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TCR signalling

Elisabeth Salzer, Deniz Cagdas, Miroslav Hons, Emily M Mace, Wojciech Garncarz, Özlem Yüce Petronczki, René Platzer, Laurène Pfajfer, Ivan Bilic, Sol A Ban, Katharina L Willmann, Malini Mukherjee, Verena Supper, Hsiang Ting Hsu, Pinaki P Banerjee, Papiya Sinha, Fabienne McClanahan, Gerhard J Zlabinger, Winfried F Pickl, John G Gribben, Hannes Stockinger, Keiryn L Bennett, Johannes B Huppa, Loïc Dupré, Özden Sanal, Ulrich Jäger, Michael Sixt, Ilhan Tezcan, Jordan S Orange, Kaan Boztug
RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1...
October 24, 2016: Nature Immunology
Michael S Zhang, Jon C D Houtman
Glycerol monolaurate (GML) is a monoglyceride with well characterized anti-microbial properties. Because of these properties, GML is widely used in food, cosmetics, and personal care products and currently being tested as a therapeutic for menstrual associated toxic shock syndrome, superficial wound infections, and HIV transmission. Recently, we have described that GML potently suppresses select T cell receptor (TCR)-induced signaling events, leading to reduced human T cell effector functions. However, how soluble host factors present in the blood and at sites of infection affect GML-mediated human T cell suppression is unknown...
2016: PloS One
Guoping Fu, Mei Yu, Yuhong Chen, Yongwei Zheng, Wen Zhu, Debra K Newman, Demin Wang, Renren Wen
Pre-T cell receptor (TCR) signaling is required for pre-T cell survival, proliferation, and differentiation from the CD4 and CD8 double negative (DN) to the double positive (DP) stage. However, the pre-TCR signal transduction pathway is not fully understood and the signaling molecules involved have not been completely identified. Phospholipase Cγ (PLCγ) 1 is an important signaling molecule that generates two second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, that are important to mediate PKC activation and intracellular Ca(2+) flux in many signaling pathways...
October 19, 2016: European Journal of Immunology
Eun-Kyung Kwon, Chan-Ki Min, Yuri Kim, Jae-Won Lee, Abdimadiyeva Aigerim, Sebastian Schmidt, Hyun-Jun Nam, Seong Kyu Han, Kuglae Kim, Jeong Seok Cha, Hoyoung Kim, Sanguk Kim, Hyun-Soo Cho, Myung-Sik Choi, Nam-Hyuk Cho
Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown...
October 15, 2016: Biochimica et Biophysica Acta
Lorenza Rattazzi, Giuseppa Piras, Samuel Brod, Koval Smith, Masahiro Ono, Fulvio D'Acquisto
T cells are known to be plastic and to change their phenotype according to the cellular and biochemical milieu they are embedded in. In this study, we transposed this concept at a macroscopic level assessing whether changes in the environmental housing conditions of C57/BL6 mice would influence the phenotype and function of T cells. Our study shows that exposure to 2 weeks in an enriched environment (EE) does not impact the T cell repertoire in vivo and causes no changes in the early TCR-driven activation events of these cells...
2016: Frontiers in Immunology
Tiantian Luo, Jing Hu, Dan Xi, Haowei Xiong, Wenshuai He, Jichen Liu, Menghao Li, Hao Lu, Jinzhen Zhao, Wenyan Lai, Zhigang Guo
Previously, we reported that heat shock protein (HSP)65 impairs the effects of high-density lipoprotein on macrophages. We also showed that immune response activation adversely affects reverse cholesterol transport (RCT). In this study, we investigated the effects of the Src family kinase lymphocyte-specific protein tyrosine kinase (Lck) and elucidated the mechanism underlying HSP65-regulated cholesterol efflux in T cells. We evaluated cell proliferation, Lck expression, and inflammatory cytokine production in Jurkat cells and CD4(+) T cells...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Alexander Puck, Stefan Hopf, Madhura Modak, Otto Majdic, Petra Cejka, Stephan Blüml, Klaus Schmetterer, Catharina Arnold-Schrauf, Jens G Gerwien, Klaus S Frederiksen, Elisabeth Thell, Judith Leitner, Peter Steinberger, Regina Aigner, Maria Seyerl-Jiresch, Gerhard J Zlabinger, Johannes Stöckl
The cytoplasmic tail of CD45 (ct-CD45) is proteolytically cleaved and released upon activation of human phagocytes. It acts on T cells as an inhibitory, cytokine-like factor in vitro. Here we show, that ct-CD45 is abundant in human peripheral blood plasma from healthy adults compared with plasma derived from umbilical cord blood and plasma from patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Plasma depleted of ct-CD45 enhanced T-cell proliferation, while addition of exogenous ct-CD45 protein inhibited proliferation and reduced cytokine production of human T lymphocytes in response to TCR signaling...
October 8, 2016: European Journal of Immunology
Stephanie Gras, Jesseka Chadderton, Claudia M Del Campo, Carine Farenc, Florian Wiede, Tracy M Josephs, Xavier Y X Sng, Michiko Mirams, Katherine A Watson, Tony Tiganis, Kylie M Quinn, Jamie Rossjohn, Nicole L La Gruta
The anti-viral T cell response is drawn from the naive T cell repertoire. During influenza infection, the CD8(+) T cell response to an H-2D(b)-restricted nucleoprotein epitope (NP366) is characterized by preferential expansion of T cells bearing TRBV13(+) T cell receptors (TCRs) and avoidance of TRBV17(+) T cells, despite the latter dominating the naive precursor repertoire. We found two TRBV17(+) TCRs that bound H-2D(b)-NP366 with a 180° reversed polarity compared to the canonical TCR-pMHC-I docking...
September 24, 2016: Immunity
Melissa Frick, Pierre Mouchacca, Grégory Verdeil, Yannick Hamon, Cyrille Billaudeau, Michel Buferne, Mathieu Fallet, Nathalie Auphan-Anezin, Anne-Marie Schmitt-Verhulst, Claude Boyer
Cancer-germline genes in both human and mice have been shown to encode antigens susceptible to targeting by cytotoxic CD8 T effector cells (CTL). We analyzed the ability of CTL to kill different tumor cell lines expressing the same cancer-germline gene P1A (Trap1a). We previously demonstrated that CTL expressing a TCR specific for the P1A35-43 peptide associated with H-2L(d) , although able to induce regression of P1A-expressing P815 mastocytoma cells, were much less effective against P1A-expressing melanoma cells...
October 7, 2016: Immunology
Nicholas R J Gascoigne, Vasily Rybakin, Oreste Acuto, Joanna Brzostek
Thymocyte selection involves the positive and negative selection of the repertoire of T cell receptors (TCRs) such that the organism does not suffer autoimmunity, yet has the benefit of the ability to recognize any invading pathogen. The signal transduced through the TCR is translated into a number of different signaling cascades that result in transcription factor activity in the nucleus and changes to the cytoskeleton and motility. Negative selection involves inducing apoptosis in thymocytes that express strongly self-reactive TCRs, whereas positive selection must induce survival and differentiation programs in cells that are more weakly self-reactive...
October 6, 2016: Annual Review of Cell and Developmental Biology
Anmol Chandele, Jaturong Sewatanon, Sivaram Gunisetty, Mohit Singla, Nattawat Onlamoon, Rama S Akondy, Haydn Thomas Kissick, Kaustuv Nayak, Elluri Seetharami Reddy, Haroon Kalam, Dhiraj Kumar, Anil Verma, HareKrushna Panda, Siyu Wang, Nasikarn Angkasekwinai, Kovit Pattanapanyasat, Kulkanya Chokephaibulkit, Guruprasad R Medigeshi, Rakesh Lodha, Sushil Kabra, Rafi Ahmed, Kaja Murali-Krishna
: Epidemiological studies suggest that India has the largest number of dengue virus infected cases world-wide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue because they have been implicated in both protection and immunopathology. Here we provide a detailed analysis of HLA-DR(+)CD38(+) and HLA-DR(-)CD38(+) effector CD8 T- cell subsets in dengue-patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation; tissue-homing and cytotoxic effector functions with the HLA-DR(+)CD38(+) subset being the most striking in these effector qualities...
October 5, 2016: Journal of Virology
Melanie R Hassler, Walter Pulverer, Ranjani Lakshminarasimhan, Elisa Redl, Julia Hacker, Gavin D Garland, Olaf Merkel, Ana-Iris Schiefer, Ingrid Simonitsch-Klupp, Lukas Kenner, Daniel J Weisenberger, Andreas Weinhaeusel, Suzanne D Turner, Gerda Egger
Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK-) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK- ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters...
October 4, 2016: Cell Reports
Preeti Sharma, David M Kranz
Adoptive T-cell therapies have shown exceptional promise in the treatment of cancer, especially B-cell malignancies. Two distinct strategies have been used to redirect the activity of ex vivo engineered T cells. In one case, the well-known ability of the T-cell receptor (TCR) to recognize a specific peptide bound to a major histocompatibility complex molecule has been exploited by introducing a TCR against a cancer-associated peptide/human leukocyte antigen complex. In the other strategy, synthetic constructs called chimeric antigen receptors (CARs) that contain antibody variable domains (single-chain fragments variable) and signaling domains have been introduced into T cells...
2016: F1000Research
Julien Leconte, Sahar Bagherzadeh Yazdchi, Vincent Panneton, Woong-Kyung Suh
The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses...
September 29, 2016: Molecular Immunology
E Bustos-Morán, N Blas-Rus, N B Martín-Cófreces, F Sánchez-Madrid
The immune synapse (IS) is a specialized structure established between different immune cells that fulfills several functions, including a role as a communication bridge. This intimate contact between a T cell and an antigen-presenting cell promotes the proliferation and differentiation of lymphocytes involved in the contact. T-cell activation requires the specific triggering of the T-cell receptor (TCR), which promotes the activation of different signaling pathways inducing the polarization of the T cell. During this process, different adhesion and signaling receptors reorganize at specialized membrane domains, concomitantly to the polarization of the tubulin and actin cytoskeletons, forming stable polarization platforms...
2016: International Review of Cell and Molecular Biology
Heleen H Van Acker, Sébastien Anguille, Yannick Willemen, Johan M Van den Bergh, Zwi N Berneman, Eva Lion, Evelien L Smits, Viggo F Van Tendeloo
BACKGROUND: Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting...
September 29, 2016: Journal of Hematology & Oncology
John P Dowling, Yubo Cai, John Bertin, Peter J Gough, Jianke Zhang
The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses...
2016: Cell Death & Disease
Elliott J Brea, Claire Y Oh, Eusebio Manchado, Sadna Budhu, Ron S Gejman, George Mo, Patrizia Mondello, James E Han, Casey A Jarvis, David Ulmert, Qing Xiang, Aaron Y Chang, Ralph J Garippa, Taha Merghoub, Jedd D Wolchok, Neal Rosen, Scott W Lowe, David A Scheinberg
The major histocompatibility complex I (MHC-I) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped...
September 28, 2016: Cancer Immunology Research
Eri Ishikawa, Hidetaka Kosako, Tomoharu Yasuda, Masaki Ohmuraya, Kimi Araki, Tomohiro Kurosaki, Takashi Saito, Sho Yamasaki
Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected...
2016: Nature Communications
Motoko Y Kimura, Julien Thomas, Xuguang Tai, Terry I Guinter, Miho Shinzawa, Ruth Etzensperger, Zhenhu Li, Paul Love, Toshinori Nakayama, Alfred Singer
Major histocompatibility complex class I (MHC I) positive selection of CD8(+) T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8(+) thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8(+) T cells...
September 26, 2016: Nature Immunology
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