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tcr zeta

Yasuhiro Shimojima, Masayuki Matsuda, Wataru Ishii, Dai Kishida, Yoshiki Sekijima
The characteristics of T cell expression in peripheral blood have been previously described in dermatomyositis (DM) and polymyositis (PM); however, their intracellular signaling profiles remain unknown. The purpose of this study was to investigate the T-cell receptor (TCR)-mediated intracellular signaling in peripheral blood T cells in DM and PM. Peripheral blood T cells from 86 patients with DM (n = 57) and PM (n = 29) were used for experimental investigations. T-cell subtypes and TCR-induced phosphorylated zeta-chain-associated protein kinase 70 (pZAP70) were analyzed by flow cytometry...
December 2017: Autoimmunity
Liling Xu, Xu Liu, Hongjiang Liu, Lei Zhu, Huaqun Zhu, Jian Zhang, Limin Ren, Pingzhang Wang, Fanlei Hu, Yin Su
Hyperactivated B cells have been demonstrated the contribution to the development of rheumatoid arthritis (RA). While the recognition of the negative regulatory function of B cells further promoted our understanding of their pathogenic role in RA. Recently, a new population of granzyme B (GrB)-producing B cells was identified, which was proved to be involved in cancer and infectious diseases. However, their characteristics and roles in RA remain to be elucidated. In the present study, we aim to further characterize whether B cells could produce GrB and reveal their potential role in the pathogenesis of RA...
2017: Frontiers in Immunology
Xuequn Xu, Jin Qiu, Yi Sun
Chimeric antigen receptor T cells are T cells genetically engineered with CAR constructs which mainly contain scFV and TCR zeta chain. With promising development in blood cancers, CAR T trials are also applied in solid cancers. However, the treatment effect in solid cancers is lower than expected. This review summarizes difference of CAR T applications in solid and blood cancers. Future challenges of CAR T cell treatment in solid cancer are also discussed using ovarian cancer as an example.
July 3, 2017: Human Vaccines & Immunotherapeutics
John C Moore, Timothy S Mulligan, Nora Torres Yordán, Daniel Castranova, Van N Pham, Qin Tang, Riadh Lobbardi, Anthony Anselmo, Robert S Liwski, Jason N Berman, Ruslan I Sadreyev, Brant M Weinstein, David M Langenau
The zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) is required for T-cell activation. ZAP70 deficiencies in humans and null mutations in mice lead to severe combined immunodeficiency. Here, we describe a zap70 loss-of-function mutation in zebrafish (zap70(y442)) that was created using TALENs. In contrast to what has been reported in morphant zebrafish, zap70(y442) homozygous mutant zebrafish displayed normal development of blood and lymphatic vasculature. Hematopoietic cell development was also largely unaffected in mutant larvae...
September 6, 2016: Molecular and Cellular Biology
Hui Chen, Hongqin You, Lifang Wang, Xuan Zhang, Jianmin Zhang, Wei He
Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors...
September 16, 2016: Journal of Biological Chemistry
Kaitao Li, Xue Xiang, Jie Sun, Hai-Tao He, Jianhua Wu, Yingxiao Wang, Cheng Zhu
The zeta-chain-associated protein kinase 70 kDa (ZAP-70), a member of the spleen tyrosine kinase (Syk) family, plays an essential role in early T cell receptor (TCR) signaling. Defects in ZAP-70 lead to impaired thymocyte development and peripheral T cell activation. To better understand its activation dynamics and regulation, we visualized ZAP-70 activities in single live T cells with a Förster resonance energy transfer (FRET)-based biosensor, which was designed for probing kinase activities of the Syk family...
December 2016: Annals of Biomedical Engineering
Qing Ma, Haven R Garber, Sijie Lu, Hong He, Eran Tallis, Xiaoling Ding, Anna Sergeeva, Michael S Wood, Gianpietro Dotti, Barbara Salvado, Kathryn Ruisaard, Karen Clise-Dwyer, Lisa St John, Katayoun Rezvani, Gheath Alatrash, Elizabeth J Shpall, Jeffrey J Molldrem
BACKGROUND AIMS: The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a T-cell receptor (TCR)-like monoclonal antibody (8F4) that binds the PR1/HLA-A2 complex on the surface of AML cells, efficiently killing them in vitro and eliminating them in preclinical models. Humanized 8F4 (h8F4) with high affinity for the PR1/HLA-A2 epitope was used to construct an h8F4- chimeric antigen receptor (CAR) that was transduced into T cells to mediate anti-leukemia activity...
August 2016: Cytotherapy
Yinpu Yue, Wei Huang, Jingjing Liang, Jing Guo, Jian Ji, Yunliang Yao, Mingzhu Zheng, Zhijian Cai, Linrong Lu, Jianli Wang
Interleukin 4-induced gene-1 (IL4I1) was initially described as an early IL-4-inducible gene in B cells. IL4I1 protein can inhibit T cell proliferation by releasing its enzymatic catabolite, H2O2, and this effect is associated with transient down-regulation of T cell CD3 receptor-zeta (TCRζ) expression. Herein, we show that IL4I1 contributes to the regulation of macrophage programming. We found that expression of IL4I1 increased during bone marrow-derived macrophage (BMDM) differentiation, expression of IL4I1 is much higher in primary macrophages than monocytes, and IL4I1 expression in BMDMs could be induced by Th1 and Th2 cytokines in two different patterns...
2015: PloS One
Mariana Tomazini Pinto, Tathiane Maistro Malta, Evandra Strazza Rodrigues, Osvaldo Massaiti Takayanagui, Yuetsu Tanaka, Dimas Tadeu Covas, Simone Kashima
Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus related to the chronic neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4(+) T cells activation appears to play a key role on HTLV-1 infection. Here we investigated the expression of genes associated to T cell activation CD3e molecule, epsilon (CD3ɛ), lymphocyte-specific protein tyrosine kinase (LCK), vav 1 guanine nucleotide exchange factor (VAV1), and zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) on T lymphocytes of HTLV-1-infected individuals and compared to healthy uninfected individuals (CT)...
November 2015: Brazilian Journal of Infectious Diseases
Wei Lin, Yuanzhen Suo, Yuting Deng, Zhichao Fan, Yijie Zheng, Xunbin Wei, Yiwei Chu
BACKGROUND: The changes in T-cell morphology during immunological synapse (IS) formation are essential for T-cell activation. Previous researches have shown that T cell changed from spherical to elongated and/or flattened during in contact with B cell. As most powerful antigen presenting cell, dendritic cell (DC) has a strong ability to activate T cells. However, the morphological change of T cell which contacts DC and the relationship between morphological change and T-cell activation are not very clear...
2015: BMC Immunology
Vaishali R Moulton, Andrew R Gillooly, Marcel A Perl, Anastasia Markopoulou, George C Tsokos
T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3ζ chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3' untranslated region (UTR) of CD3ζ mRNA...
2015: PloS One
Christian Vettermann, Hannah P Victor, Yu Sun, Cherylene Plewa, Shalini Gupta
Activation of the inducible costimulator (ICOS) signaling pathway in T cells is difficult to assess with bioassays, because most T cell lines do not constitutively express ICOS. Additionally, engagement of ICOS by its natural ligand B7 related protein 1 (B7RP1) is insufficient to elicit ICOS signaling, but requires simultaneous costimulation of the T cell receptor (TCR) to be effective. Here we describe a genetically engineered human T cell line that expresses a chimeric receptor (ICOS-CD3) consisting of full-length human ICOS fused at its C-terminal end to the cytoplasmic domain of human CD3 zeta...
September 2015: Journal of Immunological Methods
Sophie Cadra, Alexia Gucciardi, Marie-Pierre Valignat, Olivier Theodoly, Aldo Vacaflores, Jon C D Houtman, Annemarie C Lellouch
Genetically encoded FRET based biosensors allow one to visualize the spatial and temporal evolution of specific enzyme activities in live cells. We have previously reported the creation of a FRET based biosensor specific for Zeta-Associated Protein -70 kD (ZAP-70) (Randriamampita et al., 2008), a Syk family protein tyrosine kinase. ZAP-70 is essential for early T cell receptor (TCR) signaling events, T lymphocyte development and has also been implicated in integrin mediated T lymphocyte migration. In order to facilitate the study of ZAP-70 kinase activity during dynamic phenomena such as immunological synapse formation or cell migration, we have designed and prepared a second generation of ZAP-70 specific biosensors...
April 10, 2015: Biochemical and Biophysical Research Communications
Daniel W Lee, James N Kochenderfer, Maryalice Stetler-Stevenson, Yongzhi K Cui, Cindy Delbrook, Steven A Feldman, Terry J Fry, Rimas Orentas, Marianna Sabatino, Nirali N Shah, Seth M Steinberg, Dave Stroncek, Nick Tschernia, Constance Yuan, Hua Zhang, Ling Zhang, Steven A Rosenberg, Alan S Wayne, Crystal L Mackall
BACKGROUND: Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells...
February 7, 2015: Lancet
Byron B Au-Yeung, Julie Zikherman, James L Mueller, Judith F Ashouri, Mehrdad Matloubian, Debra A Cheng, Yiling Chen, Kevan M Shokat, Arthur Weiss
T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently...
September 2, 2014: Proceedings of the National Academy of Sciences of the United States of America
Huseyin Tokgoz, Umran Caliskan, Sevgi Keles, Ismail Reisli, Isabel Sánchez Guiu, Neil V Morgan
BACKGROUND: CD3 chain expression defects including CD3 gamma, epsilon, delta, and zeta chain subunits, are autosomal recessive inherited severe combined immunodeficiencies (SCID). The phenotype is usually T-B+NK+ SCID with lymphopenia where the clinical findings may be mild (CD3γ) or severe (CD3δ, ε, ζ) owing to the underlying molecular defect. There is limited information about the disease in literature. METHODS: Here, we present two siblings from non-consanguineous family with autoimmunity including Evans syndrome, autoimmune hepatitis, nephrotic syndrome, and Hashimoto's thyroiditis and with no previous history of infections...
May 2013: Pediatric Allergy and Immunology
Ana E Rodríguez-Vicente, Marcos González Díaz, Jesús M Hernández-Rivas
The clinical heterogeneity that characterizes chronic lymphocytic leukemia (CLL), with survival times ranging from months to decades, reflects its biological diversity. Our understanding of the biology of CLL has helped us identify several markers of prognostic significance, by which CLL can be differentiated into several distinct diseases. The presence of specific chromosomal abnormalities is a prognostic indicator of disease progression and survival. Conventional cytogenetic analyses have revealed chromosomal aberrations in 40-50% of patients, but the detection of abnormalities is limited by the low mitotic activity of CLL cells...
March 2013: Cancer Genetics
Tsutomu Takeuchi, Katsuya Suzuki
SLE is associated with a deficiency in cluster of differentiation 247 (CD247, also known as CD3 zeta chain), a component of the T-cell receptor (TCR)-CD3 complex. A comprehensive analysis showed that in more than half of SLE patients tested CD247 expression was either attenuated or absent. Recent evidence suggests that these variations in expression profiles may be due, at least in part, to polymorphisms in the CD247 gene. Aberrant CD247 transcript variants displaying either spliced exon 7 or short 3'-untranslated region have been detected in SLE T cells, and a recent genome-wide association study reported the existence of new CD247 single-nucleotide polymorphisms in SLE patients...
September 2013: Rheumatology
Fu-Yu Chueh, Chao-Lan Yu
Signal transducer and activator of transcription (STAT) proteins are key signaling molecules in response to cytokines and in regulating T cell biology. However, there are contradicting reports on whether STAT is involved in T-cell antigen receptor (TCR) signaling. To better define the role of STAT in TCR signaling, we activated the CD4/CD8-associated Lck kinase by co-crosslinking TCR and CD4/CD8 co-receptors in human peripheral blood T cells. Sequential STAT1, STAT3 and STAT5 activation was observed 1 h after TCR stimulation suggesting that STAT proteins are not the immediate targets in the TCR complex...
September 21, 2012: Biochemical and Biophysical Research Communications
Chih-Jung Hsu, Wan-Ting Hsieh, Abraham Waldman, Fiona Clarke, Eric S Huseby, Janis K Burkhardt, Tobias Baumgart
T cell receptor (TCR) engagement induces clustering and recruitment to the plasma membrane of many signaling molecules, including the protein tyrosine kinase zeta-chain associated protein of 70 kDa (ZAP70) and the adaptor SH2 domain-containing leukocyte protein of 76 kDa (SLP76). This molecular rearrangement results in formation of the immunological synapse (IS), a dynamic protein array that modulates T cell activation. The current study investigates the effects of apparent long-range ligand mobility on T cell signaling activity and IS formation...
2012: PloS One
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