a-novel-and-selective-indoleamine-2-3-dioxygenase-ido-1-inhibitor-3-5-fluoro-1h-indol-3-yl-pyrrolidine-2-5-dione-eos200271-pf-06840003-and-its-characterization-as-a-potential-clinical-candidate
#4
Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Marie Cordonnier, Deepak Dalvie, Frederik Deroose, Jun Li Feng, Bruno Gomes, Samantha Greasley, Stephen E Kaiser, Manfred Kraus, Michel Négrerie, Karen A Maegley, Nichol Miller, Brion W Murray, Manfred Schneider, James Solowiej, Albert E Stewart, Joseph Tumang, Vince R Torti, Benoit Van den Eynde, Martin Wythes
Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. SAR around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode...
November 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29111199/density-dependent-re-tuning-of-autoreactive-t-cells-alleviates-their-pathogenicity-in-a-lymphopenic-environment
#5
Eleanore Chuang, Marilyn Augustine, Matthew Jung, Ronald H Schwartz, Nevil J Singh
Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells...
December 2017: Immunology Letters
https://www.readbyqxmd.com/read/29093272/t-cells-presenting-viral-antigens-or-autoantigens-induce-cytotoxic-t-cell-anergy
#6
Nathalie E Blachère, Dana E Orange, Emily C Gantman, Bianca D Santomasso, Graeme C Couture, Teresa Ramirez-Montagut, John Fak, Kevin J O'Donovan, Zhong Ru, Salina Parveen, Mayu O Frank, Michael J Moore, Robert B Darnell
In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29078267/gut-dysbiosis-breaks-immunological-tolerance-toward-the-central-nervous-system-during-young-adulthood
#7
Sudhir K Yadav, Sridhar Boppana, Naoko Ito, John E Mindur, Martin T Mathay, Ankoor Patel, Suhayl Dhib-Jalbut, Kouichi Ito
Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS self-antigens has been suggested to initiate CNS autoimmunity. Age and microbial infection are well-known factors involved in the development of autoimmune diseases, including MS. Recent studies have suggested that alterations in the gut microbiota, referred to as dysbiosis, are associated with MS. However, it is still largely unknown how gut dysbiosis affects the onset and progression of CNS autoimmunity...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29074182/t-cell-ignorance-is-bliss-t-cells-are-not-tolerized-by-langerhans-cells-presenting-human-papillomavirus-antigens-in-the-absence-of-costimulation
#8
Andrew W Woodham, Lisa Yan, Joseph G Skeate, Daniel van der Veen, Heike E Brand, Michael K Wong, Diane M Da Silva, W Martin Kast
Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs...
December 2016: Papillomavirus Research
https://www.readbyqxmd.com/read/29045749/immune-checkpoint-inhibitor-related-myocarditis
#9
Kazuko Tajiri, Kazutaka Aonuma, Ikuo Sekine
Immune checkpoint inhibitors have demonstrated significant clinical benefit in many cancers. The clinical benefit afforded by these treatments can be accompanied by a unique and distinct spectrum of adverse events. Recently, several fatal cases of immune checkpoint inhibitor-related myocarditis were reported. Although its frequency is comparatively lower than that of other immune-related adverse events, myocarditis can lead to circulatory collapse and lethal ventricular arrhythmia. Immune checkpoints, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), play important roles in establishing peripheral tolerance to the heart...
October 17, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29020680/hepatic-t-cell-tolerance-induction-in-an-inflammatory-environment
#10
Janine Dywicki, Fatih Noyan, Ana Clara Misslitz, Martin Hapke, Melanie Galla, Jerome Schlue, Roland S Liblau, Richard Taubert, Michael P Manns, Elmar Jaeckel, Matthias Hardtke-Wolenski
For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre)...
October 12, 2017: Digestive Diseases
https://www.readbyqxmd.com/read/28968466/changes-in-the-cellular-microrna-profile-by-the-intracellular-expression-of-hiv-1-tat-regulator-a-potential-mechanism-for-resistance-to-apoptosis-and-impaired-proliferation-in-hiv-1-infected-cd4-t-cells
#11
María Sánchez-Del Cojo, María Rosa López-Huertas, Francisco Díez-Fuertes, Sara Rodríguez-Mora, Mercedes Bermejo, Guillermo López-Campos, Elena Mateos, Laura Jiménez-Tormo, Francisco Gómez-Esquer, Gema Díaz-Gil, José Alcamí, Mayte Coiras
HIV-1 induces changes in the miRNA expression profile of infected CD4+ T cells that could improve viral replication. HIV-1 regulator Tat modifies the cellular gene expression and has been appointed as an RNA silencing suppressor. Tat is a 101-residue protein codified by two exons that regulates the elongation of viral transcripts. The first exon of Tat (amino acids 1-72) forms the transcriptionally active protein Tat72, but the presence of the second exon (amino acids 73-101) results in a more competent regulatory protein (Tat101) with additional functions...
2017: PloS One
https://www.readbyqxmd.com/read/28947542/nur77-regulates-nondeletional-mechanisms-of-tolerance-in-t-cells
#12
Qian Nancy Hu, Alexander Y W Suen, Laura M Henao Caviedes, Troy A Baldwin
Negative selection against highly self-reactive thymocytes is critical for preventing autoimmunity. Thymocyte deletion, anergy induction, and agonist selection are all forms of negative selection that can occur following a high-affinity TCR signal. Of Bim and Nur77, two TCR-induced proteins with proapoptotic function, Bim has been shown to be important for clonal deletion in several model systems, whereas Nur77 was often dispensable. However, Nur77 has been reported to influence other aspects of T cell development by mechanisms that may not be related to its proapoptotic function...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28942020/cd25-expressing-th17-cells-mediate-cd8-t-cell-suppression-in-ctla-4-dependent-mechanisms-in-pancreatic-ductal-adenocarcinoma
#13
Cuicui Lang, Jinyan Wang, Lei Chen
The tumor-associated immune response is governed by the signalling events of various regulatory molecules, one of which is the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). In conventional T cells, CTLA-4 could outcompete CD28 in binding to CD80/86 but does not produce a co-stimulatory signal, resulting in T cell anergy. CTLA-4 in regulatory T cells (Tregs) could also function in a cell-extrinsic fashion by removing CD80/CD86 from the antigen-presenting cells (APCs), thus preventing further priming of other T cells...
November 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28939757/pd-1-blockade-promotes-epitope-spreading-in-anticancer-cd8-t-cell-responses-by-preventing-fratricidal-death-of-subdominant-clones-to-relieve-immunodomination
#14
Arash Memarnejadian, Courtney E Meilleur, Christopher R Shaler, Khashayarsha Khazaie, Jack R Bennink, Todd D Schell, S M Mansour Haeryfar
The interactions between programmed death-1 (PD-1) and its ligands hamper tumor-specific CD8(+) T cell (TCD8) responses, and PD-1-based "checkpoint inhibitors" have shown promise in certain cancers, thus revitalizing interest in immunotherapy. PD-1-targeted therapies reverse TCD8 exhaustion/anergy. However, whether they alter the epitope breadth of TCD8 responses remains unclear. This is an important question because subdominant TCD8 are more likely than immunodominant clones to escape tolerance mechanisms and may contribute to protective anticancer immunity...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28906131/effects-of-immunomodulators-on-the-response-induced-by-vaccines-against-autoimmune-diseases
#15
Dante J Marciani
A promising treatment for T-cell-mediated autoimmune diseases is the induction of immune tolerance by modulating the immune response against self-antigens, an objective that may be achieved by vaccination. There are two main types of vaccines currently under development. The tolerogenic vaccines, composed of proteins formed by a cytokine fused to a self-antigen, which usually induce tolerance by eliminating the T-cells that are immune reactive against the self-antigen. The immunogenic vaccines, comprised of a self-antigen plus a sole Th2 adjuvant either free or conjugated, that alleviate autoimmunity by switching the immune response against the self-antigen, from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity...
November 2017: Autoimmunity
https://www.readbyqxmd.com/read/28900926/immunological-disorders-regulation-of-ca-2-signaling-in-t-lymphocytes
#16
Sonal Srikanth, Jin Seok Woo, Zuoming Sun, Yousang Gwack
Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca(2+)-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28900667/ammonium-trichloro-1-2-ethanediolato-o-o-tellurate-cures-experimental-visceral-leishmaniasis-by-redox-modulation-of-leishmania-donovani-trypanothione-reductase-and-inhibiting-host-integrin-linked-pi3k-akt-pathway
#17
Preeti Vishwakarma, Naveen Parmar, Pragya Chandrakar, Tanuj Sharma, Manoj Kathuria, Pramod K Agnihotri, Mohammad Imran Siddiqi, Kalyan Mitra, Susanta Kar
In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O']-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition)...
September 12, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28887632/multipeptide-coupled-nanoparticles-induce-tolerance-in-humanised-hla-transgenic-mice-and-inhibit-diabetogenic-cd8-t-cell-responses-in-type-1-diabetes
#18
Xinyu Xu, Lingling Bian, Min Shen, Xin Li, Jing Zhu, Shuang Chen, Lei Xiao, Qingqing Zhang, Heng Chen, Kuanfeng Xu, Tao Yang
AIMS/HYPOTHESIS: Induction of antigen-specific immunological tolerance may provide an attractive immunotherapy in the NOD mouse model but the conditions that lead to the successful translation to human type 1 diabetes are limited. In this study, we covalently linked 500 nm carboxylated polystyrene beads (PSB) with a mixture of immunodominant HLA-A*02:01-restricted epitopes (peptides-PSB) that may have high clinical relevance in humans as they promote immune tolerance; we then investigated the effect of the nanoparticle-peptide complexes on T cell tolerance...
December 2017: Diabetologia
https://www.readbyqxmd.com/read/28878331/the-immunosuppressive-effect-of-the-tick-protein-salp15-is-long-lasting-and-persists-in-a-murine-model-of-hematopoietic-transplant
#19
Julen Tomás-Cortázar, Itziar Martín-Ruiz, Diego Barriales, Miguel Ángel Pascual-Itoiz, Virginia Gutiérrez de Juan, Alfredo Caro-Maldonado, Nekane Merino, Alberto Marina, Francisco J Blanco, Juana María Flores, James D Sutherland, Rosa Barrio, Adriana Rojas, María Luz Martínez-Chantar, Arkaitz Carracedo, Carolina Simó, Virginia García-Cañas, Leticia Abecia, José Luis Lavín, Ana M Aransay, Héctor Rodríguez, Juan Anguita
Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28872140/purification-of-the-membrane-compartment-for-endoplasmic-reticulum-associated-degradation-of-exogenous-antigens-in-cross-presentation
#20
Jun Imai, Mayu Otani, Takahiro Sakai, Shinichi Hatta
Dendritic cells (DCs) are highly capable of processing and presenting internalized exogenous antigens upon major histocompatibility class (MHC) I molecules also known as cross-presentation (CP). CP plays an important role not only in the stimulation of naïve CD8(+) T cells and memory CD8(+) T cells for infectious and tumor immunity but also in the inactivation of self-acting naïve T cells by T cell anergy or T cell deletion. Although the critical molecular mechanism of CP remains to be elucidated, accumulating evidence indicates that exogenous antigens are processed through endoplasmic reticulum-associated degradation (ERAD) after export from non-classical endocytic compartments...
August 21, 2017: Journal of Visualized Experiments: JoVE
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