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https://www.readbyqxmd.com/read/28214044/enhancement-of-antigen-specific-cd4-and-cd8-t-cell-responses-using-a-self-assembled-biologic-nanolipoprotein-particle-vaccine
#1
Dina Weilhammer, Alexis D Dunkle, Craig D Blanchette, Nicholas O Fischer, Michele Corzett, Doerte Lehmann, Tyler Boone, Paul Hoeprich, Adam Driks, Amy Rasley
To address the need for vaccine platforms that induce robust cell-mediated immunity, we investigated the potential of utilizing self-assembling biologic nanolipoprotein particles (NLPs) as an antigen and adjuvant delivery system to induce antigen-specific murine T cell responses. We utilized OT-I and OT-II TCR-transgenic mice to investigate the effects of NLP-mediated delivery of the model antigen ovalbumin (OVA) on T cell activation. Delivery of OVA with the TLR4 agonist monophosphoryl lipid A (MPLA) in the context of NLPs significantly enhanced the activation of both CD4(+) and CD8(+) T cells in vitro compared to co-administration of free OVA and MPLA...
February 14, 2017: Vaccine
https://www.readbyqxmd.com/read/28213500/inducible-t-cell-kinase-regulates-the-acquisition-of-cytolytic-capacity-and-degranulation-in-cd8-ctls
#2
Senta M Kapnick, Jane C Stinchcombe, Gillian M Griffiths, Pamela L Schwartzberg
Patients with mutations in inducible T cell kinase (ITK) are susceptible to viral infections, particularly EBV, suggesting that these patients have defective function of CD8(+) CTLs. In this study, we evaluated the effects of ITK deficiency on cytolysis in murine CTLs deficient in ITK, and both human and murine cells treated with an ITK inhibitor. We find that ITK deficiency leads to a global defect in the cytolysis of multiple targets. The absence of ITK both affected CTL expansion and delayed the expression of cytolytic effectors during activation...
February 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28213366/tumor-infiltrating-and-peripheral-blood-t-cell-immunophenotypes-predict-early-relapse-in-localized-clear-cell-renal-cell-carcinoma
#3
Nicolas A Giraldo, Etienne Becht, Yann Vano, Florent Petitprez, Laetitia Lacroix, Pierre Validire, Rafael Sanchez-Salas, Alexandre Ingels, Stephane Marie Oudard, Audrey Moatti, Bénédicte Buttard, Sarah Bourras, Claire Germain, Xavier Cathelineau, Wolf-Herman Fridman, Catherine Sautes-Fridman
PURPOSE: The efficacy of PD-1 Checkpoint Blockade (ChB) as adjuvant therapy in localized clear cell Renal Cell Carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help to define which patients could benefit from ChB and to uncover new therapeutic targets. EXPERIMENTAL DESIGN: We performed multiparametric flow cytometry immunophenotypic analysis of T cells isolated from tumor tissue (TIL), adjacent non-malignant renal tissue (RIL) and peripheral blood (PBL), in a cohort of patients (n=40) with localized ccRCC...
February 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28211040/anti-cd3-treatment-upregulates-pd-1-expression-on-activated-effector-t-cells-and-severely-impairs-their-inflammatory-capacity
#4
Maja Wallberg, Asha Recino, Jenny Phillips, Duncan Howie, Margaux Vienne, Christopher Paluch, Miyuki Azuma, F Susan Wong, Herman Waldmann, Anne Cooke
T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the TCR complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)(+) islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time points during treatment to assess cell presence in various organs as well as gene expression and cytokine production...
February 17, 2017: Immunology
https://www.readbyqxmd.com/read/28208397/impact-of-lipid-rafts-on-the-t-cell-receptor-and-peptide-major-histocompatibility-complex-interactions-under-different-measurement-conditions
#5
Long Li, Guang-Kui Xu, Fan Song
The interactions between T-cell receptor (TCR) and peptide-major-histocompatibility complex (pMHC), which enable T-cell development and initiate adaptive immune responses, have been intensively studied. However, a central issue of how lipid rafts affect the TCR-pMHC interactions remains unclear. Here, by using a statistical-mechanical membrane model, we show that the binding affinity of TCR and pMHC anchored on two apposing cell membranes is significantly enhanced because of the lipid raft-induced signaling protein aggregation...
January 2017: Physical Review. E
https://www.readbyqxmd.com/read/28207945/cd4-cd25-garp-tregs-display-a-compromised-suppressive-function-in-patients-with-dilated-cardiomyopathy
#6
Yuzhen Wei, Kunwu Yu, Hui Wei, Xin Su, Ruirui Zhu, Huairui Shi, Haitao Sun, Quan Luo, Wenbin Xu, Junhui Xiao, Yucheng Zhong, Qiutang Zeng
Dilated cardiomyopathy (DCM) is a lethal inflammatory heart disease and closely connected with dysfunction of the immune system. Glycoprotein -A repetitions predominant (GARP) expressed on activated CD4(+) T cells with suppressive activity has been established. This study aimed to investigate the frequency and function of circulating CD4(+) CD25(+) GARP(+) regulatory T cells (Tregs) in DCM. 45 DCM patients and 46 controls were enrolled in this study. There was a significant increase in peripheral Th1 and Th17 number and their related cytokines (IFN-γ, IL-17), and an obvious decrease in Treg number, TGF-β1 levels and the expression of FOXP3 and GARP in patients with DCM as compared with controls...
February 16, 2017: Immunology
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
#7
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/28192730/inducible-turnover-of-optineurin-regulates-t-cell-activation
#8
Angela Montecalvo, Simon C Watkins, Jordan Orange, Lawrence P Kane
Optineurin (Optn) is an adaptor protein with homology to NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) complex. Dysregulation of Optn has been linked to neurodegenerative, autoimmune and bone diseases. Optn shares a high degree of homology with NEMO, but is not part of the same high-molecular weight complex containing IKKα and IKKβ. Despite its homology with NEMO and the fact that it has been the subject of extensive study in several cell types, there are no published studies addressing the role of Optn during T cell activation...
February 10, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28192189/mir-425-regulates-inflammatory-cytokine-production-in-cd4-t-cells-via-n-ras-upregulation-in-primary-biliary-cholangitis
#9
Ryo Nakagawa, Ryosuke Muroyama, Chisato Saeki, Kaku Goto, Yoshimi Kaise, Kazuhiko Koike, Masanori Nakano, Yasuo Matsubara, Keiko Takano, Sayaka Ito, Masayuki Saruta, Naoya Kato, Mikio Zeniya
BACKGROUND & AIM: Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. Because CD4(+) T cells play a pivotal role in immunological dysfunction observed in PBC, we analysed microRNA (miRNA) and mRNA expression in CD4(+) T cells to investigate PBC pathogenesis and identify novel therapeutic targets. METHODS: We performed integral miRNA and mRNA analysis of 14 PBC patients and 10 healthy controls using microarray and quantitative real time polymerase chain reaction (qRT-PCR) with gene set enrichment analysis...
February 9, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28188673/socs-potential-immune-checkpoint-molecules-for-cancer-immunotherapy
#10
REVIEW
Shunsuke Chikuma, Mitsuhiro Kanamori, Setsuko Mise-Omata, Akihiko Yoshimura
Inhibition of immune checkpoint molecules, PD-1 and CTLA4, has been shown to be a promising cancer treatment. PD-1 and CTLA4 inhibit TCR and co-stimulatory signals, respectively. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine Interferon-γ (IFNγ) plays an important role in anti-tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway...
February 11, 2017: Cancer Science
https://www.readbyqxmd.com/read/28188290/activated-cdc42-associated-kinase-1-ack1-binds-the-sam-domain-of-adaptor-slp-76-and-phosphorylates-proximal-tyrosines
#11
Youg R Thaker, Asha Recino, Monika Raab, Asma Jabeen, Maja Wallberg, Nelson Fernandez, Christopher E Rudd
The adaptor protein Src homology 2 domain-containing leukocyte phospho-protein of 76 kDa (SLP-76) plays a crucial role in T-cell activation by linking antigen receptor (TCR) signals to downstream pathways. At its N-terminus, SLP-76 has three key N-terminus tyrosines (Y113, Y128 and Y145, or 3Y) as well as a sterile-α motif (SAM) domain, whose function is unclear. We previously showed that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non receptor 2), as a novel binding partner of SLP-76...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28188172/t-cell-repertoires-in-refractory-coeliac-disease
#12
Julia Ritter, Karin Zimmermann, Korinna Jöhrens, Stefanie Mende, Anke Seegebarth, Britta Siegmund, Steffen Hennig, Kremena Todorova, Andreas Rosenwald, Severin Daum, Michael Hummel, Michael Schumann
OBJECTIVE: Refractory coeliac disease (RCD) is a potentially hazardous complication of coeliac disease (CD). In contrast to RCD type I, RCD type II is a precursor entity of enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), we aimed to establish the small-intestinal T-cell repertoire (TCR) in CD and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis...
February 10, 2017: Gut
https://www.readbyqxmd.com/read/28185879/ctla4-ig-effectively-controls-immune-activation-and-inflammatory-disease-in-a-novel-murine-model-of-leaky-scid
#13
Stéphanie Humblet-Baron, Susann Schönefeldt, Josselyn Garcia-Perez, Frédéric Baron, Emanuela Pasciuto, Adrian Liston
BACKGROUND: Severe combined immunodeficiency (SCID) can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as RAG1, RAG2 or DCLRE1C. Defective DNA recombination causes a developmental block in T cells and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give a partial loss of T cells, in a spectrum including leaky SCID (LS) and Omenn syndrome (OS). These patients not only develop life-threatening infections due to immunodeficiency, but also develop inflammatory/autoimmune conditions due to the presence of autoreactive T cells...
February 6, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28185789/type-i-interferons-modulate-cd8-t-cell-immunity-to-mrna-vaccines
#14
REVIEW
Ans De Beuckelaer, Johan Grooten, Stefaan De Koker
mRNA vaccines have emerged as potent tools to elicit antitumor T cell immunity. They are characterized by a strong induction of type I interferons (IFNs), potent inflammatory cytokines affecting T cell differentiation and survival. Recent reports have attributed opposing roles for type I IFNs in modulating CD8+ T cell immunity to mRNA vaccines, from profoundly stimulatory to strongly inhibitory. The mechanisms behind this duality are unclear. Disentangling the factors governing the beneficial or detrimental impact of type I IFNs on CD8+ T cell responses is vital to the design of mRNA vaccines of increased potency...
February 6, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28177966/high-number-of-activated-cd8-t-cells-targeting-hiv-antigens-are-present-in-cerebrospinal-fluid-in-acute-hiv-infection
#15
Cari F Kessing, Serena Spudich, Victor Valcour, Pearline Cartwright, Thep Chalermchai, James L K Fletcher, Carmen Nichols, Benjamin J Josey, Bonnie Slike, Shelly J Krebs, Napapon Sailsuta, Sukalaya Lerdlum, Linda Jagodzinski, Somporn Tipsuk, Duanghathai Suttichom, Somprartthana Rattanamanee, Henrik Zetterberg, Joanna Hellmuth, Nittaya Phanuphak, Merlin L Robb, Nelson L Michael, Jintanat Ananworanich, Lydie Trautmann
BACKGROUND: Central nervous system (CNS) infiltration by CD8+ T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8+ T cells in the CNS during acute HIV infection is unknown. METHODS: We analyzed the phenotype, gene expression, TCR repertoire and HIV-specificity of CD8+ T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of acute HIV infection (AHI) (n=26), chronic (n=23), and uninfected (n=8)...
February 7, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28166217/drugs-and-drug-like-molecules-can-modulate-the-function-of-mucosal-associated-invariant-t-cells
#16
Andrew N Keller, Sidonia B G Eckle, Weijun Xu, Ligong Liu, Victoria A Hughes, Jeffrey Y W Mak, Bronwyn S Meehan, Troi Pediongco, Richard W Birkinshaw, Zhenjun Chen, Huimeng Wang, Criselle D'Souza, Lars Kjer-Nielsen, Nicholas A Gherardin, Dale I Godfrey, Lyudmila Kostenko, Alexandra J Corbett, Anthony W Purcell, David P Fairlie, James McCluskey, Jamie Rossjohn
The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists...
February 6, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28163304/predominant-contribution-of-dgk%C3%AE-over-dgk%C3%AE-in-the-control-of-pkc-pdk-1-regulated-functions-in-t-cells
#17
A Ávila-Flores, J Arranz-Nicolás, E Andrada, D Soutar, I Mérida
Diacylglycerol kinase (DGK)-mediated consumption of the diacylglycerol (DAG) generated in response to antigen recognition is an important mechanism to limit T cell function. Targeting DGK activity presents new opportunities for therapeutic manipulation of the immune response, but assessment of individual DGK functions is complex. T cells express two DGK isoforms, DGKα and DGKζ, and there are no isoform-specific inhibitors. Here we used siRNA-mediated gene silencing in human T cells and DGKα- and DGKζ-deficient mice to define DGK isoform-specific regulation of key signaling pathways during T cell activation...
February 6, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28159903/cd31-a-valuable-marker-to-identify-early-and-late-stages-of-t-cell-differentiation-in-the-human-thymus
#18
Marc Douaisi, Rachel S Resop, Maho Nagasawa, Joshua Craft, Beth D Jamieson, Bianca Blom, Christel H Uittenbogaart
Although CD31 expression on human thymocytes has been reported, a detailed analysis of CD31 expression at various stages of T cell development in the human thymus is missing. In this study, we provide a global picture of the evolution of CD31 expression from the CD34(+) hematopoietic precursor to the CD45RA(+) mature CD4(+) and CD8(+) single-positive (SP) T cells. Using nine-color flow cytometry, we show that CD31 is highly expressed on CD34(+) progenitors and stays high until the early double-positive stage (CD3(-)CD4(+)CD8α(+)β(-))...
February 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28159902/il-2-modulates-the-tcr-signaling-threshold-for-cd8-but-not-cd4-t-cell-proliferation-on-a-single-cell-level
#19
Byron B Au-Yeung, Geoffrey Alexander Smith, James L Mueller, Cheryl S Heyn, Rebecca Garrett Jaszczak, Arthur Weiss, Julie Zikherman
Lymphocytes integrate Ag and cytokine receptor signals to make cell fate decisions. Using a specific reporter of TCR signaling that is insensitive to cytokine signaling, Nur77-eGFP, we identify a sharp, minimal threshold of cumulative TCR signaling required for proliferation in CD4 and CD8 T cells that is independent of both Ag concentration and affinity. Unexpectedly, IL-2 reduces this threshold in CD8 but not CD4 T cells, suggesting that integration of multiple mitogenic inputs may alter the minimal requirement for TCR signaling in CD8 T cells...
February 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28158203/silymarin-suppresses-basal-and-stimulus-induced-activation-exhaustion-differentiation-and-inflammatory-markers-in-primary-human-immune-cells
#20
Erica S Lovelace, Nicholas J Maurice, Hannah W Miller, Chloe K Slichter, Robert Harrington, Amalia Magaret, Martin Prlic, Stephen De Rosa, Stephen J Polyak
Silymarin (SM), and its flavonolignan components, alter cellular metabolism and inhibit inflammatory status in human liver and T cell lines. In this study, we hypothesized that SM suppresses both acute and chronic immune activation (CIA), including in the context of HIV infection. SM treatment suppressed the expression of T cell activation and exhaustion markers on CD4+ and CD8+ T cells from chronically-infected, HIV-positive subjects. SM also showed a trend towards modifying CD4+ T cell memory subsets from HIV+ subjects...
2017: PloS One
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