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https://www.readbyqxmd.com/read/28790065/gsk-3-inhibition-drives-maturation-of-nk-cells-and-enhances-their-antitumor-activity
#1
Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey K Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart E Abbot, Daniel Shoemaker, Yenan T Bryceson, Bruce R Blazar, Scott Wolchko, Sarah Cooley, Jeffrey S Miller
Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57(+) NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation...
August 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/28783670/low-cd21-expression-defines-a-population-of-recent-germinal-center-graduates-primed-for-plasma-cell-differentiation
#2
Denise Lau, Linda Yu-Ling Lan, Sarah F Andrews, Carole Henry, Karla Thatcher Rojas, Karlynn E Neu, Min Huang, Yunping Huang, Brandon DeKosky, Anna-Karin E Palm, Gregory C Ippolito, George Georgiou, Patrick C Wilson
In this study, we report that antigen-specific CD19(+)CD27(+)CD21(lo) (CD21(lo)) B cells are transiently induced 14 to 28 days after immunization, at the time germinal centers (GCs) peak. Although clonally related to memory B cells and plasmablasts, CD21(lo) cells form distinct clades within phylogenetic trees based on accumulated variable gene mutations, supporting exit from active GCs. CD21(lo) cells express a transcriptional program, suggesting that they are primed for plasma cell differentiation and are refractory to GC differentiation, although they do not spontaneously secrete antibody...
January 27, 2017: Science Immunology
https://www.readbyqxmd.com/read/28771465/ebv-epigenetically-suppresses-the-b-cell-to-plasma-cell-differentiation-pathway-while-establishing-long-term-latency
#3
Christine T Styles, Quentin Bazot, Gillian A Parker, Robert E White, Kostas Paschos, Martin J Allday
Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes...
August 2017: PLoS Biology
https://www.readbyqxmd.com/read/28751776/hobit-expression-by-a-subset-of-human-liver-resident-cd56-bright-natural-killer-cells
#4
Sebastian Lunemann, Gloria Martrus, Hanna Goebels, Tobias Kautz, Annika Langeneckert, Wilhelm Salzberger, Martina Koch, Madeleine J Bunders, Björn Nashan, Klaas P J M van Gisbergen, Marcus Altfeld
Immune responses show a high degree of tissue specificity shaped by factors influencing tissue egress and retention of immune cells. The transcription factor Hobit was recently shown to regulate tissue-residency in mice. Whether Hobit acts in a similar capacity in humans remains unknown. Our aim was to assess the expression and contribution of Hobit to tissue-residency of Natural Killer (NK) cells in the human liver. The human liver was enriched for CD56(bright) NK cells showing increased expression levels of the transcription factor Hobit...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28738016/eomesodermin-promotes-the-development-of-type-1-regulatory-t-tr1-cells
#5
Ping Zhang, Jason S Lee, Kate H Gartlan, Iona S Schuster, Iain Comerford, Antiopi Varelias, Md Ashik Ullah, Slavica Vuckovic, Motoko Koyama, Rachel D Kuns, Kelly R Locke, Kirrilee J Beckett, Stuart D Olver, Luke D Samson, Marcela Montes de Oca, Fabian de Labastida Rivera, Andrew D Clouston, Gabrielle T Belz, Bruce R Blazar, Kelli P MacDonald, Shaun R McColl, Ranjeny Thomas, Christian R Engwerda, Mariapia A Degli-Esposti, Axel Kallies, Siok-Keen Tey, Geoffrey R Hill
Type 1 regulatory T (TR1) cells are Foxp3(-) interleukin-10 (IL-10)-producing CD4(+) T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that TR1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for TR1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages...
April 7, 2017: Science Immunology
https://www.readbyqxmd.com/read/28732506/new-insights-into-blimp-1-in-t-lymphocytes-a-divergent-regulator-of-cell-destiny-and-effector-function
#6
REVIEW
Shin-Huei Fu, Li-Tzu Yeh, Chin-Chen Chu, B Lin-Ju Yen, Huey-Kang Sytwu
B lymphocyte-induced maturation protein-1 (Blimp-1) serves as a master regulator of the development and function of antibody-producing B cells. Given that its function in T lymphocytes has been identified within the past decade, we review recent findings with emphasis on its role in coordinated control of gene expression during the development, differentiation, and function of T cells. Expression of Blimp-1 is mainly confined to activated T cells and is essential for the production of interleukin (IL)-10 by a subset of forkhead box (Fox)p3(+) regulatory T cells with an effector phenotype...
July 21, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28713870/il-10-induces-a-stat3-dependent-autoregulatory-loop-in-th2-cells-that-promotes-blimp-1-restriction-of-cell-expansion-via-antagonism-of-stat5-target-genes
#7
Amanda C Poholek, Dragana Jankovic, Alejandro V Villarino, Franziska Petermann, Angela Hettinga, Dror S Shouval, Scott B Snapper, Susan M Kaech, Stephen R Brooks, Golnaz Vahedi, Alan Sher, Yuka Kanno, John J O'Shea
Blimp-1 expression in T cells extinguishes the fate of T follicular helper cells, drives terminal differentiation, and limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in T helper 2 (TH2) cells and the molecular basis of its actions. We report that signal transducer and activator of transcription 3 (STAT3) unexpectedly played a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3...
October 2016: Science Immunology
https://www.readbyqxmd.com/read/28698287/blimp-1-dependent-and-independent-natural-antibody-production-by-b-1-and-b-1-derived-plasma-cells
#8
Hannah P Savage, Vanessa M Yenson, Sanjam S Sawhney, Betty J Mousseau, Frances E Lund, Nicole Baumgarth
Natural antibodies contribute to tissue homeostasis and protect against infections. They are secreted constitutively without external antigenic stimulation. The differentiation state and regulatory pathways that enable continuous natural antibody production by B-1 cells, the main cellular source in mice, remain incompletely understood. Here we demonstrate that natural IgM-secreting B-1 cells in the spleen and bone marrow are heterogeneous, consisting of (a) terminally differentiated B-1-derived plasma cells expressing the transcriptional regulator of differentiation, Blimp-1, (b) Blimp-1(+), and (c) Blimp-1(neg) phenotypic B-1 cells...
July 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28692065/increased-cathepsin-s-in-prdm1-dendritic-cells-alters-the-tfh-cell-repertoire-and-contributes-to-lupus
#9
Sun Jung Kim, Sebastian Schätzle, S Sohail Ahmed, Wolfgang Haap, Su Hwa Jang, Peter K Gregersen, George Georgiou, Betty Diamond
Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules...
July 10, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28677680/ctcf-orchestrates-the-germinal-centre-transcriptional-program-and-prevents-premature-plasma-cell-differentiation
#10
Arantxa Pérez-García, Ester Marina-Zárate, Ángel F Álvarez-Prado, Jose M Ligos, Niels Galjart, Almudena R Ramiro
In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves a major transcriptional switch that promotes a halt in cell proliferation and the production of secreted immunoglobulins. Here we show that the CCCTC-binding factor (CTCF) is required for the GC reaction in vivo, whereas in vitro the requirement for CTCF is not universal and instead depends on the pathways used for B-cell activation...
July 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28664185/the-mir-125a-and-mir-320c-are-potential-tumor-suppressor-micrornas-epigenetically-silenced-by-the-polycomb-repressive-complex-2-in-multiple-myeloma
#11
Mohammad Alzrigat, Helena Jernberg-Wiklund
We have previously presented the histone methyltransferase enhancer of zeste homolog 2 (EZH2) of the polycomb repressive complex 2 (PRC2) as a potential therapeutic target in Multiple Myeloma (MM). In a recent article in Oncotarget by Alzrigat. et al. 2017, we have reported on the novel finding that EZH2 inhibition using the highly selective inhibitor of EZH2 enzymatic activity, UNC1999, reactivated the expression of microRNA genes previously reported to be underexpressed in MM. Among these, we have identified miR-125a-3p and miR-320c as potential tumor suppressor microRNAs as they were predicted to target MM-associated oncogenes; IRF-4, XBP-1 and BLIMP-1...
2017: RNA & Disease
https://www.readbyqxmd.com/read/28629373/blimp-1-impairs-t-cell-function-via-upregulation-of-tigit-and-pd-1-in-patients-with-acute-myeloid-leukemia
#12
Liuluan Zhu, Yaxian Kong, Jianhong Zhang, David F Claxton, W Christopher Ehmann, Witold B Rybka, Neil D Palmisiano, Ming Wang, Bei Jia, Michael Bayerl, Todd D Schell, Raymond J Hohl, Hui Zeng, Hong Zheng
BACKGROUND: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML...
June 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28604806/prostaglandin-e2-inhibits-tr1-cell-differentiation-through-suppression-of-c-maf
#13
Kirsten Mary Hooper, Weimin Kong, Doina Ganea
Prostaglandin E2 (PGE2), a major lipid mediator abundant at inflammatory sites, acts as a proinflammatory agent in models of inflammatory/autoimmune diseases by promoting CD4 Th1/Th17 differentiation. Regulatory T cells, including the IL-10 producing Tr1 cells counterbalance the proinflammatory activity of effector Th1/Th17 cells. Tr1 cell differentiation and function are induced by IL-27, and depend primarily on sustained expression of c-Maf in addition to AhR and Blimp-1. In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits IL-27-induced differentiation and IL-10 production of murine CD4+CD49b+LAG-3+Foxp3- Tr1 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28526759/il-2-high-tissue-resident-t-cells-in-the-human-liver-sentinels-for-hepatotropic-infection
#14
Laura J Pallett, Jessica Davies, Emily J Colbeck, Francis Robertson, Navjyot Hansi, Nicholas J W Easom, Alice R Burton, Kerstin A Stegmann, Anna Schurich, Leo Swadling, Upkar S Gill, Victoria Male, TuVinh Luong, Amir Gander, Brian R Davidson, Patrick T F Kennedy, Mala K Maini
The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)-infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-bet(lo)Eomes(lo)Blimp-1(hi)Hobit(lo) T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69(+)CD103(+) CXCR6(+)CXCR3(+))...
June 5, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28506291/targeting-cd22-with-the-monoclonal-antibody-epratuzumab-modulates-human-b-cell-maturation-and-cytokine-production-in-response-to-toll-like-receptor-7-tlr7-and-b-cell-receptor-bcr-signaling
#15
Natalia V Giltiay, Geraldine L Shu, Anthony Shock, Edward A Clark
BACKGROUND: Abnormal B-cell activation is implicated in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). The B-cell surface molecule CD22, which regulates activation through the B-cell receptor (BCR), is a potential target for inhibiting pathogenic B cells; however, the regulatory functions of CD22 remain poorly understood. In this study, we determined how targeting of CD22 with epratuzumab (Emab), a humanized anti-CD22 IgG1 monoclonal antibody, affects the activation of human B-cell subsets in response to Toll-like receptor 7 (TLR7) and BCR engagement...
May 15, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28474779/a-novel-in-vivo-model-for-studying-conditional-dual-loss-of-blimp-1-and-p53-in-b-cells-leading-to-tumor-transformation
#16
Antonio Sacco, Yawara Kawano, Michele Moschetta, Oksana Zavidij, Daisy Huynh, Michaela Reagan, Yuji Mishima, Salomon Manier, Jihye Park, Elizabeth Morgan, Satoshi Takagi, Kwok K Wong, Ruben Carrasco, Irene M Ghobrial, Aldo M Roccaro
The tumor suppressors B-lymphocyte-induced maturation protein-1 (BLIMP-1) and p53 play a crucial role in B-cell lymphomas, and their inactivation contributes to the pathogenesis of a wide spectrum of lymphoid malignancies, including diffuse large B-cell lymphomas (DLBCLs). Patients with activated B-cell-like (ABC) DLBCL may present with loss of BLIMP-1, c-Myc over-expression, decreased p53, and poor prognosis. Nevertheless, there is a lack of in vivo models recapitulating the biology of high-grade ABC DLBCL...
August 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28392788/the-transcription-factor-hobit-identifies-human-cytotoxic-cd4-t-cells
#17
Anna E Oja, Felipe A Vieira Braga, Ester B M Remmerswaal, Natasja A M Kragten, Kirsten M L Hertoghs, Jianmin Zuo, Paul A Moss, René A W van Lier, Klaas P J M van Gisbergen, Pleun Hombrink
The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4(+) T cells that conforms to the phenotype of cytotoxic CD8(+) T cells has received increased recognition. These cytotoxic CD4(+) T cells display constitutive expression of granzyme B and perforin at the protein level and mediate HLA class II-dependent killing of target cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28301039/bach2-regulates-aid-mediated-immunoglobulin-gene-conversion-and-somatic-hypermutation-in-dt40-b-cells
#18
Paulina M Budzyńska, Minna K Kyläniemi, Teemu Kallonen, Anni I Soikkeli, Kalle-Pekka Nera, Olli Lassila, Jukka Alinikula
The transcription factor Bach2 is required for germinal center formation, somatic hypermutation (SHM), and class-switch recombination (CSR) of immunoglobulins. SHM and CSR are initiated by activation-induced cytidine deaminase (AID) which has potential to induce human B cell lymphoma. To understand the role of Bach2 in AID-mediated immunoglobulin gene diversification processes, we established a BACH2-deficient DT40 B cell line. We show that in addition to allowing SHM, Bach2 drives immunoglobulin gene conversion (GCV), another AID-dependent antibody gene diversification process...
March 16, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28300844/il-27-triggers-il-10-production-in-th17-cells-via-a-c-maf-ror%C3%AE-t-blimp-1-signal-to-promote-the-progression-of-endometriosis
#19
Kai-Kai Chang, Li-Bing Liu, Li-Ping Jin, Bing Zhang, Jie Mei, Hui Li, Chun-Yan Wei, Wen-Jie Zhou, Xiao-Yong Zhu, Jun Shao, Da-Jin Li, Ming-Qing Li
Endometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10(+)Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28235675/il-15-stimulates-nkg2d-while-promoting-igm-expression-of-b-1a-cells
#20
Amlan Kanti Ghosh, Debolina Sinha, Ratna Biswas, Tapas Biswas
Interleukin (IL)-15, a key manipulator of T-cell function also modulates B-1a cell activity by augmenting activation markers, turning them towards type 1 polarization and immunoglobulin (Ig) expression which is significant in the context of gut immunity. Here we show, for the first time, IL-15 mediated up-regulation of the activation receptor NKG2D and its adaptor DAP10 in B-1a cells indicating their essential coupling with IL-15 receptor signaling pathway. Our results demonstrate IL-15 treatment increases phosphorylation of STAT5 and p38 leading to translocation of NF-κB onto the nucleus, an attribute that delineates activation of B-1a cells and its role in inflammation...
July 2017: Cytokine
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