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https://www.readbyqxmd.com/read/28439570/epigenomics-of-human-cd8-t-cell-differentiation-and-aging
#1
David M Moskowitz, David W Zhang, Bin Hu, Sabine Le Saux, Rolando E Yanes, Zhongde Ye, Jason D Buenrostro, Cornelia M Weyand, William J Greenleaf, Jörg J Goronzy
The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we inferred the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1...
February 2017: Science Immunology
https://www.readbyqxmd.com/read/28438506/diacylglycerol-kinase-%C3%AE-limits-cytokine-dependent-expansion-of-cd8-t-cells-with-broad-antitumor-capacity
#2
Elena Andrada, Rosa Liébana, Isabel Merida
Interleukin-2 and -15 drive expansion/differentiation of cytotoxic CD8(+) T cells that eliminate targets via antigen-independent killing. This property is clinically relevant for the improvement of T cell-based antitumor therapies. Diacylglycerol kinase α and ζ (DGKα/ζ) metabolize the diacylglycerol generated following antigen recognition by T lymphocytes. Enhanced expression of these two lipid kinases in tumor-infiltrating CD8(+) T cells promotes a hyporesponsive state that contributes to tumor immune escape...
April 14, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28436963/a-sting-activating-nanovaccine-for-cancer-immunotherapy
#3
Min Luo, Hua Wang, Zhaohui Wang, Haocheng Cai, Zhigang Lu, Yang Li, Mingjian Du, Gang Huang, Chensu Wang, Xiang Chen, Matthew R Porembka, Jayanthi Lea, Arthur E Frankel, Yang-Xin Fu, Zhijian J Chen, Jinming Gao
The generation of tumour-specific T cells is critically important for cancer immunotherapy. A major challenge in achieving a robust T-cell response is the spatiotemporal orchestration of antigen cross-presentation in antigen-presenting cells with innate stimulation. Here, we report a minimalist nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle, PC7A NP, which generates a strong cytotoxic T-cell response with low systemic cytokine expression. Mechanistically, the PC7A NP achieves efficient cytosolic delivery of tumour antigens to antigen-presenting cells in draining lymph nodes, leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes...
April 24, 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/28435676/understanding-cd8-t-cell-responses-toward-the-native-and-alternate-hla-a-02-01-restricted-wt1-epitope
#4
Thi Ho Nguyen, Amabel Cl Tan, Sue D Xiang, Anne Goubier, Kim L Harland, E Bridie Clemens, Magdalena Plebanski, Katherine Kedzierska
The Wilms' tumor 1 (WT1) antigen is expressed in solid and hematological malignancies, but not healthy tissues, making it a promising target for cancer immunotherapies. Immunodominant WT1 epitopes, the native HLA-A2/WT1126-134 (RMFPNAPYL) (HLA-A2/RMFPNAPYL epitope (WT1A)) and its modified variant YMFPNAPYL (HLA-A2/YMFPNAPYL epitope (WT1B)), can induce WT1-specific CD8(+) T cells, although WT1B is more stably bound to HLA-A*02:01. Here, to further determine the benefits of those two targets, we assessed the naive precursor frequencies; immunogenicity and cross-reactivity of CD8(+) T cells directed toward these two WT1 epitopes...
March 2017: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28435674/the-three-rs-recruitment-retention-and-residence-of-leukocytes-in-the-liver
#5
REVIEW
Hayley A McNamara, Ian A Cockburn
The composition of leukocytes in the liver is highly distinct from that of the blood and lymphoid organs. In particular, the liver is highly enriched in non-conventional T cells such as natural killer T (NKT) cells, γδ T cells and mucosal-associated invariant T cells. In addition, there are significant populations of tissue-resident NK cells (or innate lymphoid cells (ILC1)) and memory CD8(+) T cells. These cells are joined in conditions of inflammation by neutrophils, monocytes and macrophages. In recent years a multitude of studies have generated insights into how these cells arrest, move and remain resident in the liver...
December 2016: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28435008/cortical-and-amygdalar-neuronal-ensembles-in-alcohol-seeking-drinking-and-withdrawal
#6
REVIEW
Olivier George, Bruce T Hope
Alcohol induces many alterations in the brain that are thought to contribute to alcohol addiction. Most of the known alterations are induced in all neurons of a brain area or all neurons of a given cell type, regardless of whether they were activated during behavior. While these alterations can have important modulatory effects on behavior, they cannot explain why animals respond specifically to alcohol-paired cues as opposed to all other non-paired cues, and evoke highly specific goal-directed learned responses in models of drug craving...
April 20, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28434800/medial-entorhinal-cortex-selectively-supports-temporal-coding-by-hippocampal-neurons
#7
Nick T M Robinson, James B Priestley, Jon W Rueckemann, Aaron D Garcia, Vittoria A Smeglin, Francesca A Marino, Howard Eichenbaum
Recent studies have shown that hippocampal "time cells" code for sequential moments in temporally organized experiences. However, it is currently unknown whether these temporal firing patterns critically rely on upstream cortical input. Here we employ an optogenetic approach to explore the effect of large-scale inactivation of the medial entorhinal cortex on temporal, as well as spatial and object, coding by hippocampal CA1 neurons. Medial entorhinal inactivation produced a specific deficit in temporal coding in CA1 and resulted in significant impairment in memory across a temporal delay...
April 13, 2017: Neuron
https://www.readbyqxmd.com/read/28434399/the-next-generation-of-immunotherapy-keeping-lung-cancer-in-check
#8
REVIEW
Ashwin Somasundaram, Timothy F Burns
Lung cancer is the deadliest malignancy with more cancer deaths per year than the next three cancers combined. Despite remarkable advances in targeted therapy, advanced lung cancer patients have not experienced a significant improvement in mortality. Lung cancer has been shown to be immunogenic and responsive to checkpoint blockade therapy. Checkpoint signals such as CTLA-4 and PD-1/PD-L1 dampen T cell activation and allow tumors to escape the adaptive immune response. Response rates in patients with pretreated, advanced NSCLC were much higher and more durable with PD-1 blockade therapy compared to standard-of-care, cytotoxic chemotherapy...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28432872/human-effector-memory-t-helper-cells-engage-with-mouse-macrophages-and-cause-graft-versus-host-like-pathology-in-skin-of-humanized-mice-used-in-a-nonclinical-immunization-study
#9
Bala S Sundarasetty, Valery Volk, Sebastian J Theobald, Susanne Rittinghausen, Dirk Schaudien, Vanessa Neuhaus, Constanca Figueiredo, Andreas Schneider, Laura Gerasch, Adele Mucci, Thomas Moritz, Constantin von Kaisenberg, Loukia M Spineli, Katherina Sewald, Armin Braun, Henning Weigt, Arnold Ganser, Renata Stripecke
Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4(+) T cells in peripheral blood and lymph nodes...
April 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28432326/a-novel-mechanism-linking-memory-stem-cells-with-innate-immunity-in-protection-against-hiv-1-infection
#10
Yufei Wang, Trevor Whittall, Stuart Neil, Gary Britton, Mukesh Mistry, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Xuesong Yu, Alicia Sato, Robert J O'Connell, Nelson L Michael, Merlin L Robb, Jerome H Kim, Thomas Lehner
HIV infection affects 37 million people and about 1.7 million are infected annually. Among the phase III clinical trials only the RV144 vaccine trial elicited significant protection against HIV-1 acquisition, but the efficacy and immune memory were inadequate. To boost these vaccine functions we studied T stem cell memory (TSCM) and innate immunity. TSCM cells were identified by phenotypic markers of CD4(+) T cells and they were further characterised into 4 subsets. These expressed the common IL-2/IL-15 receptors and another subset of APOBEC3G anti-viral restriction factors, both of which were upregulated...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28432133/do-memory-cd4-t-cells-keep-their-cell-type-programming-plasticity-versus-fate-commitment-t-cell-heterogeneity-plasticity-and-selection-in-humans
#11
Federica Sallusto, Antonino Cassotta, Daniel Hoces, Mathilde Foglierini, Antonio Lanzavecchia
The wide range of effector and memory T cells is instrumental for immune regulation and tailored mechanisms of protection against pathogens. Here, we will focus on human CD4 T cells and discuss T-cell plasticity and intraclonal diversification in the context of a progressive and selective model of CD4 T-cell differentiation.
April 21, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28432132/do-memory-cd4-t-cells-keep-their-cell-type-programming-plasticity-versus-fate-commitment-epigenome-a-dynamic-vehicle-for-transmitting-and-recording-cytokine-signaling
#12
John L Johnson, Golnaz Vahedi
CD4(+) T cells are critical for the elimination of an immense array of microbial pathogens. Although there are aspects of helper T-cell differentiation that can be modeled as a classic cell-fate commitment, CD4(+) T cells also maintain considerable flexibility in their transcriptional program. Here, we present an overview of chromatin biology during cellular reprogramming and, within this context, envision how the scope of cellular reprogramming may be expanded to further our understanding of the controversy surrounding CD4(+) T lymphocyte plasticity or determinism...
April 21, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28432129/do-memory-cd4-t-cells-keep-their-cell-type-programming-plasticity-versus-fate-commitment-complexities-of-interpretation-due-to-the-heterogeneity-of-memory-cd4-t-cells-including-t-follicular-helper-cells
#13
Shane Crotty
Plasticity is the ability of a cell type to convert to another cell type. There are multiple effector CD4 T-cell subtypes, including TH1, TH2, TH17, TH1*, CD4 CTL, TH9, and TFH cells. It is commonly thought that a CD4 T cell can readily show full plasticity-full conversion from one differentiated cell-and this propensity to plasticity is possessed by memory CD4 T cells. However, there remains no direct demonstration of in vivo-generated resting memory CD4 T-cell conversion to a different subtype on secondary antigen challenge in vivo in an intact animal at the single-cell level...
April 21, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28431111/correction-of-abnormal-b-cell-subset-distribution-by-interleukin-6-receptor-blockade-in-polymyalgia-rheumatica
#14
Guillermo Carvajal Alegria, Valérie Devauchelle-Pensec, Yves Renaudineau, Alain Saraux, Jacques-Olivier Pers, Divi Cornec
Objectives.: The aim was to study lymphocyte subsets and circulating cytokines at diagnosis of PMR and after tocilizumab monotherapy. Methods.: Eighteen untreated patients with PMR were included in a prospective study and received 3-monthly tocilizumab infusions without glucocorticoids. Lymphocyte subset distribution was assessed by flow cytometry and serum cytokines were assayed by a 34-cytokine array and ELISA, at baseline and during follow-up. Baseline data were also compared with age- and sex-matched controls...
April 20, 2017: Rheumatology
https://www.readbyqxmd.com/read/28430604/signal-transducing-adaptor-protein-2-promotes-generation-of-functional-long-term-memory-cd8-t-cells-by-preventing-terminal-effector-differentiation
#15
Daisuke Muraoka, Naohiro Seo, Tae Hayashi, Chisaki Hyuga-Amaike, Kana Okamori, Isao Tawara, Naozumi Harada, Hiroshi Shiku
Long-surviving memory CD8+ T cells generated by stimulation with appropriate tumor-associated antigens are the most aggressive and persistent tumoricidal effectors. In this event of memory CD8+ T cell development, the signal transducer and activator of transcription (STAT) proteins function as the crucial intracellular signaling molecules, but the regulatory mechanism of STATs in CD8+ T cells is not fully understood. In this study, we report for the first time, by using murine vaccination models, that signal-transducing adaptor protein-2 (STAP2) maintains the cytotoxicity of long-lived memory CD8+ T cells by controlling a STAT3/suppressor of cytokine signaling 3 (SOCS3) cascade...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429719/transiently-antigen-primed-b-cells-return-to-naive-like-state-in-absence-of-t-cell-help
#16
Jackson S Turner, Matangi Marthi, Zachary L Benet, Irina Grigorova
The perspective that naive B-cell recognition of antigen in the absence of T-cell help causes cell death or anergy is supported by in vivo studies of B cells that are continuously exposed to self-antigens. However, intravital imaging suggests that early B-cell recognition of large foreign antigens may be transient. Whether B cells are tolerized or can be recruited into humoural immune responses following such encounters is not clear. Here we show that in the presence of T-cell help, single transient antigen acquisition is sufficient to recruit B cells into the germinal centre and induce memory and plasma cell responses...
April 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28429640/spinal-alterations-of-reil-insula-in-alzheimer-s-disease
#17
Foivos E Petrides, Ioannis A Mavroudis, Martha Spilioti, Fotios G Chatzinikolaou, Vasiliki G Costa, Stavros J Baloyannis
Alzheimer's disease (AD) is a progressive neurodegenerative disease that involves numerous cellular and biochemical mechanisms resulting in synaptic alterations and extensive neuronal loss. It is primarily characterized by impairment of memory, associated frequently with mood disorders. Continuous studies have shown that insula may be an important target of AD, but neuropathological alterations have not been described extensively. In the present study, we attempted to describe the morphometric and morphological changes of the spines of Reil insula in AD in comparison with normal aging using a silver impregnation technique...
January 1, 2017: American Journal of Alzheimer's Disease and Other Dementias
https://www.readbyqxmd.com/read/28428882/differential-phenotypes-of-memory-cd4-and-cd8-t-cells-in-the-spleen-and-peripheral-tissues-following-immunostimulatory-therapy
#18
Gail D Sckisel, Annie Mirsoian, Christine M Minnar, Marka Crittenden, Brendan Curti, Jane Q Chen, Bruce R Blazar, Alexander D Borowsky, Arta M Monjazeb, William J Murphy
BACKGROUND: Studies assessing immune parameters typically utilize human PBMCs or murine splenocytes to generate data that is interpreted as representative of immune status. Using splenocytes, we have shown memory CD4-T cells that expand following systemic immunostimulatory therapies undergo rapid IFNg-mediated activation induced cell death (AICD) resulting in a net loss of total CD4-T cells which correlates with elevated PD-1 expression. This is in contrast to CD8-T cells which expand with minimal PD-1 upregulation and apoptosis...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28428879/a-systems-biology-approach-to-investigating-the-influence-of-exercise-and-fitness-on-the-composition-of-leukocytes-in-peripheral-blood
#19
Michael P Gustafson, Ara Celi DiCostanzo, Courtney M Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A Gastineau, Bruce D Johnson, Allan B Dietz
BACKGROUND: Exercise immunology has become a growing field in the past 20 years, with an emphasis on understanding how different forms of exercise affect immune function. Mechanistic studies are beginning to shed light on how exercise may impair the development of cancer or be used to augment cancer treatment. The beneficial effects of exercise on the immune system may be exploited to improve patient responses to cancer immunotherapy. METHODS: We investigated the effects of acute exercise on the composition of peripheral blood leukocytes over time in a male population of varying fitness...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28428787/a-possible-role-for-idiotype-anti-idiotype-b-t-cell-interactions-in-maintaining-immune-memory
#20
Victor I Seledtsov, Galina V Seledtsova
Variable regions of both B-cell receptors (BCRs) and T-cell receptors (TCRs) are completely formed in the postnatal period, and, consequently, no innate immune tolerance against these structures exists in adulthood. Indeed, antibodies (Abs) specific to TCRs have been found in both animals and humans. These facts clearly indicate the existence of B cells able to directly interact with T cells through binding of BCRs to TCRs without implicating major histocompatibility complex molecules. A novel paradigm is proposed in that the immune memory is based on idiotype/anti-idiotype interactions occurring between BCRs and TCRs following clearance of the antigen that elicited immune responses...
2017: Frontiers in Immunology
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