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https://www.readbyqxmd.com/read/28228595/hepatitis-c-virus-specific-t-cell-receptor-mrna-engineered-human-t-cells-impact-of-antigen-specificity-on-functional-properties
#1
Anangi Balasiddaiah, Haleh Davanian, Soo Aleman, Anna Pasetto, Lars Frelin, Matti Sällberg, Volker Lohmann, Sarene Koh, Antonio Bertoletti, Margaret Chen
Therapy with genetically modified autologous T cells has shown great promise in cancer therapy. For an efficient control of hepatitis C virus (HCV) infection, cytotoxic T cells (CTL) are pivotal but persistence of activated T cells may lead to liver toxicity. Here, anti-HCV T cell receptors (TCRs) recognising the HCV non-structural (NS) NS3 or NS5 viral peptide target were examined by mRNA transfection of human peripheral blood lymphocytes (PBL) derived from healthy donors as well as chronically infected HCV patients...
February 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28228556/activation-and-functional-specialization-of-regulatory-t-cells-lead-to-the-generation-of-foxp3-instability
#2
Zhongmei Zhang, Wei Zhang, Jie Guo, Qianchong Gu, Xueping Zhu, Xuyu Zhou
Accumulating evidence suggests that Foxp3(+) cells can downregulate the expression of Foxp3, but whether thymically derived regulatory T cells (tTregs; especially committed tTregs) are capable of downregulating Foxp3 expression and being reprogrammed into other T effector cells remains controversial. Using a novel tTreg lineage-tracing mouse line, we were able to label epigenetically stable Foxp3(+) cells derived from the thymus and demonstrate that mature tTregs are stable under homeostatic conditions. However, TCR engagement and sequential functional specialization of tTregs led to the generation of Foxp3 instability and reprogramming into the Th lineage...
February 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28227999/polysilicon-based-flexible-temperature-sensor-for-high-spatial-resolution-brain-temperature-monitoring
#3
Zhizhen Wu, Chunyan Li, Jed Hartings, Raj K Narayan, Chong Ahn, Zhizhen Wu, Chunyan Li, Jed Hartings, Raj K Narayan, Chong Ahn, Zhizhen Wu, Chunyan Li, Chong Ahn, Jed Hartings, Raj K Narayan
In this paper, we present a flexible temperature sensor with ultra-small polysilicon thermistors for brain temperature monitoring. In vitro sensitivity, resolution, thermal hysteresis and long term stability tests were performed. Temperature coefficient of resistance (TCR) of -0.0031/ °C and resolution of 0.1 °C were obtained for the sensor. Thermal hysteresis for temperature range of 30~45 °C was less than 0.1 °C. With silicon nitride as the passivation layer, the temperature sensor showed a drift within 0...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28213500/inducible-t-cell-kinase-regulates-the-acquisition-of-cytolytic-capacity-and-degranulation-in-cd8-ctls
#4
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/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/28202617/the-bacterial-peptidoglycan-sensing-molecules-nod1-and-nod2-promote-cd8-thymocyte-selection
#6
Marianne M Martinic, Irina Caminschi, Meredith O'Keeffe, Therese C Thinnes, Raelene Grumont, Steve Gerondakis, Dianne B McKay, David Nemazee, Amanda L Gavin
Nucleotide-binding and oligomerization domain (NOD)-like receptors NOD1 and NOD2 are cytosolic innate immune receptors that recognize microbial peptidoglycans. Although studies have addressed the role of NOD proteins in innate immune responses, little attention has been given to their impact on the developing adaptive immune system. We have assessed the roles of NOD1 and NOD2 deficiency on T cell development in mice. Our results demonstrate that NOD1 and NOD2 promote the positive selection/maturation of CD8 single-positive thymocytes in a thymocyte-intrinsic manner...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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/28193872/nf%C3%AE%C2%BAb-pim-1-eomesodermin-axis-is-critical-for-maintaining-cd8-t-cell-memory-quality
#8
Karin M Knudson, Curtis J Pritzl, Vikas Saxena, Amnon Altman, Mark A Daniels, Emma Teixeiro
T-cell memory is critical for long-term immunity. However, the factors involved in maintaining the persistence, function, and phenotype of the memory pool are undefined. Eomesodermin (Eomes) is required for the establishment of the memory pool. Here, we show that in T cells transitioning to memory, the expression of high levels of Eomes is not constitutive but rather requires a continuum of cell-intrinsic NFκB signaling. Failure to maintain NFκB signals after the peak of the response led to impaired Eomes expression and a defect in the maintenance of CD8 T-cell memory...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
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/28177966/high-number-of-activated-cd8-t-cells-targeting-hiv-antigens-are-present-in-cerebrospinal-fluid-in-acute-hiv-infection
#12
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/28163304/predominant-contribution-of-dgk%C3%AE-over-dgk%C3%AE-in-the-control-of-pkc-pdk-1-regulated-functions-in-t-cells
#13
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/28159902/il-2-modulates-the-tcr-signaling-threshold-for-cd8-but-not-cd4-t-cell-proliferation-on-a-single-cell-level
#14
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/28159798/destabilizing-the-autoinhibitory-conformation-of-zap70-induces-up-regulation-of-inhibitory-receptors-and-t-cell-unresponsiveness
#15
Lih-Yun Hsu, Debra A Cheng, Yiling Chen, Hong-Erh Liang, Arthur Weiss
Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-type T cell receptor (TCR) repertoires exhibited relatively normal T cell development. However, crossing the W131A mutant mice to OTII TCR transgenic mice resulted in increased negative selection of OTII(+) thymocytes and in increased thymic and peripheral T regulatory cells...
February 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28158245/protein-kinase-c-theta-is-required-for-efficient-induction-of-il-10-secreting-t-cells
#16
Graham J Britton, Ruth E Mitchell, Bronwen R Burton, David C Wraith
Secretion of interleukin-10 (IL-10) by CD4+ T cells is an essential immunoregulatory mechanism. The work presented here assesses the role of the signaling molecule protein kinase C theta (PKCθ) in the induction of IL-10 expression in CD4+ T cells. Using wildtype and PKCθ-deficient Tg4 T cell receptor transgenic mice, we implemented a well-described protocol of repeated doses of myelin basic protein (MBP)Ac1-9[4Y] antigen to induce Tr1-like IL-10+ T cells. We find that PKCθ is required for the efficient induction of IL-10 following antigen administration...
2017: PloS One
https://www.readbyqxmd.com/read/28154159/the-t-cell-ift20-interactome-reveals-new-players-in-immune-synapse-assembly
#17
Donatella Galgano, Anna Onnis, Elisa Pappalardo, Federico Galvagni, Oreste Acuto, Cosima T Baldari
Sustained signalling at the immune synapse (IS) requires the synaptic delivery of recycling endosome-associated TCRs. IFT20, a component of the intraflagellar transport system, controls TCR recycling to the IS as a complex with IFT57 and IFT88. Here, we used quantitative mass spectrometry to identify additional interaction partners of IFT20 in Jurkat T cells. In addition to IFT57 and IFT88, the analysis revealed new binding partners, including IFT54, GMAP-210, Arp2/3 complex subunit-3 (ARPC3), COP9 signalosome subunit-1 (CSN1), and ERGIC-53...
February 2, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28153342/calcium-nfat-transcriptional-signalling-in-t-cell-activation-and-t-cell-exhaustion
#18
REVIEW
Patrick G Hogan
A cornerstone of the adaptive immune response is the T cell receptor (TcR)-calcium-calcineurin signalling pathway leading to T cell activation. The 'nuclear factor of activated T cells' proteins NFAT1, NFAT2, and NFAT4 are transcription factors that promote expression of a panel of genes required for activation. It has become apparent that these same NFAT transcription factors underlie an alternative transcriptional program in T cells that serves to limit the immune response. This duality in NFAT transcriptional functions raises the possibility that NFAT transcriptional complexes could be targeted therapeutically to alter the relative strength of the effector and alternative transcriptional programs, thereby modulating immune responses...
January 28, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28137909/ndr1-dependent-regulation-of-kindlin-3-controls-high-affinity-lfa-1-binding-and-immune-synapse-organization
#19
Naoyuki Kondo, Yoshihiro Ueda, Toshiyuki Kita, Madoka Ozawa, Takashi Tomiyama, Kaneki Yasuda, Dae-Sik Lim, Tatsuo Kinashi
Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. Herein, LFA-1/ICAM-1 interactions were measured at the single-molecule level on supported lipid bilayers. High-affinity binding was detected at low frequencies in the inner peripheral supramolecular activation cluster (SMAC) zone that contained high levels of activated Rap1 and kindlin-3. Rap1 was essential for T cell attachment, whereas deficiencies of ste20-like kinases, Mst1/Mst2 diminished high-affinity binding, and abrogated central SMAC formation with mislocalized kindlin-3 and vesicle transport regulators involved in TCR recycling/releasing machineries, resulting in impaired T-APC interactions...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28126314/intravital-real-time-analysis-of-t-cell-activation-in-health-and-disease
#20
REVIEW
Dmitri Lodygin, Alexander Flügel
Antigenic activation is a central process in T-cell biology essential for efficient protection of the host from infections and tumors by the adaptive immune system. Furthermore, this process is of paramount importance for the initiation of autoimmunity. Many insights into the mechanisms of T-cell activation have been gained from real-time studies. The development of 2-photon microscopy transferred the focus of T cell activation to in vivo research and the analysis of the highly dynamic and complex T-cell response in the physiologic context of an animal model...
December 28, 2016: Cell Calcium
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