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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 14, 2016: Biochimica et Biophysica Acta
Pravin Kesarwani, Paramita Chakraborty, Radhika Gudi, Shilpak Chatterjee, Gina Scurti, Kyle Toth, Patt Simms, Mahvash Husain, Kent Armeson, Shahid Husain, Elizabeth Garrett-Mayer, Chethamarakshan Vasu, Michael I Nishimura, Shikhar Mehrotra
Advancements in adoptive cell transfer therapy (ACT) has led to the use of T cells engineered with tumor specific T cell receptors, which after rapid expansion can be obtained in sufficient numbers for treating patients. However, due to massive proliferation these cells are close to replicative senescence, exhibit exhausted phenotype, and also display increased susceptibility to activation induced cell death. We have previously shown that tumor reactive T cells undergo caspase-independent cell death upon TCR restimulation with cognate antigen, which involves reactive oxygen species and c-jun N-terminal kinase...
October 14, 2016: Oncotarget
Alexander U Brandt, Elena Meinert-Bohn, Jan Leo Rinnenthal, Hanna Zimmermann, Janine Mikolajczak, Timm Oberwahrenbrock, Sebastian Papazoglou, Caspar F Pfüller, Johann Schinzel, Björn Tackenberg, Friedemann Paul, Katrin Hahn, Judith Bellmann-Strobl
BACKGROUND: The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. METHODS: Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study...
2016: PloS One
Mathew Clement, James A Pearson, Stephanie Gras, Hugo A van den Berg, Anya Lissina, Sian Llewellyn-Lacey, Mark D Willis, Tamsin Dockree, James E McLaren, Julia Ekeruche-Makinde, Emma Gostick, Neil P Robertson, Jamie Rossjohn, Scott R Burrows, David A Price, F Susan Wong, Mark Peakman, Ania Skowera, Linda Wooldridge
CD8(+) T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8(+) T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8(+) T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8(+) T-cells are relatively CD8-independent...
October 17, 2016: Scientific Reports
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
Melissa Dullaers, Martijn J Schuijs, Monique Willart, Kaat Fierens, Justine Van Moorleghem, Hamida Hammad, Bart N Lambrecht
BACKGROUND: Allergic asthma is a CD4 Th2-lymphocyte driven disease characterized by airway hyper-responsiveness and eosinophilia. B cells can present antigens to CD4 T cells and produce IgE immunoglobulins which arms effector cells, however mouse models are inconclusive whether B cells are necessary for asthma development. OBJECTIVES: To address the role of B cells in a house dust mite (HDM) driven Th2-high asthma mouse model. METHODS: WT and B cell deficient muMT Mice were sensitized and challenged via the airways with HDM extracts...
October 13, 2016: Journal of Allergy and Clinical Immunology
Xiaofang Cao, Qingbiao Wa, Qidi Wang, Lin Li, Xin Liu, Lisha An, Ruikun Cai, Meng Du, Yue Qiu, Jian Han, Chunlin Wang, Xingyu Wang, Changlong Guo, Yonghong Lu, Xu Ma
Psoriasis is a T cell-mediated chronic inflammatory skin disease with inflammatory cell infiltrates in the dermis and epidermis. Previous studies suggested that there are some expanded T-cell receptor (TCR) clones in psoriatic skin. However, the effect of psoriasis on the immunological characteristics of TCR in circulating blood has not been reported. To address this, we performed high-throughput sequencing to reveal the immunological characteristics of TCR beta chain (TRB) in both psoriasis patients and healthy controls...
October 12, 2016: International Immunopharmacology
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
Matthew J Scheffel, Gina Scurti, Patricia Simms, Elizabeth Garrett-Mayer, Shikhar Mehrotra, Michael I Nishimura, Christina Voelkel-Johnson
Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T-cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53...
October 15, 2016: Cancer Research
Guojun Zhang, Mingkai Xu, Huiwen Zhang, Yubo Song, Jian Wang, Chenggang Zhang
Staphylococcal enterotoxin C2 (SEC2), a member of bacterial superantigen, is one of the most potent known activators of T lymphocytes. With this property, SEC2 has already been used in clinic as a tumor immunotherapy agent in China. To increase the antitumor activity, a SEC2 mutant named ST-4 (GKVTG102-106WWH) with amino acid substitutions in T cell receptor (TCR)-binding domain was generated by site-directed mutagenesis, and the molecular mechanism of the enhanced antitumor activity was investigated. Results showed that ST-4 could activate much more Vβ 8...
October 11, 2016: Toxicology and Applied Pharmacology
Siri Tähtinen, Carolin Blattner, Markus Vähä-Koskela, Dipongkor Saha, Mikko Siurala, Suvi Parviainen, Jochen Utikal, Anna Kanerva, Viktor Umansky, Akseli Hemminki
The immunosuppressive microenvironment of solid tumors renders adoptively transferred T cells hypofunctional. However, adenoviral delivery of immunostimulatory cytokines IL2 and TNFα can significantly improve the efficacy of adoptive T-cell therapy. Using ret transgenic mice that spontaneously develop skin malignant melanoma, we analyzed the mechanism of action of adenoviruses coding for IL2 and TNFα in combination with adoptive transfer of TCR-transgenic TRP-2-specific T cells. Following T-cell therapy and intratumoral virus injection, a significant increase in antigen-experienced, tumor-reactive PD-1 CD8 T cells was seen in both cutaneous lesions and in metastatic lymph nodes...
November 2016: Journal of Immunotherapy
William J Liu, Shuguang Tan, Min Zhao, Chuansong Quan, Yuhai Bi, Ying Wu, Shuijun Zhang, Haifeng Zhang, Haixia Xiao, Jianxun Qi, Jinghua Yan, Wenjun Liu, Hongjie Yu, Yuelong Shu, Guizhen Wu, George F Gao
BACKGROUND:  The emergence of infections by the novel avian influenza A (H7N9) virus has posed a threat to human health. Cross-immunity between H7N9 and other heterosubtypic influenza viruses affected by antigenicity-dependent substitutions needs to be investigated. METHODS:  We investigated the cellular and humoral immune responses against H7N9 and the 2009 pandemic H1N1 influenza viruses, by serological and T-cell-specific assays in a healthy population. The molecular bases of the cellular and humoral antigenic variability of H7N9 were illuminated by structural determination...
October 12, 2016: Journal of Infectious Diseases
Hao Zhang, Hong-Sheng Lim, Berhard Knapp, Charlotte M Deane, Milos Aleksic, Omer Dushek, P Anton van der Merwe
The interaction between the T cell antigen receptor (TCR) and antigenic peptide in complex with major histocompatibility complex (MHC) molecules is a crucial step in T cell activation. The relative contributions of TCR:peptide and TCR:MHC contacts to the overall binding energy remain unclear. This has important implications for our understanding of T cell development and function. In this study we used site directed mutagenesis to estimate the contribution of HLA-A2 side-chains to the binding of four TCRs. Our results show that these TCRs have very different energetic 'footprints' on HLA-A2, with no residues contributing to all TCR interactions...
October 13, 2016: Scientific Reports
Dane M Newman, Anne K Voss, Tim Thomas, Rhys S Allan
Histone acetylation has an important role in gene regulation, DNA replication, and repair. Because these processes are central to the development of the immune system, we investigated the role of a previously unstudied histone acetyltransferase named KAT7 (also known as Myst2 or HBO1) in the regulation of thymopoiesis and observed a critical role in the regulation of conventional and innate-like T cell development. We found that KAT7-deficient thymocytes displayed normal, positive selection and development into mature single-positive αβ thymocytes; however, we observed few peripheral CD4(+) or CD8(+) T cells...
October 12, 2016: Journal of Leukocyte Biology
Yen Leong Chua, Ka Hang Liong, Chiung-Hui Huang, Hok Sum Wong, Qian Zhou, Say Siong Ler, Yafang Tang, Chin Pei Low, Hui Yu Koh, I-Chun Kuo, Yongliang Zhang, W S Fred Wong, Hong Yong Peh, Hwee Ying Lim, Moyar Qing Ge, Angela Haczku, Veronique Angeli, Paul A MacAry, Kaw Yan Chua, David M Kemeny
Previous studies have highlighted the importance of lung-draining lymph nodes in the respiratory allergic immune response, whereas the lung parenchymal immune system has been largely neglected. We describe a new in vivo model of respiratory sensitization to Blomia tropicalis, the principal asthma allergen in the tropics, in which the immune response is focused on the lung parenchyma by transfer of Th2 cells from a novel TCR transgenic mouse, specific for the major B. tropicalis allergen Blo t 5, that targets the lung rather than the draining lymph nodes...
October 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Béatrice Breart, Philippe Bousso
T cells are sequestered for several days in lymph nodes following antigen recognition but the precise mechanism regulating their timing of egress is not fully understood. In particular, whether interactions with antigen-presenting cells (APCs) and/or strength of the TCR stimulation shape T-cell residence time is unclear. We report here that the probability of T-cell egress decreases upon stimulation with high affinity TCR ligands. In contrast, low affinity peptides favor early egress, a phenomenon that could be reversed by sustaining antigen availability...
October 11, 2016: European Journal of Immunology
Colleen M Kiernan, Martin A Whiteside, Carmen C Solorzano
BACKGROUND: Cancer registries are used to report cancer care trends and outcomes. Information from these data sets is utilized to craft practice guidelines and management recommendations. Limited knowledge is available regarding the quality of the data contained within registries. We sought to determine the accuracy of a single variable, 'surgery of the primary site', in the Tennessee Cancer Registry (TCR). METHODS: A retrospective review of the TCR thyroid database was performed...
October 11, 2016: Annals of Surgical Oncology
Elisabetta Volpe, Manolo Sambucci, Luca Battistini, Giovanna Borsellino
Fas and Fas Ligand (FasL) are two molecules involved in the regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor (TCR) genes and of those that recognize self-antigens, a process called negative selection; moreover, Fas-FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens...
2016: Frontiers in Immunology
Kazutaka Kitaura, Tadasu Shini, Takaji Matsutani, Ryuji Suzuki
BACKGROUND: High-throughput sequencing of T cell receptor (TCR) genes is a powerful tool for analyses of antigen specificity, clonality and diversity of T lymphocytes. Here, we developed a new TCR repertoire analysis method using 454 DNA sequencing technology in combination with an adaptor-ligation mediated polymerase chain reaction (PCR). This method allows the amplification of all TCR genes without PCR bias. To compare gene usage, diversity and similarity of expressed TCR repertoires among individuals, we conducted next-generation sequencing (NGS) of TRA and TRB genes in peripheral blood mononuclear cells from 20 healthy human individuals...
October 11, 2016: BMC Immunology
(no author information available yet)
Our back cover features an immunofluorescence staining for TCR Vα7.2 on both the surface and the cytoplasm of the T lymphocytes (red) in human tonsil. The image is taken from article by Wang et al. (pp. 2409-2419), in which the authors show that Vα7.2(+) mucosa- associated invariant T (MAIT) cells are numerically and functionally altered in peripheral blood (PB) of primary Sjögren's syndrome (pSS) patients. The reduction of MAIT cells in PB might be partially due to migration into the target tissue, as supported by MAIT cells detected in the salivary gland tissue from pSS patients, but not in controls...
October 2016: European Journal of Immunology
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