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1
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.
2
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.
3
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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4
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.
Full textAbstract:
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.
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Ruppert, Shannon Moore. "Signals Delivered By Interleukin-7 Regulate The Activities Of Bim And JunD In T Lymphocytes." Doctoral diss., University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5475.
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Interleukin-7 (IL-7) is an essential cytokine for lymphocyte growth that has the potential for promoting proliferation and survival. While the survival and proliferative functions of IL-7 are well established, the identities of IL-7 signaling components in pathways other than JAK/STAT, that accomplish these tasks remain poorly defined. To this end, we used IL-7 dependent T-cells to examine those components necessary for cell growth and survival. Our studies revealed two novel signal transducers of the IL-7 growth signal: BimL and JunD. IL-7 promoted the activity of JNK (Jun N-terminal Kinase), and that JNK, in turn, drove the expression of JunD, a component of the Activating Protein 1 (AP-1) transcription factors. Inhibition of JNK/JunD blocked glucose uptake and HXKII gene expression, indicating that this pathway was responsible for promoting HXKII expression. After a bioinformatics survey to reveal possible JunD-regulated genes activated early in the IL-7 signaling cascade, our search revealed that JunD could control the expression of proteins involved in signal transduction, cell survival and metabolism, including Pim-1. Pim-1, an IL-7 induced protein, was inhibited upon JNK or JunD inhibition. Our hypothesis that JunD positively regulated proliferation was confirmed when the proliferation of primary CD8+ T-cells cultured with IL-7 was impaired upon treatment with JunD siRNA. These results show that the IL-7 signal is more complex than the JAK/STAT pathway, activating JNK and JunD to induce rapid growth through the expression of metabolic factors like HXKII and Pim-1. When metabolic activities are inhibited, cells undergo autophagy, or cell scavenging, to provide essential nutrients. Pro-apoptotic Bim was evaluated for its involvement in autophagy. Bim is a BH3-only member of the Bcl-2 family that contributes to T-cell death. Partial rescue of T-cells occurs when Bim and the interleukin-7 receptor are deleted, implicating Bim in IL-7-deprived T-cell apoptosis. Alternative splicing results in three different isoforms: BimEL, BimL, and BimS. To study the effect of Bim deficiency and define the function of the major isoforms, Bim-containing and Bim-deficient T-cells, dependent on IL-7 for growth, were used. Loss of Bim in IL-7-deprived T-cells delayed apoptosis, but blocked the degradative phase of autophagy. The conversion of LC3-I to LC3-II was observed in Bim-deficient T-cells, but p62, which is degraded in autolysosomes, accumulated. To explain this, BimL, was found to support acidification of lysosomes associated with autophagic vesicles. Key findings showed that inhibition of lysosomal acidification accelerated death upon IL-7 withdrawal only in Bim-containing T-cells, indicating that in these cells autophagy was protective. IL-7 dependent T-cells lacking Bim were insensitive to inhibition of autophagy or lysosomal acidification. BimL co-immunoprecipitated with dynein and Lamp1-containing vesicles, indicating BimL could be an adaptor for dynein to facilitate loading of lysosomes. In Bim deficient T-cells, lysosome-tracking probes revealed vesicles of less acidic pH. Over-expression of BimL restored acidic vesicles in Bim deficient T-cells, while other isoforms, BimEL and BimS, associated with intrinsic cell death. These results reveal a novel role for BimL in lysosomal positioning that may be required for the formation of functional autolysosomes during autophagy.ID: 031001292; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Error in paging: p. v followed by 1 unnumbered page and then followed by p. ii-vii.; Adviser: Annette R. Khaled.; Title from PDF title page (viewed March 1, 2013).; Thesis (Ph.D.)--University of Central Florida, 2012.; Includes bibliographical references (p. 99-121).
Ph.D.
Doctorate
Molecular Biology and Microbiology
Medicine
Biomedical Sciences
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Maurer, Gaëtan. "Analyse du rôle du facteur de transcription Ikaros dans le développement des lymphocytes TH17." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ115.
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Les cellules T auxiliaires TH17 sont caractérisées par l’expression de la cytokine IL-17A, ainsi que le facteur de transcription RORɣt. Elles sont connues pour jouer un rôle clé dans la pathogenèse de la sclérose en plaques. Ces cellules existent sous deux formes : les cellules régulatrices, immunomodulatrices, et les cellules pathogènes qui sont critiques pour l'inflammation. Il est donc important de comprendre le mécanisme qui sous-tend la différenciation des cellules TCD4+ naïves en ces deux types cellulaires. J'ai trouvé que le facteur de transcription Ikaros est un répresseur indirect de la transcription des gènes pathogéniques (Il3, Csf2, Ifng, Stat4…) dans les cellules TCD4+ naïves murines, cultivées pour induire une polarisation vers le phénotype TH17 régulateur. De plus, en absence d’Ikaros et en conditions de culture régulatrice, l’ajout d’IL-6 seul augmente l’expression de GM-CSF, facteur clé dans l’induction des maladies auto-immunes, suggérant un rôle d’Ikaros dans la régulation de cette voie. En conclusion, nos résultats suggèrent que Ikaros est nécessaire pour polariser correctement les cellules TCD4+ naïves dans le programme TH17TH17 cells are characterized by the expression of the cytokine IL-17A, as well as the transcription factor RORɣt. They are known to play key role in the pathogenesis of the multiple sclerosis. These cells exist in two forms: the regulating cells, immunomodulatory, and the pathogenic cells which are critical for the inflammation. Thus it is important to understand the mechanism which underlies the differentiation of naïve CD4+ T cells in these two cellular types. I found that the transcription factor Ikaros is an indirect repressor of the transcription of pathogenic genes (Il3, Csf2, Ifng, Stat4…) in naïve CD4+ T cells, cultured to induce a polarization toward regulatory TH17 cells. Moreover, in absence of Ikaros and in regulatory condition of culture, adding IL-6 alone increases the expression of GM-CSF, key factor to induce auto-immune diseases, suggesting a role of Ikaros in this pathway. In conclusion, our results suggest that Ikaros is necessary to polarize correctly naïve CD4+ T cells in TH17 cells
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Houlard, Martin. "Étude de l'adressage et de l'implication nucléaire du proto-oncogène Vav-1." Paris 7, 2002. http://www.theses.fr/2002PA077098.
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Sims, Danica Anne. "The role of T-box transcription factor TBX3 in rhabdomyosarcoma." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/28264.
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Cancer remains one of the leading causes of death worldwide due to late diagnosis and ineffective treatment options. To address this problem requires the elucidation of the molecular mechanisms, including the signaling pathways and transcription factors that drive cancer initiation and progression. In this regard, our laboratory has been particularly interested in the embryonically important T - box family of transcription factors which has been heavily implicated in promoting initiation and progression of a long list of cancers. For example, the overexpression of the T - box factor TBX3, has been reported to function in promoting immortalization, migration, invasion and tumour formation in a number of epithelial - derived malignancies. Furthermore, our laboratory recently reported that TB X3 is also overexpressed in a wide range of sarcoma subtypes including rhabdomyosarcomas. This suggests that TBX3 may also contribute to the development and/or progression of sarcomas and potentially may serve as a biomarker for their diagnosis and targete d therapy. This is exciting because sarcomas are diverse and heterogeneous cancers with varying clinical behaviours, high rates of metastasis and recurrence and are notoriously resistant to current chemotherapies. However, whether TBX3 is a molecular drive r of these mesenchymal - derived cancers remains to be determined. This project therefore aimed to elucidate the role of TBX3 overexpression in embryonal rhabdomyosarcomas (ERMS) which is the most common soft tissue sarcoma in children and adolescents. To this end, ERMS cell culture models were established in which TBX3 was either stably knocked down or stably overexpressed and the resulting cells were tested for several features of the cancer phenotype using in vitro and in vivo experiments. The results show that TBX3 promotes cell proliferation, anchorage independent growth and cell migration in vitro and tumour formation and invasion in vivo. This study also provides evidence that nucleolin binds to, and co - operates with, TBX3 to promote proliferation and migration of ERMS cells. Furthermore, data from initial experiments reveal that Hsc70 interacts with TBX3, to possibly increase its protein stability, and that oncogenic c - Myc and AKT 1 positively regulat e TBX3 levels in ERMS. This, albeit preliminary data, suggest that Hsc70, c - Myc and AKT1 are responsible, in part, for the overexpression of TBX3 in ERMS. Together findings from this study implicate TBX3 as an oncogene in ERMS and suggest that TBX3, nucleolin, Hsc70, c - Myc and AKT may be used in combination as biomarkers for the diagnosis and targeted therapy of ERMS.
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Yeo, Crystal Jing Jing. "The role of the T box transcription factor T-bet in the CD8+ T Cell." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611838.
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Restorick, Siobhan Margaret. "Overlap of cytokine and transcription factor expression in T helper cell subsets." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/4808/.
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Until recently, CD4\(^+\)THelper (T\(_H\)) cells were thought to be permanently committed to a single lineage (e.g. T\(_H\)1, T\(_H\)17, T\(_H\)2 etc.). However there is now increasing evidence that T\(_H\) cells are plastic in nature and can gain phenotypic feature of other TH cells. Within this study I have investigated the overlap and plasticity of T\(_H\)1 cells and their presence in health and in the inflammatory setting of multiple sclerosis. Although CCR6 is considered a T\(_H\)17 marker there are other T\(_H\)cell subsets that express CCR6. I have identified a novel subset of T\(_H\)1 cells that express functional CCR6. CCR6\(^+\)T\(_H\)1 cells transcriptionally express 'T\(_H\)17'-related genes (e.g. RORC, IL-23R and IL4I1) but are distinct from IFN\(\gamma\)\(^+\)IL-17\(^+\) cells that also express CCR6, RORC and T-bet. Additionally I have identified candidate miRNAs that may play a role in controlling phenotypic features of these cells. T\(_H\)17 cells have been implicated in the pathogenesis of multiple sclerosis and enter the cerebrospinal fluid through CCR6-dependent migration. CCR6\(^+\)IFN\(\gamma\)\(^+\) cells were increased within the cerebrospinal fluid of patients with multiple sclerosis, suggesting a possible role in disease pathogenesis.
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Alberdi, Ibarzabal Maria 1986. "Regulation of T cell fates by the transcription factor NFAT5 in different microenvironments." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/481990.
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CD4+ T cells can adopt specific functional programs in response to changes in microenvironment variables, such as cytokine availability, cell-to-cell contacts and stress conditions. It has been described that the elevation of the extracellular concentrations of sodium can stimulate T cells to enhance the expression of diverse cytokines and receptors, some of which are regulated by the transcription factor NFAT5. NFAT5 is a general regulator of osmotic stress responses in mammals, although it also has hypertonicity-independent roles, such as in the regulation of thymocyte development and the activation of macrophages by Toll-like receptors. Here we have used mice that lack NFAT5 specifically in T cells to analyze the involvement of NFAT5 in the acquisition of polarized functions in T cells when they are activated in osmostress conditions and in the absence of hypertonicity. We describe that exposure of CD4+ T cells to hypertonic stress during stimulation with signals that mimic their T cell receptor enhances the expression of various genes associated with a T helper 17 (Th17) polarization profile, and analyze the role of NFAT5 and the Th17 master transcription factor ROR-γt in the hypertonicity-induced Th17 bias. We have also explored the potential relevance of NFAT5 as a regulator of pathogenic T cell responses in vivo in an experimental mouse model of inflammatory disease. Altogether, our results indicate that NFAT5 can modulate T cell polarization in different microenvironments, and that this capability may play a relevant role in inflammatory responses in vivo.Les cèl·lules T CD4+ poden adoptar programes funcionals diferents com a resposta a canvis en l’entorn com ara la disponibilitat de citocines, contactes entre cèl·lules i condicions d’estrès. Per exemple, s’ha descrit que un increment en la concentració extracel·lular de sodi promou en les cèl·lules T l’augment de l’expressió de gens que codifiquen per citocines i receptors, alguns dels quals són regulats pel factor de transcripció NFAT5. Aquesta proteïna és un regulador general de la resposta a l’estrès osmòtic en mamífers, encara que també té un paper en la regulació del desenvolupament dels timòcits i l’activació de receptors de tipus Toll en macròfags. En aquest estudi hem fet servir ratolins que no expressen NFAT5 en les cèl·lules T per tal d’analitzar quin és el paper d’aquest factor de transcripció en la polarització de les cèl·lules T activades en condicions isotòniques o d’estrès osmòtic. Hem descrit que l’exposició de les cèl·lules T CD4+ a estrès hipertònic durant la seva activació mitjançant l’estimulació del receptor de cèl·lules T, augmenta l’expressió de gens associats al perfil de polarització Th17. Hem analitzat el paper de l’NFAT5 i del factor de transcripció que regula la diferenciació de les cèl·lules Th17, el ROR-γt, en la polarització a cèl·lules Th17 induïda per hipertonicitat. També hem explorat el paper de l’NFAT5 en la resposta in vivo de les cèl·lules T en un model experimental de malaltia inflamatòria murina. En resum, els nostres resultats indiquen que l’NFAT5 pot modular la polarització de cèl·lules T en diferents microambients, i que aquesta capacitat pot jugar un paper important en respostes inflamatòries in vivo.
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Andreou, Artemisia Maria. "The role of T-box transcription factor TBX22 in craniofacial development." Thesis, Imperial College London, 2007. http://hdl.handle.net/10044/1/8517.
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X-linked cleft palate and ankyloglossia (CPX) is a semi-dominant condition caused by mutations in the T-box transcription factor gene TBX22, which accounts for around 5% of all cleft palate patients. TBX22 is expressed in the developing palatal shelves and tongue in both human and mouse embryos, however, biochemical function of the protein and its precise role in the cleft palate phenotype are still lacking. Various types of mutations have been identified in CPX patients, but notably most of the missense mutations localize within the DNA-binding T-box domain. This project set out to investigate the effects of naturally occurring missense mutations on protein function. Full-length wild type and mutant proteins were expressed in vitro and compared for DNA binding ability, localization to the nucleus and transcriptional activity. Protein trafficking into the nucleus was unaffected for all ten mutants tested. Both DNA-binding and transcriptional repression was abolished or considerably compromised for many of the mutants compared to wild-type although some were more mildly affected, perhaps reflecting their role in protein-DNA or protein-protein interaction. Many transcriptional repressors are subject to post-translational modification by the small ubiquitin-related modifier SUMO. In silico analysis of TBX22 shows that it contains several consensus SUMOylation sequences. Direct interaction between the two proteins was demonstrated both by western blotting and co-immunoprecipitation studies. Treatment with SUMO-specific proteases or mutation of the SUMO attachment sites show that SUMOylation is required for transcriptional repression. Cell based analysis of the CPX missense mutants showed that they uniformly fail to be modified by endogenous SUMO, suggesting involvement of a common mechanism. Collectively, the data suggests that the CPX phenotype results from loss of TBX22 repressor activity and that SUMO conjugation is likely to be a key factor during normal craniofacial development.
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Barra, Melanie Marianne [Verfasser], and Markus [Akademischer Betreuer] Feuerer. "Transcription factor 7 limits regulatory T cell generation and influences peripheral T cell subsets / Melanie Marianne Barra ; Betreuer: Markus Feuerer." Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1180735056/34.
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Dryden, Nicola Helen. "The transcription factor ERG is a gatekeeper of endothelial cell homeostasis." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9798.
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Endothelial cells (EC) maintain homeostasis through the tightly controlled balance between expression of protective genes and repression of pro-inflammatory genes, and loss of this balance can cause endothelial dysfunction, leading to inflammatory diseases including atherosclerosis. We have previously shown that the ETS transcription factor Erg is involved in maintaining EC homeostasis through transactivation of genes involved in key functions including angiogenesis, migration and survival. In addition to the role for Erg as a transcriptional activator, recent genome wide gene expression analysis has also highlighted a role for Erg in the repression of multiple pro-inflammatory genes. In this Thesis I describe a novel mechanism for Erg-mediated repression of these pro-inflammatory genes using ICAM-1 as a model. We identify two ETS binding sites (EBS) within the ICAM-1 promoter (EBS-118 and -181) which are required for Erg mediated repression. One of these EBS is within a functional NF-κB binding site. We show that the increase in ICAM-1 expression upon Erg inhibition is NF-κB dependent, and that Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene Set Enrichment Analysis (GSEA) of transcriptome profiles of Erg and NF-κB dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other pro-inflammatory genes, including cIAP2 and IL8. We investigate the role of chromatin modifying enzymes and histone modifications in Erg-mediated repression and show that in quiescent EC the ICAM-1 promoter is also bound by the histone methyltransferase ESET, and by HDAC1, both indicators of a repressed chromatin structure. Moreover, in silico data on histone modifications suggest that in quiescent EC the ICAM-1 promoter is in a repressed conformation. The results from this Thesis suggest that Erg acts as a gatekeeper to inhibit transactivation of pro-inflammatory genes in quiescent EC, providing an important barrier to protect against inappropriate endothelial activation.
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Hunter, Patricia Jean. "A role for BCL6b transcription factor in CD8+ T cell secondary expansion and memory." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604817.
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Lymphocyte development following encounter with microbial antigen is driven by the need to combat infection over the short and long term. This requires the generation and expansion of cells capable of immediate effector function as well as a population that endures to combat chronic infection or the reappearance of the same infection at a later time. BCL6b is a POZ family transcription factor and close homologue of BCL6. We found increased expression of BCL6b in memory compared to naïve CD8+ T cells. BCL6b deficient mice were generated by gene targeting in order to determine its function. In comparing wild type and BCL6b deficient CD8+ T cells, we demonstrated equivalent cytotoxicity and IFN-g production in individual antigen-specific cells. However, following a second challenge with antigen, BCL6b deficient CD8+ T cells failed to undergo proliferative expansion and significantly fewer antigen-specific cells were present at the end of the response compared with wild type. Therefore, BCL6b is required for the development of CD8+ T cells capable of expanding in response to secondary immune stimulation. By analogy to BCL6, which suppresses terminal differentiation in B cells, BCL6b may create a self-renewing stage of CD8+ T cell development that enables the continuous generation of effector T cells to combat sporadic or chronic infection over the lifetime of the host.
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Zhong, Yi. "Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice." Kyoto University, 2008. http://hdl.handle.net/2433/135795.
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Murphy, Timothy. "NFκB REGULATION OF PLACENTA GROWTH FACTOR AND ITS PRIMARY TRANSCRIPTION FACTOR, GLIAL CELL MISSING 1." OpenSIUC, 2014. https://opensiuc.lib.siu.edu/theses/1504.
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Preeclampsia is one of the most common complications of human pregnancy. Though its pathophysiology is not fully understood, it is thought that shallow migration of cytotrophoblast and the subsequent insufficient conversion of the maternal spiral arteries into utero-placental arteries play important roles. As fetal demands for oxygen and nutrients increase during gestation, this aberrant remodeling of the vasculature at the maternal-fetal interface results in a relatively hypoxic and nutrient-deficient placenta bed. Hypoxia is known to decrease placenta growth factor (PGF) expression in trophoblast and may play a key role in the suppression of PGF levels associated with preeclampsia. Systemic vasodilation, also critical to facilitate a healthy pregnancy, is significantly correlated with higher serum levels of PGF. Dysregulation of certain pro-inflammatory pathways, including NFκB, has also been implicated in preeclampsia development. The goal of our studies was to determine the mechanism governing NFκB regulation of PGF in trophoblast. Over-expression of NFκBp65, an active subunit of the NFκB complex, significantly decreases PGF mRNA expression in trophoblast - an effect which is ablated by co-expression of a dominant negative (dn) IκB which inhibits NFκB complex activity. Similarly, over-expression of NFκBp65 functionally inhibits glial cell missing 1 (GCM1), the primary transcription factor of PGF in trophoblast. Previous reports show that GCM1 protein is degraded during hypoxia. Because hypoxia and activation of NFκB have similar effects on both PGF and its transcription factor, GCM1, we have investigated the possibility of cross-talk between these two pathways. Over-expression of NFκBp65 was able to inhibit GCM1 protein stability and expression, but transient transfection with dnIκB was unable to prevent hypoxia-induced inhibition of PGF reporter activity. Collectively, these results indicate that hypoxia and NFκB activation utilize independent pathways to decrease PGF expression in trophoblast. To facilitate future investigation of these pathways, we have also established a novel stable cell line which can be used to induce high levels of NFκBp65 expression in a controllable manner, and observe its effects without the need for co-transfection.
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Bredenkamp, Nicholas. "Prevention and reversal of thymus involution mediated by the transcription factor Foxn1." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/7819.
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Central to the age-associated decrease in immune system function, characterised by the increase in the frequency and severity of infections and autoimmune diseases, is the decrease in production of naïve T cells by the thymus. This results from the targeted degeneration or involution of the thymus with age. One of the principal causes of involution is the loss of organisation and functionality of the thymic epithelium, which confers the primary function of the organ via interactive regulation of T cell development. Although the mechanisms that govern the deterioration of the thymic epithelium are poorly understood, a number of recent reports indicate that the transcription factor, Foxn1, is required to maintain this compartment in the postnatal thymus. Thus, the first aim of this study was to precisely profile Foxn1 expression levels in aging postnatal thymic epithelial cells. The second aim was to investigate the effects of upregulating Foxn1 in the aging thymus, which was achieved using a novel, regulatable Foxn1 mouse model generated during this study. In this study I show that Foxn1 is expressed at different levels in different postnatal thymic epithelial cell (TEC) sub-populations suggesting a dosage-dependent mode of action for Foxn1. Additionally, using two experimental approaches, I show that Foxn1 expression decreases with age in TECs, supporting the current data that implicate the loss of Foxn1 as a potential cause of thymus involution. Next, I generated a tissue-specific, regulatable Foxn1 mouse model that allowed me to modulate Foxn1 expression in the postnatal thymus. Firstly, using this model, I show that thymus involution can be prevented by the up-regulation and maintenance of Foxn1 expression from the onset of involution. Thymi that up-regulated Foxn1 were overtly larger and exhibited greater cellularity in both the thymocyte and epithelial compartments compared to age matched controls. Additionally, the larger TEC compartment contained a higher proportion of functional and proliferating TECs that upregulated a panel of genes involved in TEC development and function. Next, I show that Foxn1 up-regulation in aged, involuted thymi is sufficient to partially reverse involution, as shown by an increase in TEC organisation and intrathymic T cell numbers. While other strategies that promote thymic rebound or reversal have been reported, including cytokine treatment or sex steroid ablation, these approaches are complicated by side effects and toxicity. Hence, I propose a novel model for immune reconstitution through the regulation of Foxn1 expression in the postnatal thymus.
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Drews-Elger, Katherine. "Role of the transcription factor NFAT5 in mammalian cell cycle regulation." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7177.
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The transcription factor NFAT5/TonEBP belongs to the Rel family, which also comprises NF ÛB and NFATc proteins. NFAT5 only shares structural and functional homology with other Rel family members at the level of the DNA binding domain, and differs from them considerably in other regions. NFAT5 enables mammalian cells to adapt to and withstand hypertonicity by orchestrating an osmoprotective gene expression program whose products include chaperones as well as ransporters and enzymes that increase the intracellular concentration of compatible osmolytes. NFAT5-null mice suffer severe embryonic and perinatal lethality, and surviving adults manifest growth defects, pronounced renal atrophy and lymphocyte dysfunction associated with ineffective responses to hypertonicity. To circumvent the lethality of these mice and study the function of NFAT5 in specific cell types without the possible side effects of generalized defects in the organism, we have produced conditional knockout mice that allow the deletion of NFAT5 in specific cell types. Here we have investigated the hypertonic stress response in wild-type and NFAT5-/- lymphocytes. Proliferating lymphocytes exposed to hypertonic conditions exhibited an early, NFAT5- independent, genotoxic stress-like response with induction of p53, p21 and GADD45, downregulation of cyclins E1, A2 and B1 mRNA, and arrest in S and G2/M. This was followed by an NFAT5-dependent adaptive phase in wild-type cells, which induced osmoprotective gene products, downregulated stress markers, and resumed cyclin expression and cell cycle progression. NFAT5-/- cells, however, failed to induce osmoprotective genes and though they downregulated genotoxic stress markers, they displayed defective cell cycle progression associated with reduced expression of cyclins E1, A2, B1, and aurora B kinase. Finally, T cell receptor-induced expression of cyclins, aurora B kinase, and cell cycle progression were inhibited in NFAT5-/- lymphocytes exposed to hypertonicity levels in the range reported in plasma in patients and animal models of osmoregulatory disorders. Our results support the conclusion that the activation of an osmoprotective gene expression program by NFAT5 enables cells to proliferate under hypertonic stress conditions by maintaining the expression of S and G2/M cyclins and cell cycle progression.
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Gibson, Paul David. "The BCL6-IRF4-BLIMP1 transcription factor axis as a therapeutic target in T-cell lymphoma." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3246.
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Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of clinically aggressive malignancies derived from mature (post-thymic) T-cells or Natural Killer cells, which comprise approximately 10-15% of all non-Hodgkin lymphomas. In contrast to aggressive B-cell malignancies, which are often curable and for which advances in understanding disease biology have resulted in new targeted treatment approaches, the treatment of PTCL remains inadequate. Apart from those with ALK-positive anaplastic large cell lymphoma (ALCL), patients presenting with PTCL have a poor outcome with only approximately 25% cured of their disease. The pathogenesis of T-cell lymphoma is poorly understood and few new targeted therapies are emerging. The transcription factors BCL6, IRF4 and BLIMP1 function in a regulatory network to direct mature B-cell differentiation. They are genetically altered and dysregulated in B-cell malignancy, and BCL6 and IRF4 represent potential therapeutic targets. These transcription factors also interact to regulate T-cell differentiation and emerging data indicated genetic alteration in some PTCL. This project investigated the importance of BCL6, IRF4, and BLIMP1 in the regulation of PTCL cell line proliferation and survival using ALCL cell lines in vitro as a model. Lentiviral-mediated knockdown of BCL6 and IRF4, and overexpression of BLIMP1, each resulted in reduced proliferation/survival of some, but not all, ALCL cell lines tested, and no clear pattern of response emerged. These effects were associated with small changes in cell cycle progression and induction of apoptosis. Modulation of each of the transcription factors had small effects on the expression of the others, again with variable patterns between cell lines. IRF4 knockdown revealed a positive interaction with c-MYC and BLIMP1α in 2/3 ALK+ ALCL cell lines. Intriguingly, ALK inhibition with crizotinib revealed different patterns of NPM-ALK mediated dysregulation of the transcription factors across the cell lines. These data support a positive role for BCL6 and IRF4 in the maintenance of ALCL, and an inhibitory/tumour suppressor role for BLIMP1, but show variability in dependencies between cell lines which could reflect clinically important disease heterogeneity which must be considered when targeting this transcription factor axis therapeutically.
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Williams, Luke M. "The roles of the transcription factor Foxp3 in the development and maintenance of the regulatory T cell lineage /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8329.
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David, Rachel. "Regulation of T cell migration by the guanidine exchange factor Vav1." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/1361.
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T cell migration to sites of inflammation is an essential step of an effective immune response. T cell recruitment is enhanced by the recognition of their cognate antigen presented by the endothelium and their retention in the tissue is controlled by resident antigen presenting cells. Vav1 is a guanidine exchange factor for RhoGTPases that is activated through TCR signalling and is important for the cytoskeletal re-arrangements occurring during T cell activation and migration. In this study we have investigated the role of Vav1 in the recruitment and retention of antigen-specific T cells to sites of inflammation. HY-specific Ab-restricted WT and Vav1-/- T cells were generated and fully characterised for specificity and expression of migration-related markers. Vav1-/- T cells showed defects in adhesion, migration in response to ICAM-1, CXCL12 and CXCL10 and increased migratory speed in in vitro assays. Despite displaying defective motility in vitro, both constitutive migration and recruitment of Vav1-/- T cells to antigenic sites occurred normally. However, retention of Vav-1-/- T cells into antigenic tissue was profoundly impaired. This may be due to the inability by Vav-1-/- T cells to respond to ‘stop’ signals delivered by co-engagement of TCR and CD28. In contrast to recent reports on wild type T cells, Vav1-/- T cell migration and retention to sites of inflammation was not affected by engagement of the co-stimulatory molecule CD28, suggesting that Vav-1 recruitment during CD28-mediated signalling is instrumental for Vav-1-mediated regulation of T cell traffic
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Choi, AHyun. "RUNX1 Is an Oncogenic Transcription Factor that Regulates MYB and MYC Enhancer Activity in T-ALL." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/957.
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RUNX1, a transcription factor required for hematopoiesis and lymphocyte differentiation, is one of the most commonly targeted genes in hematopoietic malignancies. Mutations in the RUNX1 gene are associated with a poor prognosis in a subset of T cell acute lymphoblastic leukemia (T-ALL) and RUNX1 has been proposed as a tumor suppressor in TLX1/3-transformed human T-ALL. Recent ChIP-seq studies in human T-ALL cell lines demonstrated that a large portion of TAL1- and NOTCH1- bound regions contain RUNX binding sites in promoter or enhancer regions, suggesting oncogenic roles for RUNX1 in T-ALL. To interrogate RUNX1 functions in leukemogenesis, we depleted RUNX1 in a T-ALL mouse model and in human T-ALL cell lines. We found that RUNX1 is required for the maintenance of mouse T-ALL growth in vivo and the survival of human T-ALL cell lines in vitro. In addition, inhibition of the RUNX1 activity with a small molecule inhibitor impairs the growth of human T-ALL cell lines and primary patient samples. RUNX1 depletion reduces the expression of a subset of TAL1- and NOTCH1- regulated genes including the MYB and MYC oncogenes, respectively. We demonstrate that RUNX1 regulates transcription factor binding and acetylation of H3K27 at the Myb and Myc enhancer loci. These studies provide genetic and pharmacological evidences that RUNX1 supports T-ALL cell survival and suggest RUNX1 inhibitor as a therapeutic strategy in T-ALL treatment.
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Wendler, Christopher Charles. "Expression and function of transcription factor Mox-1 during early heart valve development." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284125.
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Epithelial to mesenchymal cell transformation (EMT) in the atrioventricular canal (AV canal) produces a population of fibroblast cells that contribute to the mitral and tricuspid valves of the fully formed heart. Formation of these cells is critical for normal heart development and disruption of this process leads to congenital heart disease. This study describes the role of the homeodomain containing transcription factor Mox-1 during this cell transformation process. Mox-1 protein and mRNA expression were detected during cell transformation in the cardiac cushions. This expression corresponded in time to stages of EMT characterized by cell shape change and invasion of the extracellular matrix. Antisense oligonucleotides to Mox-1 inhibited cell transformation in cultured AV canal explants. Previous reports indicated that the TGFβ3 signaling pathway also regulates cell transformation at similar stages. Experiments inhibiting the TGFβ3 pathway also inhibit Mox-1 expression. A 2kb portion of the Mox-1 promoter was cloned and a portion of this construct demonstrated a capacity to initiate transcription in AV canal cultures. The active fragment of the Mox-1 promoter was responsive to TGFβ3 signaling. This study indicates that Mox-1 is necessary but not sufficient for cell transformation in the AV canal cushions and is regulated by an important signaling pathway involved in this process.
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Zhao, Xiaosu. "NRC-interacting factor 1 interacts with p35 and regulates neuronal differentiation /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BICH%202006%20ZHAO.
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Ascough, Stephanie. "Analysis of the CD4+ T cell immune response to Anthrax Lethal Factor." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9465.
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The Gram-positive bacterium Bacillus anthracis is the causative agent of the potentially fatal illness, anthrax. A major determinant of B. anthracis pathogenicity is a binary toxin composed of Protective Antigen (PA) and one of two subunits; Lethal Factor (LF) or Edema Factor (EF). Translocation by PA into the host cell cytosol allows LF, which is a zinc metalloprotease, to inactivate the mitogen-activated protein kinase (MAPK) pathway. The expected consequences for the immune response include subversion of antigen presentation and T cell priming. In contrast to this, long term CD4+ T cell responses to LF were identified following natural human anthrax infection and vaccination, indicating that this toxin component is a principle B. anthracis antigen which may confer protective immunity. It has been observed that polymorphism in the HLA class II alleles at the DR and DQ loci affects susceptibilty to infectious disease outcome. In order to map the human response within a defined genetic background, transgenic mice expressing individual HLA heterodimers in the absence of endogenous MHC class II were utilised. HLA-DR1, HLA-DR15, HLA-DR4, HLA-DQ8 and HLA-DQ6 (the latter generated as part of this project) transgenic mice were compared in terms of response magnitude to LF and HLA expression levels. This was correlated with survival following live anthrax challenge. Immunodominant epitopes within LF were elucidated for all HLA-transgenic lines. Immunogenicity in the transgenic model was shown to be primarily restricted to epitopes from domains II and IV. Dominant epitopes, which were common to all HLA types, were identified in domain II. HLA-DR specific epitopes were also identified. T cell responses to cryptic epitopes, revealed following immunisation with the individual peptides, were compared to the immunodominant epitope hierarchy. A peptide epitope of LF was identified with a strong relative binding affinity for HLA-DR15, making it a candidate therapeutic for ‘MHC blockade’ strategies. This epitope was tested for therapeutic blockade in a humanised transgenic mouse model which develops spontaneous paralysis with central nervous system (CNS) pathology similar to human multiple sclerosis (MS). Disease is characterised by an autoimmune response to a DR15 restricted epitope of myelin basic protein (MBP). The LF peptide was found to prevent induction of antigen-specific T cell responses, presumably by HLA class II, reducing the inflammatory response to self-peptide both in vitro and in vivo.
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柴山, 史朗. "IFN-α Directly Promotes Programmed Cell Death-1 Transcription and Limits the Duration of T Cell-Mediated Immunity." 京都大学, 2011. http://hdl.handle.net/2433/147347.
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Hankel, Isaiah Luke. "The developmental regulator Gon4-like functions within the transcriptional networks that control B lymphopoiesis and CD4+ T cell responses." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2712.
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B and T lymphocytes are critical to the adaptive immune response against invading microorganisms. B and T cells develop in the bone marrow and thymus, respectively, and initiate a series of proliferative responses once they encounter their cognate antigen in the peripheral lymphoid organs. These developmental and functional processes are controlled by different networks of transcriptional regulators that repress and activate gene expression. Identifying proteins that activate or repress specific genes and integrating these proteins into their transcriptional networks is critical to understanding lymphocyte development and function. The study of B lymphopoiesis and CD4+ T cell functional responses has greatly increased our understanding of how transcriptional regulators and other proteins cooperate to specify cell fates and responses. While many of the key components of these protein networks have been defined, several factors have yet to be described.
Chemically induced random mutagenesis is a powerful tool for identifying genes that have critical biological functions. Justy mutant mice were generated by injecting wild-type mice with of N-Ethyl-N-Nitrosourea (ENU), a mutagen, which generated a unique point mutation in the mouse Gon4-like (Gon4l) gene. This mutation was found to specifically blunt B cell development and impair the functional responses of CD4+ T cells. Given that the Gon4l protein contains domains implicated in transcriptional regulation and B lymphopoiesis and T cell responses are regulated transcriptionally, the aim of this project was to characterize T and B lymphocyte populations from Justy mice and provide insights into the mechanisms underlying the regulation of gene expression during these biological processes. The work presented in this dissertation demonstrates that the protein encoded by Gon4l is essential for B lymphopoiesis, likely through the repression of alternate lineage genes. This work also shows that in CD4+ T cells, decreased Gon4l protein expression results in reduced levels of proliferation in response to exogenous IL-2 or T cell receptor (TCR) engagement. Additionally, Justy mutant CD4+ T cells display a reduced ability to generate IFNγ-producing cells in response to Th1 polarization in vitro. Collectively, these defects correlate with elevated levels of genes known to specifically inhibit the above developmental and functional processes. Thus, this dissertation proposes that Gon4l acts as a transcriptional repressor within the protein networks controlling B lymphopoiesis and CD4+ T cell responses.
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涂文偉 and Wenwei Tu. "Effects of insulin-like growth factor 1 on cord blood T cell development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31239377.
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Tu, Wenwei. "Effects of insulin-like growth factor 1 on cord blood T cell development /." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B2102893X.
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MA, CI Miss. "THE TRANSCRIPTION FACTOR BTB AND CNC HOMOLOG 1 IN THE REGULATION OF CELL DIFFERENTIATION AND ORGANOGENESIS." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1185995222.
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Zhang, Jiang. "Transcriptional Control of NK and iNKT Cell Development." Thesis, Lyon, 2020. http://www.theses.fr/2020LYSEN033.
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Les cellules tueuses naturelles (NK) sont des cellules lymphoïdes innées largement reconnues comme des effecteurs importants lors des réponses antivirales et anti-tumorales. T-bet et Eomes sont deux facteurs de transcription de la famille des T-box dont le domaine de liaison à l‘ADN est très homologue. Il a été précédemment démontré que ces deux facteurs régulent le développement des cellules NK, mais la façon dont ils se coordonnent demeure mal connue. Dans cette étude, nous avons identifié des rôles complémentaires d'Eomes et de T-bet dans le contrôle de l'expression des gènes pendant la maturation des cellules NK et avons constaté que T-bet et Eomes régulent principalement différents groupes de gènes et à différents stades de maturation. L'analyse de la liaison génomique a révélé un chevauchement significatif entre Eomes et T-bet. De plus, l'analyse in silico de la liaison à l'ADN suggère qu’Eomes et T-bet dépendent d'autres co-facteurs pour exercer leur activité spécifique. De plus, T-bet et Eomes régulent l'accessibilité à la chromatine, ce qui entraîne le contrôle de la différenciation des cellules NK. Les cellules T tueuses naturelles invariantes (iNKT) sont des cellules T non conventionnelles portant un récepteur de cellules T (TCR) invariant et sont distinctes des cellules T CD4 et CD8 conventionnelles. Des analyses précédentes ont suggéré un rôle pour Zeb1 dans le développement des cellules T. Nous avons démontré que Zeb1 était essentiel pour le développement des cellules T NK1.1 + en particulier les cellules iNKT. Dans les souris mutantes « Cellophane » une forme de Zeb1 tronquée est exprimée, ce qui entraine un défaut de développement des cellules iNKT principalement par dérégulation de la signalisation du TCR et par une répression de la prolifération et de la survie dans les progéniteurs des lymphocytes T aux stades DN2 et DP. Une analyse transcriptomique sur WT et Cellophane DP a révélé que Zeb1 régulait l'expression de plusieurs gènes impliqués dans le cycle cellulaire et la signalisation TCR, ce qui était cohérent avec les phénotypes que nous avons observés chez la souris. Enfin, plusieurs éléments de preuve suggèrent que Zeb1 agit en coordination avec les protéines E telles que TCF1 et HEB pendant le développement des lymphocytes TNatural killer (NK) cells are innate lymphoid cells widely recognized as important effectors during antiviral and anti-tumor responses. T-bet and Eomes are two transcription factors from the T-box family that are homologous with each other for protein sequence and DNA binding preferences. Both factors were previously shown to regulate NK cell development, but how they work together remains unclear. In this study, we identified complementary roles of Eomes and T-bet in the control of gene expression during NK cell maturation and found that T-bet and Eomes regulate mostly different gene sets and at different maturation stages. Analysis of genomic binding revealed a significant overlap between Eomes and T-bet. In addition, in silico analysis of DNA binding suggests that Eomes and T-bet rely on other co-factors to allow TF-specific activity. Moreover, T-bet or Eomes also regulate chromatin accessibility resulting in the control of NK cell development. Invariant natural killer T (iNKT) cells are unconventional T cells bearing an invariant T cell receptor and are distinct from conventional CD4 or CD8 single positive T cells. Previous analyses suggested a role for Zeb1 in T cell development. We demonstrated that Zeb1 was essential for the development of NK1.1+ T cell especially iNKT cells. The truncated form of Zeb1 in the Cellophane mutant mouse abrogated iNKT cell development mainly through the deregulation of TCR signaling and survival and the repression of proliferation in T cell progenitors including DN2 and DP stages. A transcriptomic analysis on WT and Cellophane DP revealed that Zeb1 regulated the expression of multiple genes involved in cell cycle and TCR signaling, which was consistent with the phenotypes that we observed in mice. Finally, multiple lines of evidence suggest that Zeb1 acts in coordination with E-proteins such as TCF1 and HEB during T cell development
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Chen, Aichun. "Regulation of lozenge transcription factor activity and blood cell development by MLF and its partner DnaJ-1." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30064/document.
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L'hématopoïèse est le processus de formation des cellules sanguines différenciées à partir de cellules souches hématopoïétiques. Ce processus est étroitement contrôlé par l'intégration de signaux de développementaux et homéostatiques pour assurer une production équilibrée des différents types de cellules sanguines. Au niveau moléculaire, la régulation de ce processus est médiée par un certain nombre de facteurs de transcription, en particulier par les membres de la famille RUNX. Ainsi, des mutations affectant les membres de cette famille peuvent entrainer une déréglementation du programme de différenciation hématopoïétique et causer des hémopathies, dont des leucémies. D'une manière intrigante, de nombreux régulateurs de la transcription et des voies de signalisation contrôlant le développement des cellules sanguines sont évolutivement conservés des humains à Drosophila melanogaster, qui est donc utilisée comme organisme modèle pour étudier les mécanismes sous-jacents à la spécification des lignages sanguins et au contrôle de l'homéostasie des cellules sanguines. Les membres de la famille Myeloid Leukemia Factor (MLF) ont été impliqués dans l'hématopoïèse et dans la transformation oncogénique des cellules sanguines, mais leur fonction et leur mécanisme d'action moléculaire restent insaisissables. Des travaux précédents chez la Drosophile ont montré que MLF stabilise le facteur de transcription de type RUNX Lozenge (LZ) et contrôle le nombre de cellules sanguines LZ+. Au cours de ma thèse, j'ai cherché à déchiffrer le mécanisme moléculaire d'action de MLF sur Lozenge dans les cellules sanguines. Par une approche protéomique puis par des expériences de co-immunoprécipitation dans les cellules de Drosophile Kc167, nous avons identifié le co-chaperon de type Hsp40 DnaJ-1, et son partenaire le chaperon Hsc70-4, comme deux partenaires de MLF. De façon importante, nous avons montré que l'inhibition de l'expression de DnaJ-1 ou de Hsc70-4 dans les cellules Kc167 induit une réduction du niveau de protéine Lozenge et une diminution de sa capacité à activer la transcription très semblable à celles observées suite à l'inhibition de l'expression de MLF. De plus, la sur-expression de mutants de DnaJ-1 incapables d'activer le chaperon Hsc70-4 entraîne aussi une réduction du niveau de Lozenge et de sa capacité de transactivation et des expériences de coimmunoprécipitation montrent que Lozenge interagit avec MLF, DnaJ-1 et Hsc70-4. Nos résultats suggèrent donc que MLF agit au sein d'un complexe chaperon composé de DnaJ-1 et Hsc70-4 pour contrôler le niveau de Lozenge. En utilisant différents mutants de MLF ou DnaJ-1, nous avons montré que MLF et DnaJ-1 interagissent ensemble et avec Lozenge via des domaines phylogénétiquement conservés. D'autre part, des expériences de GST " pull down " in vitro suggèrent que ces trois protéines peuvent interagir ensemble directement. Nous proposons donc que MLF et DnaJ-1 contrôlent le niveau de protéine Lozenge en interagissant avec elle et en favorisant son repliement et/ou sa solubilité via l'activité chaperon de Hsc70-4. En parallèle, nous avons étudié la fonction de DnaJ-1 in vivo dans le développement des cellules sanguines de la Drosophile. Nos résultats montrent que, comme mlf, la perte de dnaj-1 s'accompagne d'une augmentation de la taille et du nombre des cellules sanguines LZ+, ainsi que d'une hyperactivation de la voie de signalisation Notch dans ces cellules. Nos résultats suggèrent que des hauts niveaux de Lozenge sont nécessaires pour contrôler le nombre et la taille des cellules LZ+ et pour inhiber l'expression de Notch. Nous proposons que le complexe MLF/DnaJ-1 contrôle le développement du lignage LZ+ en régulant le niveau de protéine Lozenge, et ainsi le niveau d'activité de la voie Notch. En conclusion, nos résultats ont mis à jour un lien fonctionnel entre MLF, le co-chaperon de type Hsp40 DnaJ-1 et un facteur de transcription de type RUNX, qui pourrait être conservé dans d'autres espècesHematopoiesis is the process of formation of fully differentiated blood cells from hematopoietic stem cells (HSCs). This process is tightly controlled by the integration of developmental and homeostatic signals to ensure the generation of an appropriate number of each blood cell type. At the molecular level, the regulation of this developmental process is mediated by a number of transcription factors, especially by members of the RUNX family, and mutations affecting these factors are at the origin of numerous hemopathies, including leukemia. Intriguingly, many transcriptional regulators and signaling pathways controlling blood cell development are evolutionarily conserved from humans to Drosophila melanogaster. Hence, the fruit fly has become a potent and simplified model to study the mechanisms underlying the specification of blood cell lineages and the regulation of blood cell homeostasis. Members of the Myeloid Leukemia Factor (MLF) family have been implicated in hematopoiesis and in oncogenic blood cell transformation, but their function and molecular mechanism of action remain elusive. Previous work in Drosophila showed that MLF stabilizes the RUNX transcription factor Lozenge (LZ) and controls the number of LZ+ blood cells. During my PhD, I sought to further decipher the molecular mechanism of action of MLF on Lozenge during blood cell development. Using a proteomic approach in Drosophila Kc167 cells, we identified the Hsp40 co-chaperone family member DnaJ-1 and its chaperone partner Hsc70-4 as two partners of MLF. These interactions were confirmed by co-immunoprecipitations and in vitro pull-down assays. Importantly, we found that knocking down DnaJ-1 or Hsc70-4 expression in Kc167 cells caused a reduction in the level of Lozenge protein and a concomitant decrease in Lozenge transactivation activity, which were very similar to those caused by MLF knock-down. Similarly, over-expression of two DnaJ-1 mutants that are unable to stimulate the chaperone activity of Hsc70-4 also decreased Lozenge level and impaired its capacity to activate transcription. These results suggest that MLF could act within a chaperone complex composed of DnaJ-1 and Hsc70-4 to control Lozenge stability and activity. Along that line, we showed by co-immunoprecipitation that Lozenge interacts with MLF, DnaJ-1 and Hsc70-4, respectively. Using various truncated mutants of MLF or DnaJ-1, we showed that MLF and DnaJ-1 interact and together with Lozenge through their conserved MLF homology domain (MHD) and C-terminal region, respectively. Furthermore, in vitro GST pull-down assays suggested that the interactions between MLF, DnaJ-1 and Lozenge are direct. Thus, we propose that MLF and DnaJ-1 control Lozenge protein level by interacting with it and by promoting its folding and/or solubility via the Hsc70 chaperone machinery. In parallel, we assessed DnaJ-1 function in Drosophila blood cells in vivo using a null allele of dnaj-1 generated by CRISPR/Cas9 technique. We found that, like mlf, dnaj-1 mutation leads to an increase in the number and size of LZ+ blood cells, as well as to an over-activation of the Notch signaling pathway in these cells. Moreover, our data suggested that high levels of active Lozenge are required to control the number and size of LZ+ blood cells, and to down-regulate Notch expression. We propose that the MLF/DnaJ-1 complex controls LZ+ blood cell development in vivo by regulating Lozenge protein level/activity and thereby Notch pathway activation. In sum, our results establish a functional link between MLF, the Hsp40 co-chaperone DnaJ-1 and the RUNX transcription factor Lozenge, which could be conserved in other species
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Takiuchi, Yoko. "HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia." Kyoto University, 2018. http://hdl.handle.net/2433/232095.
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Svensson, Alexandra. "Immune regulation of herpes simplex virus type 2 infection : special emphasis on the transcription Factor T-bet /." Göteborg : Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, Göteborg University, 2006. http://hdl.handle.net/2077/852.
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Lehmkuhl-Dakhwe, K. Virginia. "Regulation of p53, p21, ARF, BIM, and BAX by the Transcription Factor Trip-Br1." Ohio University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1194549826.
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Gao, Weiwei, and 高蔚为. "Salt-inducible kinases function as a host restriction to human T-cell leukemia virus type 1 transcription." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B4818309X.
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Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax is the major viral transactivator and transforming protein centrally involved in the proviral transcription, transformation and proliferation of infected T-cells as well as progression of diseases caused by HTLV-1 infection. Salt-inducible kinases (SIKs) are serine/threonine protein kinases belonging to the AMPK-related kinase (AMPK-RK) family. SIK subfamily consists of three isoforms named SIK1, SIK2 and SIK3 respectively. We have previously demonstrated the negative regulatory role of SIK1 in Tax-mediated activation of proviral transcription from long terminal repeats (LTR). In this study, we reported that both SIK2 and SIK3 exhibited a kinase-dependent suppressive effect on Tax-activated LTR transcription. We also found that SIK1, SIK2 and SIK3 act additively to suppress Tax activation of LTR. We further demonstrated that the SIK2- and SIK3-mediated suppression on LTR transcription was achieved through phosphorylation of TORC1, an essential transcriptional coactivator of CREB required for Tax-mediated transcriptional activation of LTR. Our findings revealed a new function of SIK2 and SIK3 in host restriction to HTLV-1 transcription. Pharmaceutical activation of SIKs or upstream kinase such as LKB1 may provide a new strategy for anti-HTLV-1 therapy.published_or_final_version
Biochemistry
Master
Master of Medical Sciences
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Kamath, Meghana B. "Reduced PU.1 concentrations lead to hematopoietic stem cell defects and lineage-inappropriate gene expression." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1232633475.
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Wikström, Ingela. "Molecular genetics of B- and T-lymphocyte development." Doctoral thesis, Umeå universitet, Medicinsk biovetenskap, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-802.
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Lymphocytes are essential for the generation of specific immunity. Development of B cells in the bone marrow and T cells in the thymus have several analogous features, and are tightly regulated processes. Even though there is an increasing amount of information concerning lymphopoiesis, a lot of questions remain. The aim of this thesis has been to understand some of the molecular events that contribute to the control of lymphocyte development. Expression of the B cell receptor is an important checkpoint in B lymphocyte development. The Dµ protein is a truncated B cell receptor that can induce some of the signals elicited by full length µ, but cannot promote further B cell differentiation. In order to determine if this could stem from an impaired survival signal, we introduced Bcl-2 into RAG2 deficient Dµ transgenic mice. Analysis of these mice showed that Dµ could not support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, data from recombination competent Dµ transgenic mice demonstrated that the Dµ induced partial block is permissive for marginal zone B cell development, whereas the formation of follicular B cells is severely reduced. The bHLH family of transcription factors is known to be involved in the regulation of lymphocyte development. Whereas the roles of E2A and HEB have been well documented in both B- and T-lymphocytes, detailed knowledge concerning E2-2 is lacking. To address the role of E2-2 in B cell development, we have reconstituted mice, using E2-2 deficient fetal liver cells, and analysed the B cell compartments. We also measured mRNA expression patterns for the three E-proteins in wildtype mice. Resulting data show that, in addition to a role in B cell lineage entry, E2-2 is required for efficient expansion of pro-B cells, and also influences the follicular versus marginal zone decision. While focusing on assigning a role for E2-2 in T-cell development, we analyzed the expression of the E-proteins during this process and performed functional studies in fetal thymic organ cultures. E2-2 deficient mouse embryos were shown to display a partial block at the DN3 stage, which was not due to proliferation or apoptosis defects. In addition, analysis of expression levels of the pre-Talpha chain suggests that E2-2 may play a role in the regulation of transcription of pre-Talpha, and therefore in the assembly of the pre-T cell receptor.
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Jehn, Birgit. "The role of transcription factor AP-1 during terminal differentiation and programmed cell death of mammary epithelial cells /." [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Hagiya, Keita. "ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells." Kyoto University, 2012. http://hdl.handle.net/2433/152491.
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Nelson, Nadine D. "Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5810.
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Pancreatic cancer is one of the deadliest cancers with a five-year survival rate of 6%. Pancreatic cancer is resistant to conventional chemotherapy and is usually diagnosed at late stages. Current treatment options have minimal effects in extending patients' lives beyond 10 months. One significant limitation in developing treatments to combat pancreatic cancer is its immunosuppressive microenvironment. Pancreatic cancer secretes factors that activate immunosuppressive cells, such as regulatory T cells (Tregs). These Tregs suppress effector CD4+ and CD8+ T cell anti-tumor immune responses. Therefore, novel treatment options to reduce Treg-mediated immune suppression and increase the numbers and functions of CD4+ and CD8+ T cells are paramount to enhance anti-tumor immunity in pancreatic cancer tumor-bearing (TB) hosts.
The alternatively spliced transcription factor Ikaros is essential for lymphocyte development and is considered a tumor suppressor in T cells. Ikaros' protein stability and function are regulated by its phosphorylation and dephosphorylation by protein kinase CK2 and phosphatase 1 (PP1), respectively. Mutations and functional inactivation of Ikaros have mainly been investigated in T cell leukemias and lymphomas. In this dissertation, we investigated the role of Ikaros in regulating T cell homeostasis in murine pancreatic cancer.
In this study, we report that Ikaros proteins are degraded by the ubiquitin-proteasome pathway in response to factors produced by murine pancreatic cancer cells. Our results further suggest that an increase in CK2 activity leads to Ikaros' degradation and disrupts its localization to pericentromeric heterochromatin in our murine pancreatic TB model. This loss of Ikaros expression is accompanied by an imbalance in T cell homeostasis. More specifically, we observe a significant decrease in effector CD4+ and CD8+ T cells but an increase in Treg percentages in TB and spontaneous pancreatic cancer models. T-cell specific defects in Ikaros protein expression were also observed in TB CD3+ T cells. Apigenin, a natural plant flavonoid and CK2 inhibitor, restored expression of some Ikaros isoforms in our TB model. Apigenin also displayed immunological benefits evident by enhanced anti-tumor immunity in TB mice. These data provide mechanistic and functional evidence that pharmacological inhibition of CK2 can regulate Ikaros expression and identifies the possible involvement of Ikaros in regulating T cell immune responses in murine pancreatic cancer.
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Pusch, Tobias [Verfasser], Edgar [Gutachter] Serfling, and Thomas [Gutachter] Rudel. "The transcription factor NFATc1 mediates cytotoxic T cell function in vitro and in vivo / Tobias Pusch. Gutachter: Edgar Serfling ; Thomas Rudel." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1111887268/34.
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Symonds, Alistair. "The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis." Thesis, Queen Mary, University of London, 2009. http://qmro.qmul.ac.uk/xmlui/handle/123456789/409.
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Tolerance of T cells to self-antigen is crucial to prevent the development of autoimmune disease. How self-tolerance is controlled at the transcriptional level is, however, unknown. We discovered that the transcription factor Early Growth Response 2 (Egr-2) was expressed by tolerant T cells, and by CD4+CD44high T cells in the absence of overt antigen stimulation, in vivo. To investigate the roles of Egr-2 in T cells, we generated CD2 cell specific Egr-2 deficient (Egr-2 cKO) mice. The proliferation of Egr-2 cKO CD44high T cells in vivo was markedly increased leading to progressive accumulation as the mice aged. By 15 months of age CD4+CD44high cells constituted the predominant T cell population in the peripheral lymphoid organs of Egr-2 cKO mice and expressed high levels of the activation markers CD25 and CD69. In addition to this lymphoproliferative disorder, 15 month old Egr-2 cKO mice showed signs of lupus-like autoimmune disease. This autoimmune syndrome was characterised by glomerulonephritis and proteinuria, infiltration of T cells into internal organs and, crucially, auto-antibodies directed against nuclear components; the hallmark of lupus. We observed decreased expression of the cyclin-dependent kinase inhibitor p21cip1 in Egr-2 cKO CD4+CD44high T cells while TCR stimulation induced IFN-γ, and, in particular, IL-17A and IL-17F expression was markedly increased. Consistent with these findings, we observed increased numbers of IFN-γ and IL-17 producing CD4+ T cells in Egr-2 cKO mice. The numbers of IFN-γ and IL-17 producing CD4+ T cells further increased as the mice aged in parallel with the gradual development of symptoms of lupus-like disease. These results demonstrate that Egr-2 is an intrinsic regulator of both T cell homeostasis and T cell tolerance.