Academic literature on the topic 'T Cell Transcription Factor 1'
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Journal articles on the topic "T Cell Transcription Factor 1"
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Marti, Francesc, Nicholas H. Post, Elena Chan, and Philip D. King. "A Transcription Function for the T Cell–Specific Adapter (Tsad) Protein in T Cells." Journal of Experimental Medicine 193, no. 12 (June 18, 2001): 1425–30. http://dx.doi.org/10.1084/jem.193.12.1425.
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T cell–specific adapter (TSAd) protein is an Src homology 2 (SH2) domain–containing adapter molecule implicated in T cell receptor for antigen (TCR)-mediated interleukin 2 (IL-2) secretion in T cells. Here, we demonstrate that a substantial fraction of TSAd is found in the T cell nucleus. Nuclear import of TSAd is an active process that depends on TSAd SH2 domain recognition of a phosphotyrosine-containing ligand. Importantly, we show that TSAd can act as a potent transcriptional activator in T cells. Furthermore, the TSAd SH2 domain appears to be essential for this transcription-activating function independent of its role in nuclear import. Biochemical analyses suggest that a single TSAd SH2 domain ligand of 95–100 kD may be involved in these processes. Consistent with a role as a transcription activator, cotransfection of TSAd with an IL-2 promoter–reporter gene construct results in a considerable upregulation of IL-2 promoter activity. Further, we show that this augmentation requires a functional TSAd SH2 domain. However, TSAd does not appear to modulate the activity of the major recognized IL-2 gene transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T cells (NFAT), or activator protein 1 (AP-1). These findings point to the function of TSAd as a novel transcription-regulatory protein in T cells and illustrate the importance of the TSAd SH2 domain in this role.
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Hokello, Joseph, Adhikarimayum Lakhikumar Sharma, and Mudit Tyagi. "Efficient Non-Epigenetic Activation of HIV Latency through the T-Cell Receptor Signalosome." Viruses 12, no. 8 (August 8, 2020): 868. http://dx.doi.org/10.3390/v12080868.
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Human immunodeficiency virus type-1 (HIV-1) can either undergo a lytic pathway to cause productive systemic infections or enter a latent state in which the integrated provirus remains transcriptionally silent for decades. The ability to latently infect T-cells enables HIV-1 to establish persistent infections in resting memory CD4+ T-lymphocytes which become reactivated following the disruption or cessation of intensive drug therapy. The maintenance of viral latency occurs through epigenetic and non-epigenetic mechanisms. Epigenetic mechanisms of HIV latency regulation involve the deacetylation and methylation of histone proteins within nucleosome 1 (nuc-1) at the viral long terminal repeats (LTR) such that the inhibition of histone deacetyltransferase and histone lysine methyltransferase activities, respectively, reactivates HIV from latency. Non-epigenetic mechanisms involve the nuclear restriction of critical cellular transcription factors such as nuclear factor-kappa beta (NF-κB) or nuclear factor of activated T-cells (NFAT) which activate transcription from the viral LTR, limiting the nuclear levels of the viral transcription transactivator protein Tat and its cellular co-factor positive transcription elongation factor b (P-TEFb), which together regulate HIV transcriptional elongation. In this article, we review how T-cell receptor (TCR) activation efficiently induces NF-κB, NFAT, and activator protein 1 (AP-1) transcription factors through multiple signal pathways and how these factors efficiently regulate HIV LTR transcription through the non-epigenetic mechanism. We further discuss how elongation factor P-TEFb, induced through an extracellular signal-regulated kinase (ERK)-dependent mechanism, regulates HIV transcriptional elongation before new Tat is synthesized and the role of AP-1 in the modulation of HIV transcriptional elongation through functional synergy with NF-κB. Furthermore, we discuss how TCR signaling induces critical post-translational modifications of the cyclin-dependent kinase 9 (CDK9) subunit of P-TEFb which enhances interactions between P-TEFb and the viral Tat protein and the resultant enhancement of HIV transcriptional elongation.
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Jabeen, Rukhsana, Hua-Chen Chang, Ritobrata Goswami, Stephen L. Nutt, and Mark H. Kaplan. "The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis." PLoS ONE 6, no. 7 (July 14, 2011): e22189. http://dx.doi.org/10.1371/journal.pone.0022189.
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Wang, C. Y., A. G. Bassuk, L. H. Boise, C. B. Thompson, R. Bravo, and J. M. Leiden. "Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors." Molecular and Cellular Biology 14, no. 2 (February 1994): 1153–59. http://dx.doi.org/10.1128/mcb.14.2.1153-1159.1994.
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The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene has been studied extensively as a model system of transcriptional induction during T-lymphocyte activation. The GM-CSF gene is not expressed in resting peripheral blood T cells but is rapidly induced at the transcriptional level following activation through the cell surface T-cell receptor. A highly conserved 19-bp element located immediately 5' of the human GM-CSF TATA box (bp -34 to -52), herein called purine box 1 (PB1), has been shown to bind a T-cell nuclear protein complex and to be required for transcriptional induction of the GM-CSF gene following T-cell activation. The PB1 sequence motif is highly conserved in both human and murine GM-CSF genes. In this report, we demonstrate that the PB1 element alone confers inducibility on a heterologous promoter following transfection into human Jurkat T cells. In addition, we identify a major PB1 nuclear protein-binding complex that is not present in resting peripheral blood T cells but is rapidly induced following T-cell activation. Sequence analysis revealed that PB1 is composed of adjacent binding sites for Ets and AP-1 transcription factors. In vitro mutagenesis experiments demonstrated that both the Ets and AP-1 sites are required for binding of the inducible PB1 nuclear protein complex and for the transcriptional activity of this element and the GM-CSF promoter in activated T cells. Using antibodies specific for different Ets and AP-1 family members, we demonstrate that the major inducible PB1-binding activity present in activated T-cell nuclear extracts is composed of the Elf-1, c-Fos, and JunB transcription factors. Taken together, these results suggest that cooperative interactions between specific Ets and AP-1 family members are important in regulating inducible gene expression following T-cell activation.
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Wang, C. Y., A. G. Bassuk, L. H. Boise, C. B. Thompson, R. Bravo, and J. M. Leiden. "Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors." Molecular and Cellular Biology 14, no. 2 (February 1994): 1153–59. http://dx.doi.org/10.1128/mcb.14.2.1153.
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The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene has been studied extensively as a model system of transcriptional induction during T-lymphocyte activation. The GM-CSF gene is not expressed in resting peripheral blood T cells but is rapidly induced at the transcriptional level following activation through the cell surface T-cell receptor. A highly conserved 19-bp element located immediately 5' of the human GM-CSF TATA box (bp -34 to -52), herein called purine box 1 (PB1), has been shown to bind a T-cell nuclear protein complex and to be required for transcriptional induction of the GM-CSF gene following T-cell activation. The PB1 sequence motif is highly conserved in both human and murine GM-CSF genes. In this report, we demonstrate that the PB1 element alone confers inducibility on a heterologous promoter following transfection into human Jurkat T cells. In addition, we identify a major PB1 nuclear protein-binding complex that is not present in resting peripheral blood T cells but is rapidly induced following T-cell activation. Sequence analysis revealed that PB1 is composed of adjacent binding sites for Ets and AP-1 transcription factors. In vitro mutagenesis experiments demonstrated that both the Ets and AP-1 sites are required for binding of the inducible PB1 nuclear protein complex and for the transcriptional activity of this element and the GM-CSF promoter in activated T cells. Using antibodies specific for different Ets and AP-1 family members, we demonstrate that the major inducible PB1-binding activity present in activated T-cell nuclear extracts is composed of the Elf-1, c-Fos, and JunB transcription factors. Taken together, these results suggest that cooperative interactions between specific Ets and AP-1 family members are important in regulating inducible gene expression following T-cell activation.
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Ai, Di, Jun Wang, Melanie Amen, Mei-Fang Lu, Brad A. Amendt, and James F. Martin. "Nuclear Factor 1 and T-Cell Factor/LEF Recognition Elements Regulate Pitx2 Transcription in Pituitary Development." Molecular and Cellular Biology 27, no. 16 (June 11, 2007): 5765–75. http://dx.doi.org/10.1128/mcb.01848-06.
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ABSTRACT Pitx2, a paired-related homeobox gene that is mutated in Rieger syndrome I, is the earliest known marker of oral ectoderm. Pitx2 was previously shown to be required for tooth, palate, and pituitary development in mice; however, the mechanisms regulating Pitx2 transcription in the oral ectoderm are poorly understood. Here we used an in vivo transgenic approach to investigate the mechanisms regulating Pitx2 transcription. We identified a 7-kb fragment that directs LacZ expression in oral ectoderm and in many of its derivatives. Deletion analysis of transgenic embryos reduced this fragment to a 520-bp region that directed LacZ activity to Rathke's pouch. A comparison of the mouse and human sequences revealed a conserved nuclear factor 1 (NF-1) recognition element near a consensus T-cell factor (TCF)/LEF binding site. The mutation of either site individually abolished LacZ activity in transgenic embryos, identifying Pitx2 as a direct target of Wnt signaling in pituitary development. These findings uncover a requirement for NF-1 and TCF factors in Pitx2 transcriptional regulation in the pituitary and provide insight into the mechanisms controlling region-specific transcription in the oral ectoderm and its derivatives.
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Yang, Zhuoying, and James Douglas Engel. "Human T cell transcription factor GATA-3 stimulates HIV-1 expression." Nucleic Acids Research 21, no. 12 (1993): 2831–36. http://dx.doi.org/10.1093/nar/21.12.2831.
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Wherry, E. John. "Molecular Basis of T-Cell Exhaustion." Blood 122, no. 21 (November 15, 2013): SCI—38—SCI—38. http://dx.doi.org/10.1182/blood.v122.21.sci-38.sci-38.
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Abstract T-cell exhaustion is common during chronic infections, cancer, exposure to persisting antigens, and can prevent optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. Our work has recently defined transcriptional networks of T-cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes), in controlling the sustainability and terminal differentiation of exhausted T cell populations. Chronic infections and persisting antigen exposure often strains the sustainability or regenerative capacity of exhausted T cell populations resulting in an eventual collapse in immunity. We have found a key role for T-bet in sustaining a progenitor pool of exhausted CD8 T cells during chronic infection, while the related transcription factor Eomes governs terminal differentiation. These represent unique functions for T-bet and Eomes since these transcription factors are associated with different roles in functional memory T cells, highlighting the contextual dependence of transcriptional regulation guiding T-cell exhaustion. Additional studies are focusing on the role of other transcription factors such as BATF in T-cell activation and exhaustion, and on the role of inhibitory receptors including PD-1 in shaping the differentiation of exhausted CD8 T-cell subsets. Ultimately, a more precise molecular understanding of T-cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer. Disclosures: Wherry: Genentech: Patents & Royalties.
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Clemens, K. E., G. Piras, M. F. Radonovich, K. S. Choi, J. F. Duvall, J. DeJong, R. Roeder, and J. N. Brady. "Interaction of the human T-cell lymphotropic virus type 1 tax transactivator with transcription factor IIA." Molecular and Cellular Biology 16, no. 9 (September 1996): 4656–64. http://dx.doi.org/10.1128/mcb.16.9.4656.
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The Tax protein of human T-cell lymphotropic virus type 1 (HTLV-1) is a 40-kDa transcriptional activator which is critical for HTLV-1 gene regulation and virus-induced cellular transformation. Tax is localized to the DNA through its interaction with the site-specific activators cyclic AMP-responsive element-binding protein, NF-kappaB, and serum response factor. It has been suggested that the recruitment of Tax to the DNA positions Tax for interaction with the basal transcriptional machinery. On the basis of several independent assays, we now report a physical and functional interaction between Tax and the transcription factor, TFIIA. First, Tax was found to interact with the 35-kDa (alpha) subunit of TFIIA in the yeast two-hybrid interaction system. Importantly, two previously characterized mutants with point mutations in Tax, M32 (Y196A, K197S) and M41 (H287A, P288S), which were shown to be defective in Tax-activated transcription were unable to interact with TFIIA in this assay. Second, a glutathione-S-transferase (GST) affinity-binding assay showed that the interaction of holo-TFIIA with GST-Tax was 20-fold higher than that observed with either the GST-Tax M32 activation mutant or the GST control. Third, a coimmunoprecipitation assay showed that in HTLV-1-infected human T lymphocytes, Tax and TFIIA were associated. Finally, TFIIA facilitates Tax transactivation in vitro and in vivo. In vitro transcription studies showed reduced levels of Tax-activated transcription in cell extracts depleted of TFIIA. In addition, transfection of human T lymphocytes with TFIIA expression vectors enhanced Tax-activated transcription of an HTLV-1 long terminal repeat-chloramphenicol acetyltransferase reporter construct. Our study suggests that the interaction of Tax with the transcription factor TFIIA may play a role in Tax-mediated transcriptional activation.
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Gounari, Fotini, and Marei Dose. "Lef-1: NOTCHed up in T-cell lymphomas." Blood 110, no. 7 (October 1, 2007): 2227. http://dx.doi.org/10.1182/blood-2007-07-100156.
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In this issue of Blood, Spaulding and colleagues show that Lef-1, one of the transcription factors mediating Wnt signaling, is a transcriptional target of Notch in T-cell lymphomas. Notch-activating mutations are commonly found in human T-lineage acute lymphoblastic leukemia (T-ALL) cases, while activation of Wnt/β-catenin signaling has recently been shown to induce T-cell leukemia in mice. The proposed regulation of Lef-1 transcription by Notch suggests the intriguing possibility that the Notch and Wnt pathways are closely intertwined in the etiology of T-cell leukemia.
Dissertations / Theses on the topic "T Cell Transcription Factor 1"
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Gullicksrud, Jodi Ann. "T cell factor-1 regulates CD4+ and CD8+ T cell responses in a stage-specific manner." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5765.
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CD4+ and CD8+ T cells are critical components of the adaptive arm of immune responses. During viral infection, CD8+ T cells utilize their cytotoxic function to kill infected cells and clear the infection. In addition, CD4+ T cells differentiate into either T helper 1 (Th1) or T follicular helper (Tfh) cells, which provide essential help to enhance the efficacy of other response immune cells, including macrophages, CD8+ T cells, and B cells. The transcription factor, T cell factor-1 (TCF1), and its homologue, Lymphoid enhancer-binding factor-1 (LEF1), have critical roles in the development, differentiation, and persistence of both CD4+ and CD8+ T cells. However, the influence of TCF1 and LEF1 on Th1 and Tfh differentiation remains to be examined. Furthermore, due to alternative promoter usage, TCF1 and LEF1 are expressed as both long and short isoforms. The distinct roles of the long and short isoforms of TCF1 in the context of CD4+ and CD8+ T cell responses have not been defined.
My studies utilized multiple novel mouse strains to examine the roles of TCF1 and LEF1 in Tfh and Th1 differentiation during viral infection, and the unique requirements of TCF1 long isoforms in CD4+ and CD8+ T cell responses. Specifically, my initial studies characterized a new TCF1 reporter construct (referred to as p45GFP reporter) and used this reporter to address the specific contributions of TCF1 long isoforms to the CD8+ T cell response. Previous studies have abrogated all TCF1 isoforms and shown that in the absence of TCF1, the memory CD8+ T cell population is dramatically impaired and exhibits defective persistence over time. Here, I showed that TCF1 short isoforms are sufficient for the generation of memory CD8+ T cells, however TCF1 long isoforms are important for the maturation of memory CD8+ T cells.
Another critical component of pathogen clearance and long-term protection is a productive humoral response, which is optimized by the B cell help provided by Tfh cells. Using the p45GFP reporter, I showed that TCF1 is specifically retained in Tfh cells, but downregulated in Th1 cells. I utilized a huCd2-Cre system to conditionally delete TCF1 and LEF1 in mature T cells. In response to viral infection, TCF1 and LEF1 double-deficient mice showed normal Th1 responses, but severely defective Tfh differentiation and a concomitant impaired B cell response. I further demonstrated that TCF1 promotes Tfh differentiation by directly regulating many Tfh-associated genes. Furthermore, I used the p45GFP reporter to I identified distinct, but critical, roles for both long and short isoforms of TCF1 in driving Tfh differentiation and repressing differentiation toward Th1 or germinal center Tfh cells.
Finally, while TCF1 is known to be critical in the formation of memory CD8+ T cells, its impact on memory CD4+ T cell generation has not been assessed. Once again utilizing the p45GFP reporter, my studies identified an important role for TCF1 long isoforms in the survival of both Th1 and Tfh cells through contraction. In the absence of TCF1 long isoforms, the memory CD4+ T cell population is severely reduced. Taken together, my work has demonstrated critical roles for TCF1 during both effector and memory phases of the CD4+ T cell response to viral infection.
In summary, TCF1 is crucial for CD4+ T cells to effectively differentiate and provide important help to B cells during viral infection. Moreover, my studies have identified critical and unique roles for long and short isoforms of TCF1. Finally, TCF1 is necessary for optimal formation of memory CD4+ and CD8+ T cells, and thus is an essential component in achieving protective immunological memory after viral infection.
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Pyzik, Michal. "TGF-[beta]1 selectively induces Foxp3 transcription factor and regulatory functions in CD4+CD25⁻CD45RBLow T cell population." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101737.
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CD4+ regulatory T (TREG) cells are important contributors to the induction and maintenance of peripheral tolerance. This heterogeneous population consists of naturally occurring and induced CD4 + TREG cells that share between themselves key immunoregulatory characteristics. Their phenotype and function often relies on the expression of Foxp3 transcription factor and the presence of the immunomodulating cytokine TGF-beta1. The inter-dependence between TGF-beta1 and Foxp3 in the induction and maintenance of peripheral tolerance is gradually being elucidated. Thus, we investigated the effects of TGF-beta1 on induction or maintenance of regulatory functions in CD4+CD25- as well as CD4+CD25+ T cells. TGF-beta1 treatment was able, independent from APCs, to promote TREG cell differentiation from non-regulatory CD4+CD25- T cells in a concentration-dependent fashion through Foxp3 induction. Next, we investigated the effect of TGF-beta1 on purely naive CD4+CD25- CD45RBHIGH T cell subset. Fresh or TGF-beta1-treated CD45RBHIGH T cells did not display regulatory functions nor Foxp3 expression. In stark contrast, TGF-beta1 treatment promoted regulatory activity in the CD4 +CD25- CD45RBLOW T cells and enhanced Foxp3 expression. Interestingly, fresh CD45RBLOW cells, albeit expressing noticeable levels of Foxp3 mRNA and protein, were unable to suppress effector T (TEFF) cell proliferation. Furthermore, addition of neutralizing anti-IL-10R Ab completely abrogated this suppression, consistent with the ability of TGF-beta1 treated CD45RBLOW to synthesize IL-10 mRNA upon re-stimulation in vitro. TGF-beta1 treatment or blockade did not lead to preferential growth or enhanced function of naturally-occurring CD4+CD25+ TREG cells, yet it caused a significant increase in Foxp3 expression. Altogether, TGF-beta1 preferentially promotes the induction of IL-10 secreting CD4+ regulatory T cells from CD45RBLOW precursors through Foxp3 induction.
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Phelan, James D. B. S. "Transcriptional Control of Normal Lymphopoiesis and T-cell Neoplasia by Growth Factor Independent 1." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1337351444.
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Nayar, Ribhu. "IRF4 Does the Balancing Act: A Dissertation." eScholarship@UMMS, 2001. http://escholarship.umassmed.edu/gsbs_diss/746.
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CD8+ T cell differentiation is a complex process that requires integration of signals from the TCR, co-stimulatory molecules and cytokines. Ligation of the peptide-MHC complex with the cognate TCR initiates a downstream signaling cascade of which the IL-2 inducible T-cell kinase (ITK) is a key component. Loss of ITK results in a measured reduction in T cell activation. Consequently, Itk deficient mice have defects in thymic selection, CD8+ T cell expansion and differentiation in response to virus infections, and generate a unique population of innate-like CD8+ T cells. The mechanisms that translate TCR and ITK-derived signals into distinct gene transcription programs that regulate CD8+ T cell differentiation are not defined. Our microarray screen identified IRF4 as a potential transcription factor mediating the differentiation of innate-like T cells, and antiviral CD8+ T cell in response to acute and chronic LCMV infections.
Innate-like CD8+ T cells are characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor Eomesodermin (Eomes). One component of this altered development is a non-CD8+ T cell-intrinsic role for IL-4. We show that IRF4 expression is induced upon TCR signaling and is dependent on ITK activity. In contrast to WT cells, activation of IRF4-deficient CD8+ T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8+ T cell activation and that this signaling xii pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8+ T cells.
ITK deficient mice also have reduced expansion of CD8+ T cells in response to acute LCMV infections. We show that IRF4 is transiently upregulated to differing levels in murine CD8+ T cells, based on the strength of TCR signaling. In turn, IRF4 controls the magnitude of the CD8+ T cell response to acute virus infection in a dose-dependent manner. Furthermore, the expression of key transcription factors such as T cell factor 1 and Eomesodermin are highly sensitive to graded levels of IRF4. In contrast, T-bet expression is less dependent on IRF4 levels and is influenced by the nature of the infection. These data indicate that IRF4 is a key component that translates the strength of TCR signaling into a graded response of virus-specific CD8+ T cells.
The data from these studies indicated a pivotal role of IRF4 in regulating the expression of T-bet and Eomes. During persistent LCMV infections, CD8+ T cells differentiate into T-bethi and Eomeshi subsets, both of which are required for efficient viral control. We show that TCR signal strength regulates the relative expression of T-bet and Eomes in antigen-specific CD8+ T cells by modulating levels of IRF4. Reduced IRF4 expression results in skewing of this ratio in favor of Eomes, leading to lower proportions and numbers of T-bet+ Eomes- precursors and poor control of LCMV Clone 13 infection. Altering this ratio in favor of T-bet xiii restores the differentiation of T-bet+ Eomes- precursors and the protective balance of T-bet to Eomes required for efficient viral control. These data highlight a critical role for IRF4 in regulating protective anti-viral CD8+ T cell responses by ensuring a balanced ratio of T-bet to Eomes, leading to the ultimate control of this chronic viral infection.
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Nayar, Ribhu. "IRF4 Does the Balancing Act: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/746.
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CD8+ T cell differentiation is a complex process that requires integration of signals from the TCR, co-stimulatory molecules and cytokines. Ligation of the peptide-MHC complex with the cognate TCR initiates a downstream signaling cascade of which the IL-2 inducible T-cell kinase (ITK) is a key component. Loss of ITK results in a measured reduction in T cell activation. Consequently, Itk deficient mice have defects in thymic selection, CD8+ T cell expansion and differentiation in response to virus infections, and generate a unique population of innate-like CD8+ T cells. The mechanisms that translate TCR and ITK-derived signals into distinct gene transcription programs that regulate CD8+ T cell differentiation are not defined. Our microarray screen identified IRF4 as a potential transcription factor mediating the differentiation of innate-like T cells, and antiviral CD8+ T cell in response to acute and chronic LCMV infections.
Innate-like CD8+ T cells are characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor Eomesodermin (Eomes). One component of this altered development is a non-CD8+ T cell-intrinsic role for IL-4. We show that IRF4 expression is induced upon TCR signaling and is dependent on ITK activity. In contrast to WT cells, activation of IRF4-deficient CD8+ T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8+ T cell activation and that this signaling xii pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8+ T cells.
ITK deficient mice also have reduced expansion of CD8+ T cells in response to acute LCMV infections. We show that IRF4 is transiently upregulated to differing levels in murine CD8+ T cells, based on the strength of TCR signaling. In turn, IRF4 controls the magnitude of the CD8+ T cell response to acute virus infection in a dose-dependent manner. Furthermore, the expression of key transcription factors such as T cell factor 1 and Eomesodermin are highly sensitive to graded levels of IRF4. In contrast, T-bet expression is less dependent on IRF4 levels and is influenced by the nature of the infection. These data indicate that IRF4 is a key component that translates the strength of TCR signaling into a graded response of virus-specific CD8+ T cells.
The data from these studies indicated a pivotal role of IRF4 in regulating the expression of T-bet and Eomes. During persistent LCMV infections, CD8+ T cells differentiate into T-bethi and Eomeshi subsets, both of which are required for efficient viral control. We show that TCR signal strength regulates the relative expression of T-bet and Eomes in antigen-specific CD8+ T cells by modulating levels of IRF4. Reduced IRF4 expression results in skewing of this ratio in favor of Eomes, leading to lower proportions and numbers of T-bet+ Eomes- precursors and poor control of LCMV Clone 13 infection. Altering this ratio in favor of T-bet xiii restores the differentiation of T-bet+ Eomes- precursors and the protective balance of T-bet to Eomes required for efficient viral control. These data highlight a critical role for IRF4 in regulating protective anti-viral CD8+ T cell responses by ensuring a balanced ratio of T-bet to Eomes, leading to the ultimate control of this chronic viral infection.
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Bharath, Krishnan Nair Sreekumar. "The Role of IkZF Factors in Mediating TH1/TFH Development and Flexibility." Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/96583.
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The ability of cells within the adaptive immune system to develop into specialized subsets allow for a robust and tailored immune response in the advent of an infection or injury. Here, CD4+ T-cells are a crucial component within this system, with subsets such as TH1, TH2, TH17, TFH and TREG cells playing vital roles in propagating cell-mediated immunity. For example, TH1 cells are essential in combating intracellular pathogens such as viruses, while TFH cells communicate with B-cells to optimize antibody responses against an invading pathogen. The development (and functionality) of these subsets is ultimately dictated by the appropriate integration of extracellular cues such as cytokines with cell intrinsic transcription factors, thereby promoting the necessary gene profile. Moreover, the observation that T-helper cells could exhibit a flexible nature (i.e having shared gene profiles and effector functions) not only demonstrate the efficiency of our immune system but also how such flexibility could have unintended consequences during adverse events such as autoimmunity. An important mediator of such flexibility is cytokines. However, the complete network of factors that come together to co-ordinate cytokine mediated plasticity remain unknown. Thus, the work in this dissertation hope to delineate the factors that collaborate to regulate cytokine induced T-helper cell flexibility. As such, we see that in the presence of IL-2, the Ikaros Zinc Finger (IkZF) transcription factor Eos is upregulated in TH1 cells, with this factor playing a significant role in promoting regulatory and effector functions of TH1 cells. Moreover, we show that Eos forms a novel protein complex with STAT5 and promotes STAT5 activity in TH1 cells. However, depleting IL-2 from the micro-environment leads to the upregulation of two other members within the IkZF family, Ikaros and Aiolos. Aiolos in turn collaborate with STAT3, induces Bcl-6 expression within these cells, thus promoting these cells to exhibit characteristic features of TFH cells. The work in this dissertation hopes to advance our understanding of the regulatory mechanisms involved in cytokine mediated T-cell flexibility thereby hoping to open new avenues for the development of novel therapeutic strategies in the event of autoimmunity.Ph. D.
T-helper (TH) cells are an important component of the immune system, as these cells aid in the fight against pathogens by secreting factors that either accentuate the inflammatory response during infection or attenuate immune responses post infection. Such effects are made possible because T-helper cells can differentiate into a variety of subsets, with each subset being an important mediator in maintaining immune homeostasis. For example, the T-helper cell subset called TH1 plays a vital role in the fight against intracellular pathogens such as viruses and certain parasites, while T-follicular helper (TFH) cells aid in the production of antibodies specific to the invading pathogen. The development of such subsets occur when cell extrinsic signals, called cytokines, lead to the activation or induction of cell intrinsic proteins called transcription factors. Interestingly, research over the years have shown that T-helper cells are highly adaptable in nature, with one subset having the ability to attain certain characteristic features of other subsets. This malleable nature of T-helper cells relies on several factors, with cytokines within the micro-environment being an important one. Although this form of flexibility is efficient and beneficial at times, it can also be detrimental, as such flexibility is known to promote certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Such detrimental effects are thought to be due to cytokines within the environment. Therefore understanding how cytokines influence the flexible nature of T-helper cells is important; as controlling such flexibility (either by regulating cytokines or the transcription factors activated as a consequence) could prevent the propagation of undesired T-helper cell functions. As such, the work in this dissertation hopes to uncover how one such cytokine, termed Interleukin-2 (IL-2) mediates the flexibility between TH1 and TFH cells. The work highlighted in this dissertation broadens our understanding of how cytokines influence T-helper cell development and flexibility, and consequently allows the design of novel therapeutic strategies to combat autoimmune diseases.
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Noman, Muhammad zaeem. "Influence of hypoxia on tumour cell susceptibility to cytotoxic T lymphocyte mediated lysis." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T051/document.
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L’hypoxie est une caractéristique commune des tumeurs solides et l’une des spécificités du micro environnement tumoral. L’hypoxie tumorale joue un rôle important dans l’angio génèse, la progression maligne, le développement de métastases, la chimio/radio-résistance et favorise l’échappement au système immunitaire du fait de l’émergence de variant tumoraux avec un potentiel de survie et de résistance à l’apoptose augmenté. Cependant, très peu de travaux ont étudié l’impact de l’hypoxie tumorale sur la régulation de la susceptibilité des tumeurs à la lyse induite par la réponse immune cytotoxique. Nous nous sommes donc demandé si l’hypoxie pouvait conférer aux tumeurs une résistance à la lyse induite par les lymphocytes T cytotoxiques (CTL). Nous avons démontré que l’exposition de cellules cibles tumorales à l’hypoxie possédait un effet inhibiteur sur la lyse de ces cellules tumorales par des CTL autologues. Cette inhibition n’est pas associée à des altérations de la réactivité de CTL ou de la reconnaissance des cellules cibles. Cependant, nous avons montré que l’induction hypoxique concomitante de la phosphorylation de STAT3 (pSTAT3) au niveau de la tyrosine 705 et du facteur HIF-1α (Hypoxia Inducible Factor-1 alpha) est liée fonctionnellement à l’altération de la susceptibilité de cellules tumorales bronchiques non à petites cellules (NSCLC) à la mort induite par les CTL. Nous avons aussi montré que la résistance de cellules tumorales bronchiques à la lyse CTL induite par l’hypoxie était associée à une induction d’autophagie dans les cellules cibles. En effet, l’inhibition de l’autophagie empêche la phosphorylation de STAT3 (via l’inhibition de la kinase Src) et restaure la susceptibilité des cellules tumorales hypoxiques à la lyse induite par les CTL. De plus, l’inhibition in vivo de l’autophagie par l’hydroxychloroquine (HCQ) dans le modèle murin portant la tumeur B16F10 and chez les souris vaccinée avec le peptide TRP2 augmente de façon drastique l’inhibition de la croissance tumorale. Collectivement, cette étude établit un nouveau lien fonctionnel entre l’autophagie induite par l’hypoxie et la régulation de la lyse induite par les cellules T spécifique d’antigènes et souligne le rôle majeur de l’autophagie dans le contrôle de la croissance tumorale in vivo.Finalement, étant donné que le la résistance tumorale à la lyse induite par les cellules tueuses est très probablement régulée par de multiples facteurs, nous avons aussi eu pour but d’identifier les micro-ARNs (miRs) régulés par l’hypoxie dans des modèles de NSCLC et de mélanome et leur implication putative dans la régulation de la susceptibilité tumorale à la lyse induite par les cellules T spécifique d’antigènes. Le micro-ARN 210 (miR-210) est ainsi significativement induit de manière dépendante de HIF-1α dans des cellules de NSCLC et de mélanome, et miR-210 est exprimé dans les zones hypoxiques de tissus issus de NSCLC. De plus, nous avons démontré que l’induction de miR-210 par l’hypoxie régule la susceptibilité tumorale à la lyse induite par les CTL en partie grâce à l’inhibition de l’expression de PTPN, HOXA1 et TP53I11, indiquant que miR-210 joue un rôle potentiel dans la régulation de la réponse immune antitumoraleHypoxia is a common feature of solid tumors and one of the hallmarks of tumor microenvironment. Tumor hypoxia plays an important role in angiogenesis, malignant progression, metastatic development, chemo-radio resistance and favours immune evasion by the emergence of tumor variants with increased survival and anti-apoptotic potential. There is very little work done on the impact of tumor hypoxia on the regulation of tumor susceptibility to the lysis induced by cytotoxic antitumor response. Therefore, we asked whether hypoxia confers tumor resistance to cytotoxic T lymphocyte (CTL)-mediated killing. We demonstrated that exposure of target cells to hypoxia has an inhibitory effect on the CTL-mediated autologous target cell lysis. Such inhibition was not associated with an alteration of CTL reactivity and tumor target recognition. We also showed that the concomitant hypoxic induction of Signal transducer and activator of transcription 3 (STAT3) phosphorylation on tyrosine 705 residue (pSTAT3) and hypoxia inducible factor 1 alpha (HIF-1α) is functionally linked to the alteration of Non small cell lung carcinoma (NSCLC) target susceptibility to CTL-mediated killing. We also showed that hypoxia-induced resistance of lung tumor to CTL-mediated lysis was associated with autophagy induction in target cells. Inhibition of autophagy resulted in impairment of pSTAT3 (via inhibition Src kinase) and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine (HCQ) in B16F10 tumor bearing mice and mice vaccinated with TRP2 peptide dramatically increased tumor growth inhibition. Collectively, the current study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen specific T cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.Finally, as resistance of tumor targets to killer cells is likely to be regulated by multiple factors, we further aimed to identify the microRNA’s regulated by hypoxia in NSCLC and melanoma and their putative involvement in the regulation of tumor susceptibility to antigen-specific CTL-mediated killing. MicroRNA-210 (miR-210) was significantly induced in a HIF-1α dependent manner in NSCLC and melanoma cells and miR-210 was expressed in hypoxic zones of human NSCLC tissues. Moreover, we demonstrated that hypoxia-induced miR-210 regulates tumor cell susceptibility to CTL-mediated lysis in part by suppressing PTPN, HOXA1 and TP53I11 expression indicating that miR-210 plays a potential role in the regulation of anti-tumor immune response
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Jasinski, Jean Marie. "Simplification of the immunogenetics of type 1A diabetes through transgenic T cell receptor mouse models /." Connect to abstract via ProQuest. Full text is not available online, 2008.
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Noman, Muhammad Zaeem. "Influence of hypoxia on tumour cell susceptibility to cytotoxic T lymphocyte mediated lysis." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-01024170.
Full textAbstract:
Hypoxia is a common feature of solid tumors and one of the hallmarks of tumor microenvironment. Tumor hypoxia plays an important role in angiogenesis, malignant progression, metastatic development, chemo-radio resistance and favours immune evasion by the emergence of tumor variants with increased survival and anti-apoptotic potential. There is very little work done on the impact of tumor hypoxia on the regulation of tumor susceptibility to the lysis induced by cytotoxic antitumor response. Therefore, we asked whether hypoxia confers tumor resistance to cytotoxic T lymphocyte (CTL)-mediated killing. We demonstrated that exposure of target cells to hypoxia has an inhibitory effect on the CTL-mediated autologous target cell lysis. Such inhibition was not associated with an alteration of CTL reactivity and tumor target recognition. We also showed that the concomitant hypoxic induction of Signal transducer and activator of transcription 3 (STAT3) phosphorylation on tyrosine 705 residue (pSTAT3) and hypoxia inducible factor 1 alpha (HIF-1α) is functionally linked to the alteration of Non small cell lung carcinoma (NSCLC) target susceptibility to CTL-mediated killing. We also showed that hypoxia-induced resistance of lung tumor to CTL-mediated lysis was associated with autophagy induction in target cells. Inhibition of autophagy resulted in impairment of pSTAT3 (via inhibition Src kinase) and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine (HCQ) in B16F10 tumor bearing mice and mice vaccinated with TRP2 peptide dramatically increased tumor growth inhibition. Collectively, the current study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen specific T cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.Finally, as resistance of tumor targets to killer cells is likely to be regulated by multiple factors, we further aimed to identify the microRNA's regulated by hypoxia in NSCLC and melanoma and their putative involvement in the regulation of tumor susceptibility to antigen-specific CTL-mediated killing. MicroRNA-210 (miR-210) was significantly induced in a HIF-1α dependent manner in NSCLC and melanoma cells and miR-210 was expressed in hypoxic zones of human NSCLC tissues. Moreover, we demonstrated that hypoxia-induced miR-210 regulates tumor cell susceptibility to CTL-mediated lysis in part by suppressing PTPN, HOXA1 and TP53I11 expression indicating that miR-210 plays a potential role in the regulation of anti-tumor immune response.
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Bishop, Kenneth D. "Egr-2 and PD-1 Are Required for Induction and Maintenance of T Cell Anergy: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/354.
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The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness in CD4+ T cells. The focus of this thesis is a description of factors shown to be specific to the induction and maintenance of T cell anergy, whose loss reverses the anergic phenotype, restoring the ability of the cells to proliferate in response to antigen. The first of these is Egr-2, a zinc-finger transcription factor, whose presence is required for the induction of anergy induced in T cell clones by TCR stimulation in the absence of costimulation. Egr-2 is shown to be important to anergy induction but not anergy maintenance. In contrast, a negative costimulation receptor, PD-1, is shown to be necessary for the maintenance of anergy. It is possible that learning more about the genetic factors that orchestrate T cell anergy will prove useful in the development of tolerance-based protocols for organ and tissue transplantation without the use of long-term immunosuppression.
Books on the topic "T Cell Transcription Factor 1"
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Hartigan-O’Connor, Dennis J., and Christian Brander. Immunology. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190493097.003.0005.
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The key factor in HIV pathogenesis is the decline in CD4+ T cells with resultant immunodeficiency and chronic inflammation. Depletion of CD4+ T cells from the gastrointestinal mucosa followed by microbial translocation and subsequent immune activation are components of disease progression in untreated patients. Symptomatic and occult opportunistic infections including cytomegalovirus contribute to chronic inflammation in persons infected with HIV. Antiretroviral therapy (ART) results in immune reconstitution, with increases in peripheral CD4+ T cell lymphocytes in most persons infected with HIV, although immune recovery is quite variable. A subset of patients with AIDS will develop immune reconstitution inflammatory syndromes after initiation of ART. Approximately 1% of persons with HIV are able to control infection without the need for ART (“elite” controllers). A variety of immune-based therapies, including hydroxyurea, growth hormone, and statins, are being studied in clinical trials and may ultimately play a role in treating persons with HIV infection.
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Klingenberg, Roland, and Ulf Müller-Ladner. Mechanisms of inflammation. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0270.
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This chapter provides a brief summary of the immune pathogenesis of atherosclerosis, highlighting shared features with inflammatory pathways in rheumatoid arthritis (RA) described in detail in Chapter 25.4. RA constitutes a prototype autoimmune disease primarily affecting the joints but also the heart and vessels associated with increased cardiovascular mortality. Recent years have produced a wealth of novel insights into the diversity of immune cell types which either propagate or dampen inflammation in atherogenesis. Expansion of this inherent anti-inflammatory component carried by regulatory T cells may constitute a new therapeutic target to harness the progression of atherosclerotic cardiovascular disease. Among the various inflammatory mediators involved in RA pathology, cytokines (tumour necrosis factor-α and interleukin-6) have gained major interest as therapeutic targets with approved therapies available. In light of the many common features in the pathogenesis of RA and atherosclerosis, these biologics are currently being evaluated in cardiovascular patients. The recently published CANTOS trial showed that IL-1 inhibition reduced adverse cardiovascular events in patients with coronary artery disease demonstrating that inflammation is a genuine therapeutic target. The near future will provide more information whether inflammation is a bona fide cardiovascular risk factor based on completion of several clinical trials using anti-inflammatory approaches in patients with both cardiovascular disease and rheumatoid arthritis.
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Pitzalis, Costantino, Frances Humby, and Michael P. Seed. Synovial pathology. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0052.
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Synovial pathology is seen in a variety of disease states, including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis, and systemic lupus erythmatosus (SLE). This chapter highlights recent advances that characterize the cellular composition of these tissues according to surface markers and chemokine and cytokine expression, and describes synovial functional status and response to therapeutics. In RA, after initiation, pannus migrates over and under cartilage, and into subchondral bone, in a destructive process. Cartilage-pannus junction (CPJ) is characterized as invasive or 'quiescent' or 'indistinct'. Invasive CPJ can comprise macrophages, fibroblast-like synoviocytes (FLS), mast cells, and/or neutrophils. CPJ activity is related to the state of activation of the overlying subintima. Subintimal inflammation can be graded to a variety of degrees (I–IV) according to established criteria and is illustrated. In some RA synovia, cellular aggregates organize into ectopic lymphoid structures (ELS) through the expression of lymphorganogenic signals, to exhibit T- or B-cell zones accompanied by dendritic cells and lymphangiogenesis. ELS synthesize rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACAP), considered to be indicative of aggressive disease. The selective cellular expression of macrophage and dendritic cell chemokines and cytokines such as TNF, GMCSF, TGFβ, IL-1, IL-6, IL-23, and chemokines can be seen in synovia, to form a regulated and cooperative environment that sustains the cellular organization and pathological function. Important to this process are FLS and CD68+ macrophages. CD68 expression correlates with disease severity and can be useful as a surrogate marker of disease modifying activity of therapeutics, such as anti-TNF and anti-B-cell biologics.
Book chapters on the topic "T Cell Transcription Factor 1"
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Busslinger, Meinrad, and Stephen L. Nutt. "Role of the Transcription Factor BSAP (Pax-5) in B-Cell Development." In Molecular Biology of B-Cell and T-Cell Development, 83–110. Totowa, NJ: Humana Press, 1998. http://dx.doi.org/10.1007/978-1-4757-2778-4_6.
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Orkin, Stuart H. "Transcription Factors Regulating Early Hematopoietic Development and Lineage Commitment." In Molecular Biology of B-Cell and T-Cell Development, 41–54. Totowa, NJ: Humana Press, 1998. http://dx.doi.org/10.1007/978-1-4757-2778-4_3.
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Humblin, Etienne, François Ghiringhelli, and Frédérique Végran. "Transcription Factor Binding Studies in CD4+ T Cells: siRNA Transfection, Chromatin Immunoprecipitation, and Liquid Luminescent DNA Precipitation Assay." In Methods in Molecular Biology, 167–77. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-6877-0_13.
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Hecht, A. "Members of the T-Cell Factor Family of DNA-Binding Proteins and Their Roles in Tumorigenesis." In Transcription Factors, 123–65. Berlin, Heidelberg: Springer Berlin Heidelberg, 2004. http://dx.doi.org/10.1007/978-3-642-18932-6_5.
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Miyamoto-Sato, Etsuko. "Next-Generation Sequencing Coupled with a Cell-Free Display Technology for Reliable Interactome of Translational Factors." In Transcription Factor Regulatory Networks, 23–32. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-0805-9_3.
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Bruce, Jacqueline L., Brendan D. Price, and Stuart K. Calderwood. "Activation of the Heat Shock Transcription Factor During G1." In The Cell Cycle, 155–61. Boston, MA: Springer US, 1994. http://dx.doi.org/10.1007/978-1-4615-2421-2_17.
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Arya, Suresh K., and M. G. Sarngadharan. "T-Cell Growth Factor (Interleukin-2)." In New Experimental Modalities in the Control of Neoplasia, 165–82. Boston, MA: Springer US, 1986. http://dx.doi.org/10.1007/978-1-4684-5242-6_11.
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Slansky, Jill E., and Peggy J. Farnham. "The Role of the Transcription Factor E2F in the Growth Regulation of DHFR." In The Cell Cycle, 149–54. Boston, MA: Springer US, 1994. http://dx.doi.org/10.1007/978-1-4615-2421-2_16.
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Chen, Fei, and Xianglin Shi. "NF-кB, a pivotal transcription factor in silica-induced diseases." In Oxygen/Nitrogen Radicals: Cell Injury and Disease, 169–76. Boston, MA: Springer US, 2002. http://dx.doi.org/10.1007/978-1-4615-1087-1_19.
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Brasier, Allan R., M. Jamaluddin, Youqi Han, Cam Patterson, and Marschall S. Runge. "Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-кB (NF-кB) transcription factor." In Control of Gene Expression by Catecholamines and the Renin-Angiotensin System, 155–69. Boston, MA: Springer US, 2000. http://dx.doi.org/10.1007/978-1-4615-4351-0_18.
Full textConference papers on the topic "T Cell Transcription Factor 1"
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O'Brien, Shaun, Rajan M. Thomas, Steven M. Albelda, Andrew D. Wells, and Liang-Chuan S. Wang. "Abstract B12: Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor." In Abstracts: AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/2326-6074.tumimm14-b12.
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Andreasen, P. A., A. Riccio, L. R. Lund, K. G. Welinder, F. Blasi, and K. Danø. "PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1: STUDIES ON STRUCTURE AND REGULATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642810.
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Human plasminogen activator inhibitor type-1 is an Mr∼54,000 protein which specifically inhibits urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators. During inhibition, u-PA and t-PA convert PAI-1 to an inactive form with Mr∼50,000. We have determined the amino-terminal amino acid sequence of native and converted PAI-1, and isolated and partly sequenced PAI-1 cDNA. The data show that the conversion of PAI-1 consists of cleavage of an Arg-Met bond 33 residues from the carboxy-terminus, thus localizing the reactive center of the inhibitor to that position, and identifying PAI-1 as an "arg-serpin". PAI-1 activity is known to be influenced by a number of agents; we have studied the mechanisms of the stimulation of PAI-1 activity by transforming growth factor-β (TGF-β) and the synthetic glucocorticoid dexame-thasone in human WI-38 lung fibroblasts and HT-1080 fibrosarcoma cells. Bytheuse of PAI-1 cDNA, TGF-β was found to course a rapid increase in PAI-1 mRNA level in WI-38 cells, reaching a maximal 50-fold enhancement after 8 hours. Dexamethasone caused a 10-fold increase in PAI-1 mRNA in HT-1080 cells, which was detectable after 4 hours and became maximal after 16 hours. In both cases, the 3.4 as well as the 2.4 Kb-PAI-1-mRNA species were increased. Quantitative studies on the effect of these agents on PAI-1 protein levels in cell extracts and culture media by ELISA gave results consistent with the effects on PAI-1 mRNA. These studies suggest that TGF-β and glucocorticoids may exert important controls over plasminogen activation-mediated extracellular proteolysis through an enhancement of PAI-1 gene transcription.
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Vishwamitra, Deeksha, Choladda V. Curry, Serhan Alkan, Ping Shi, and Hesham M. Amin. "Abstract A36: Decreased levels of the transcription factors Ik-1 and MZF1 contribute to upregulation of IGF-IR expression in NPM-ALK+ T-cell anaplastic large-cell lymphoma." In Abstracts: AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1557-3265.hemmal14-a36.
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Schleuning, W. D. "THE BIOCHEMISTRY AND CELL BIOLOGY OF SINGLE CHAIN UROKINASE TYPE PLASMINOGEN ACTIVATOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642956.
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Urokinase was discovered in the late nineteenth century, as an enzymatic principle in urine, that initiates the dissolution of blood clots. The basis of this phenomenon was recognized more than fifty years ago as the activation of plasminogen, the precursor of a tryptic protease, then known as profibrinolysin. Despite this long history, detailed data on the biochemistry of plasminogen activation have only become available recently. Urokinase (now designated urokinase-type plasminogen activator : u-PA) is synthesized and secreted as a single chain polypeptide (Mr-: 53,000) by many cell types. Single chain u-PA (scu-PA) is with equal justification called prourokinase (pro-u-PA), notwithstanding its low catalytic activity for synthetic peptide substrates and plasminogen, as most proenzymes of proteases display a certain degree of activity. The structure of pro-u-PA has been elucidated by protein and cDNA sequencing. It consists of three domains, exhibiting characteristic homology to other proteins: a serine protease domain, homologous to trypsin, chymotrypsin and elastase; a kringle domain, likewise found in prothrombin, plasminogen, tissue-type plasminogen activator (t-PA) and Factor XII; and an epidermal growth factor (EGF)-like domain, found in many other proteins, including certain clotting factors. Pro-u-PA is activated by the cleavage of its LYS158-Ile159 h1 bY either plasmin or kallikrein. This cleavage leads to a high increase of Kcat values with respect to both plasminogen and synthetic peptide substrates, but apparently to a reduction of its affinity to plasminogen. Thrartoin inactivates pro-u-PA irreversibly by the cleavage of the Arg156-Phe157 bond. U-PA but not pro-u-PA rapidly forms ccnplexes with plasminogen activator inhibitors (PAI)-l and PAI-2: second order rate constants Kass are respectively > 107 and 0.9xl06 (M-11sec-1). Unknown enzymes process pro-u-PA and u-PA to low molecular weight (LMW) pro-u-PA and LMW u-PA (Mr: 33,000) by cutting off a fragment consisting of the kr ingle and the EGF—like region. Pro—u—PA mediated plasminogen activation is fibrin dependent in vivo, and to a certain degree in vitro. Hie biochemical basis of this fibrin specificity is at present uncertain, although there are reports indicating that it may require polyvalent cations. Through its EGF-like region HMW pro-u-PA and HMW u-PA are capable of binding to specific membrane protein receptors which are found on many cells. Thus, u-PA activity may be restricted to the cell surface. According to a recent report, binding of u—PA to the receptor may also mediate signal transduction in auto- or paracrine growth control. In cells permissive for the respective pathways, pro-u-PA gene transcription is stimulated by mechanisms of signal transduction, that include the cAMP, the tyrosine specific kinase and the protein kinase C dependent pathways. Glucocorticoid hormones downregulate pro-u-PA gene transcription in cells where the gene is canstitutively expressed. Although different cells vary greatly in their response to agents that stimulate urokinase biosynthesis, growth factors and other mitogens are in many cases effective inducers. Significantly elevated levels of u-PA are also found in many malignant tissues. These findings and many others suggest that plasminogen activation by u-PA provides localized extracellular matrix degradation which is required for invasive growth, cell migration and other forms of tissue remodelling. Fibrin represents in this view only a variant of an extracellular matrix, which is provided through the clotting system in the case of an emergency.
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Wiewrodt, Rainer, Juergen Burg, Guido Rapp, Lars-Henning Schmidt, Christian Taube, Roland Buhl, Charles J. Kirkpatrik, and Susetta Finotto. "EXPRESSION OF T-CELL TRANSCRIPTION FACTOR T-BET IS INCREASED IN COPD." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2912.
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Dixit, VM. "Abstract BS1-1: Transcription factor stability and stem cell maintenance." In Abstracts: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.sabcs16-bs1-1.
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Koga, Hironori, Yasuko Imamura, Yu Ikezono, Fumitaka Wada, Toru Nakamura, Hideki Iwamoto, Atsutaka Masuda, Takahiko Sakaue, Hirohisa Yano, and Takuji Torimura. "Abstract 4601: Regulation of Hes1 expression by the Wnt transcription factor T-cell factor-4." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4601.
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Popay, Tessa M., Lance R. Thomas, Jing Wang, Qi Liu, and William P. Tansey. "Abstract 2600: Interaction of host cell factor-1 with the oncoprotein transcription factor MYC." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2600.
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Popay, Tessa M., Lance R. Thomas, Jing Wang, Qi Liu, and William P. Tansey. "Abstract 2600: Interaction of host cell factor-1 with the oncoprotein transcription factor MYC." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2600.
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Laukkanen, Saara, Laura Oksa, Atte Nikkilä, Juha Mehtonen, Petri Pölönen, Mari Lahnalampi, Merja Heinäniemi, and Olli Lohi. "Abstract 3588: SIX6 is a TAL1-regulated transcription factor in T-cell acute lymphoblastic leukemia." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-3588.
Full textReports on the topic "T Cell Transcription Factor 1"
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Brown, Powel H. Prevention of Breast Cell Transformation by Blockade of the AP-1 Transcription Factor. Fort Belvoir, VA: Defense Technical Information Center, October 2000. http://dx.doi.org/10.21236/ada394179.
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Brown, Powel H. Prevention of Breast Cancer Cell Transformation by Blockade of the AP-1 Transcription Factor. Fort Belvoir, VA: Defense Technical Information Center, October 2001. http://dx.doi.org/10.21236/ada404992.
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Brown, Powel. Prevention of Breast Cancer Cell Transformation by Blockade of the AP-1 Transcription Factor. Fort Belvoir, VA: Defense Technical Information Center, October 1998. http://dx.doi.org/10.21236/ada378104.
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