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1
Carson, Bryan David. "Impaired T cell receptor signaling in regulatory T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8337.
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Stefkova, Martina. "Regulatory T cells control the CD4 T cell repertoire." Doctoral thesis, Universite Libre de Bruxelles, 2016. https://dipot.ulb.ac.be/dspace/bitstream/2013/233151/3/Table.pdf.
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Des études récentes menées chez l’homme et la souris ont suggéré que la diversité du répertoire TCR pourrait jouer un rôle dans la protection contre des pathogènes à haut pouvoir mutagène. Afin d’étudier le répertoire des lymphocytes T CD4, nous avons utilisé un modèle de souris TCRβ transgéniques exprimant une chaine β spécifique du peptide env122-141 dans le contexte du MHCII. Suite à l’immunisation des souris TCRβ transgéniques avec des cellules dendritiques pulsées avec le peptide env, une rapide prolifération et une restriction du répertoire des lymphocytes T Vα2 CD4 spécifiques est observée. L’analyse de la diversité du répertoire de ces cellules par séquençage à haut débit, a montré l’émergence d’un répertoire plus divers dans des souris déplétées en lymphocytes T régulateurs. Ces résultats suggèrent qu’en plus du rôle des Tregs dans le contrôle de la magnitude de la réponse immunitaire, ces cellules pourraient également contrôler la diversité du répertoire des lymphocytes T suite à une stimulation antigénique.Recent studies conducted in mice and humans have suggested a role for the TCR repertoire diversity in immune protection against pathogens displaying high antigenic variability. To study the CD4 T cell repertoire, we used a mouse model in which T cells transgenically express the TCRβ chain of a TCR specific to a MHCII-restricted peptide, env122-141. Upon immunization with peptide-pulsed dendritic cells, antigen-specific Vα2+ CD4+ T cells rapidly expand and display a restricted TCRα repertoire. In particular, analysis of receptor diversity by high-throughput TCR sequencing in immunized mice suggests the emergence of a broader CDR3 Vα2 repertoire in Treg-depleted mice. These results suggest that Tregs may play a role in the restriction of the CD4 T cell repertoire during an immune response, raising therefore the possibility that in addition to controlling the magnitude of an immune response, regulatory cells may also control the diversity of TCRs in response to antigen stimulation.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
3
Sarris, Milka. "Dynamics of helper T cell and regulatory T cell interactions with dendritic cells." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611896.
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Nadal-Melsio, Elisabet. "Regulatory T cells after allogeneic stem cell transplantation." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523746.
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Mavin, Emily. "Regulatory T cells in haematopoietic stem cell transplantation." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2731.
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Graft-versus-host disease (GvHD) remains the main complication associated with haematopoietic stem cell transplantation (HSCT). GvHD is caused by allo-reactive donor T cells mounting an attack against specific target tissues. CD4+CD25HiFoxp3+ regulatory T cells have been shown to modulate GvHD in vitro and also in vivo animal models. More recently early stage clinical trials have described the successful use of Treg to reduce the incidence of GvHD following HSCT. The aim of this study was to investigate further the suppressive mechanisms by which Treg are able to modulate GvHD and assess the influence of Treg on the beneficial graft-versus-leukaemia (GvL) effect therefore providing further insight into the use of Treg in the therapeutic management of GVHD. Data presented in this thesis demonstrates the successful isolation and expansion of a highly pure Treg population which maintained suppressive capacity throughout culture. We also confirmed that Treg retain suppressive capacity following cryopreservation resulting in reduced workload and increased consistency when used for in vitro functional studies. We also provide the first human in vitro evidence that Treg are able to prevent cutaneous GvH reaction by blocking the migration of effector T cells into the target tissues. The presence of Treg during allo-stimulation caused reduced effector cell activation, proliferation, IFNγ secretion and decreased skin homing receptor expression. Further investigation into the Treg modulation of dendritic cells demonstrated, for the first time in experimental in vitro human GvHD, that this was due to ineffective effector T cell priming in the presence of Treg caused by impairment of dendritic cell functions. Comprehensive phenotypic and functional analysis of Treg treated moDC showed their decreased antigen processing ability and allostimulatory capacity, resulting in a less severe GvH reaction in the skin explant model. Furthermore, this work has revealed that despite Treg impairing in vitro GvL mechanisms at a cellular level there was no association observed between increased Treg levels and the incidence of relapse in a small clinical cohort of HSCT patients. In conclusion this study has provided further insight into the mechanisms by which Treg are able to modulate GvHD. This would inform future clinical trials using Treg as a therapeutic alternative to current GvHD treatment and prophylaxis.
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Raynor, Jana L. "Regulatory T Cell Homeostasis in Aging." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416570329.
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Smith, Trevor Robert Frank. "Modulation of CD4+ T cell responses by CD4+CD25+ regulatory T cells and modified T cell epitopes." Thesis, Imperial College London, 2004. http://hdl.handle.net/10044/1/11317.
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Soper, David Michael. "Interleukin-2 receptor and T cell receptor signaling in regulatory T cells /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8344.
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Cabbage, Sarah E. "Reversible regulatory T cell-mediated suppression of myelin basic protein-specific T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5034.
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Vanderleyden, Ine. "Follicular regulatory T cell migration and differentiation." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288422.
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The germinal centre (GC) response is critical for generating highly effective humoral immune responses and immunological memory that forms the basis of successful immunisation. Control of the output of the GC response requires Follicular regulatory T (Tfr) cells, a subset of Foxp3+ Treg cells located within germinal centres. Tfr cells were first characterised in detail in 2011 and because of this relatively little is known about the exact role of Tfr cells within the GC, and the mechanism/s through which they exert their suppressive function. At the outset of this work, the major barrier to understanding Tfr cell biology was the lack of appropriate tools to study Tfr cells specifically, without affecting Tfh cells or other Treg cell subsets. This thesis set out to develop a strain of mice that specifically lacks Tfr cells. A unique feature of Tfr cells is their CXCR5-dependent localisation within the GC. Therefore, genetic strategies that exclude Treg cells from entering the GC are a rational approach to generating a mouse model that lacks Tfr cells. To this end, I generated a strain of mice that lacks CXCR5 on Foxp3+ Treg cells. These animals show a ~50% reduction in GC localised Tfr cells, and a GC response that is comparable to control animals. These data indicated that redundant mechanisms are involved in Treg cell homing to the GC. I identified CXCR4 as a chemokine receptor that is also highly expressed on Tfr cells, and hypothesised that it may also be involved in Tfr cell localisation to the GC. Surprisingly, simultaneous deletion of both CXCR4 and CXCR5 in Treg cells resulted in a less marked reduction in Tfr cells compared to deletion of CXCR5 alone, suggesting that CXCR4 might be involved in negative regulation of Treg homing to the GC. These data identify both CXCR4 and CXCR5 as key regulators of Tfr cell biology. Bcl6 drives Tfr cell differentiation, but how this transcriptional repressor facilitates commitment to the Tfr cell subset is unknown. I hypothesised that Bcl6 drives Tfr cell differentiation by repressing Tbx21, the transcriptional regulator involved in the differentiation of Th1-like Treg cells. I tested this hypothesis in Bcl6fl/fl CD4cre/+ animals and unexpectedly found that loss of Bcl6 regulates Treg cell differentiation in the absence of immunisation or infection. I have demonstrated that thymic loss of Bcl6 results in an increase in activated effector Treg cells, which occurs very early in life. These data point to a novel role for Bcl6 in preventing early thymic Treg activation, indicating that Bcl6 has a global role in Treg development and differentiation that is not simply limited to Tfr cells.
11
Wright, G. P. "Generation of antigen-specific regulatory T cells by T cell receptor gene transfer." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18952/.
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Regulatory T cells (Tregs) have shown considerable potential in the treatment of murine models of immuno-pathology. Whilst poly-clonal Tregs are able to suppress immuno-pathology in a number of models, the superiority of Ag-specific Treg treatment has been demonstrated using Tregs from T cell receptor (TCR)- transgenic animals. Translation of these promising results to the clinic has been hampered by difficulties in isolating or enriching the rare Ag-specific Tregs from the polyclonal population. Here I describe two distinct approaches to generate Ag-specific T cells with regulatory ability: firstly, TCR gene transfer into purified CD4+CD25+ T cells was used to redirect the specificity of naturally occurring Tregs. Secondly, co-transfer of FoxP3 and TCR genes served to convert conventional CD4+ T cells into Ag-specific ‘Treg-like’ cells. Both approaches generated T cells that suppressed in vitro and engrafted efficiently, retaining TCR and FoxP3 expression, when adoptively transferred into recipient mice. Using an established arthritis model, I demonstrate Ag-driven accumulation of the gene modified T cells at the site of joint inflammation, which resulted in a reduction of joint swelling. In animals treated with TCR-transferred natural Tregs this was accompanied by a local reduction in the number of inflammatory Th17 cells and a significant decrease in arthritic bone destruction. Together, I have described a strategy to rapidly generate Ag-specific Tregs capable of antigen-dependent amelioration of autoimmune damage in the absence of general immune suppression. These approaches could practicably be translated into the clinic in order to treat numerous different immuno-pathologies.
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Paiva, Ricardo de Sousa. "T cell Maturation and Regulatory T Cell Differentiation:From the Thymus to the Periphery." Doctoral thesis, Universidade Nova de Lisboa.Instituto de Tecnologia Química e Biológica, 2012. http://hdl.handle.net/10362/10587.
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Immunological tolerance, that is, the failure to mount an immune response to
an otherwise immunogenic molecule, is one of the fundamental questions in
immunology. The fact that lymphocytes express antigen receptors that are
generated randomly and have the potential to recognize any conceivable
antigen, adds another puzzle to the physiology of immunological tolerance.
The other side of the coin, the general absence of immune responses to self
antigens, is ensured by a tight regulation and several selection steps during
T and B cell differentiation. One of these processes is the differentiation of
regulatory T cells (Treg). While developing in the thymus, T cell clones
bearing receptors with high affinity/avidity to antigens present at the time of
differentiation may be eliminated by apoptosis or, alternatively, express
Foxp3 and become Treg. Treg are key players in the regulation of
immunological tolerance since humans and mice with complete loss of
function variants of this gene develop fatal autoimmune conditions early in
life.(...)Dissertation presented to obtain the Ph.D degree in Immunology
13
Lindqvist, Camilla. "T Regulatory Cells – Friends or Foes?" Doctoral thesis, Uppsala universitet, Enheten för klinisk immunologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128837.
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T regulatory cells (Tregs) have been extensively studied in patients with cancer or autoimmunity. These cells hamper the immune system’s ability to clear tumor cells in cancer patients. In autoimmune diseases, on the other hand, they are not able to restrain autoreactive immune responses. If we manage to understand Tregs and their role in health and diseases we may be able to develop better immunomodulatory therapies. Early studies demonstrated that tolerance was maintained by a subset of CD25+ T-cells. CD25 was the earliest marker for Tregs and is still often used to define these cells. Several Treg-associated markers have been suggested throughout the years. However, these markers can be upregulated by activated T-cells as well. The most specific marker for Tregs is currently the transcription factor forkhead box P3 (FoxP3). In this thesis, we investigated the presence of CD25- Tregs in patients with B-cell malignancies and in patients with autoimmunity. These cells were identified in both patient groups. Further, patients with B-cell malignancies often have high levels of soluble CD25 (sCD25) in the periphery. In our patient cohorts, the level of peripheral Tregs correlated with the level of sCD25 in patients with lymphoma. Tregs were shown to release sCD25 in vitro and sCD25 had a suppressive effect on T-cell proliferation. These data show that Tregs may release CD25 to hamper T-cell proliferation and that this may be an immune escape mechanism in cancer patients. Previous studies have demonstrated that an increased infiltration of FoxP3+ cells into lymphoma-affected lymph nodes is associated with a better patient outcome. This is in contrast to studies from non-hematological cancers where an increased presence of Tregs is associated with a poor prognosis. Since previous studies have shown that Tregs are able to kill B-cells, we wanted to investigate if Tregs are cytotoxic in patients with B-cell tumors. In the subsequent studies, Tregs from patients with B-cell lymphoma and B-cell chronic lymphocytic leukemia (CLL) were phenotyped to investigate the presence of cytotoxic markers on these cells. FoxP3-expressing T-cells from both patients with CLL and B-cell lymphoma displayed signs of cytotoxicity by upregulation of FasL and the degranulation marker CD107a. Tregs from CLL patients could further kill their autologous B-cells in in vitro cultures. Taken together the studies in this thesis have demonstrated two possible new functions of Tregs in patients with B-cell malignancies and the presence of CD25- Tregs in both cancer and autoimmunity.
14
Sather, Blythe Duke. "CD4+ Foxp3+ regulatory T cell homing & homeostasis /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8343.
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Warth, Sebastian. "A microRNA network in regulatory T cell differentiation." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-185611.
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Kolodin, Dmitriy Pavlovich. "Dynamics of Tissue-Resident Regulatory T Cell Populations." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11555.
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In recent years, there has been a worldwide increase in obesity, which parallels a rise in pathologies, including type 2 diabetes, collectively termed the metabolic syndrome. Chronic, low-grade inflammation has been implicated as a major link between these diseases. Recent work showed the presence of a unique subset of CD4+Foxp3+ regulatory T cells residing in visceral adipose tissue (VAT Treg) with PPAR-g being the key transcription factor responsible for their phenotype and function in controlling adipose tissue inflammation and, thereby, insulin sensitivity. VAT Tregs inversely correlated with insulin resistance. In contrast, there was a dramatic age-associated increase in frequency of VAT Tregs in lean animals, correlating with continued insulin sensitivity, despite significant increases in body and adipose tissue weights. This increase in Treg frequencies was not observed in other lymphoid and non-lymphoid tissues, including the subcutaneous fat depot. We characterized this unique age-associated increase in VAT Tregs through the use of adoptive transfer models, in vivo labeling and tracking systems, parabiosis, and analysis of the T cell receptor (TCR) repertoire used by VAT Tregs. Our findings indicate that the progressive increase in VAT Tregs is not due to conversion of conventional CD4+ T cells nor to substantial infiltration of Tregs from the circulation and secondary lymphoid organs. However, by analyzing the TCR repertoire on a single-cell level we uncovered a striking oligo-clonal expansion of VAT Tregs, suggesting their accumulation results from in situ proliferation. We further showed that this accumulation is dependent on major histocompatibility complex (MHC) class II, but not on CD1d. Finally, we showed that IL-33 was able to induce proliferation of VAT Tregs. In parallel, we extended our analysis of TCR repertoire to the Treg population residing in skeletal muscle. In acute and chronic models of muscle injury, muscle-resident Tregs underwent a substantial clonal expansion, with a particular clone being detected in multiple individuals. Taken together these studies highlight the importance of proliferation as a mechanism of Treg accumulation in tissues in response to acute and chronic inflammation.
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Himmel, Megan Elizabeth. "Phenotypic and functional characterization of T cells and Foxp3⁺ T regulatory cells in inflammatory bowel disease : steps towards T regulatory cell therapy in mucosal disease." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42517.
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Because of their potent suppressive capacity and critical role in the normal function of the human immune system, T regulatory cells (Tregs) have long been considered candidates for the therapeutic treatment of autoimmune and chronic inflammatory diseases. However, the clinical implementation of these cells has proven challenging in practice, in part due to a lack of knowledge surrounding this T cell subset. Specifically, an evaluation of the unique functions of individual Treg cell lineages, along with a comprehensive investigation of the non-suppressive capacities of these cells, including chemokine production, is necessary. Furthermore, in the application of Treg cellular therapy in mucosal diseases such as inflammatory bowel disease, the identification of putative antigens that can be targeted by Tregs is warranted. To these aims, I evaluated the phenotypic and functional characteristics of Helios⁺ and Helios⁻ Treg subsets, with the knowledge that expression of Helios, an Ikaros family transcription factor, may differentiate natural, thymic derived Tregs from their in vivo peripherally induced counterparts. I found that Helios positive and negative Treg subsets expressed similar Treg markers and displayed a similar capacity for suppression and plasticity. However, these Tregs did differ in terms of cytokine/chemokine production as well as methylation state of the FOXP3 Treg-specific demethylated region. Futhermore, total populations of FOXP3⁺ Tregs were evaluated for chemokine expression; I found that Tregs produce significant quantities of CXCL8 and other acute phase chemokines, and are able to attract inflammatory cells of the innate immune system. In addition, FOXP3 expression enhances CXCL8 production, likely because of its ability to bind the CXCL8 gene promoter. To evaluate putative antigens that can be targeted by Treg therapy in inflammatory bowel disease, I assessed the role of flagellin in disease. Flagellin exacerbates colitic disease in mice in a TLR5 independent manner and flagellin-specific T cells can be identified in patients with CD. Collectively, these findings bring us closer to the effective application of Treg cellular therapy in the setting of mucosal disease.
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Sandalova, Elena. "Regulation of the pro-apoptotic protein bim by T cell receptor triggering in human T cells /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-041-1/.
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Terry, Alexandra Margaret. "The Roles of CD4+ T cells and Regulatory T cells in Antitumour Immunity." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/17331.
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Although the immune system is rapidly becoming a key target for cancer treatment we still lack a comprehensive understanding of how the immune system affects cancer progression. Animal models, such as the one used in this thesis, help to delineate the complex feedback interactions between the immune system and cancer and to identify novel cellular and molecular targets for anticancer drugs. The negative role of regulatory T cells (Tregs) in cancer is well but their mechanism and cellular targets are not fully understood. This thesis uses a novel transgenic mouse model to establish how tumour-specific thymic Tregs (tTregs) and peripheral Tregs (pTregs) affect CD4+ T cell mediated tumour immunity and consequently altering the tumour microenvironment. Tumour-specific CD4+ T cells eradicated subcutaneous B16 melanoma despite a lack of direct interaction with tumour cells due to MHCII mismatch. Tumour rejection was driven by IFNγ+TNFα+IL2+ Th1 cells and was associated with neutrophil influx into the tumour. In some animals tumours recurred in the context of reduced Th1 and early CD4+ T cell conversion into pTregs, yet pTreg depletion did not trigger tumour rejection. Thymic Tregs suppressed CD4+ T cell-mediated tumour rejection in an antigen-dependent manner by reducing Th1 expansion. The response was rescued if tTregs were depleted from hosts prior to CD4+ T cell priming. Analysis of the tumour microenvironment identified several subsets of antigen-presenting cells (APCs) capable of presenting tumour antigen to CD4+ T cells ex vivo. Three previously unappreciated distinct dendritic cell (DC) populations (CD11b+, CD103+ and CD103-) were characterised and shown to have superior antigen-presenting capacity. CD4+ T cell transfer led to upregulation of both costimulatory and inhibitory markers on tumour APCs, while tTregs suppressed DC costimulation. These findings reported advance our understanding of the complex immune feedback mechanisms that control cancer progression.
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Varikuti, Sanjay. "Role of CD4+CD25+ Regulatory T Lymphocytes in Experimental Toxoplasmosis." TopSCHOLAR®, 2009. http://digitalcommons.wku.edu/theses/113.
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Toxoplasmosis is an important cause of congenital disease, and it is one of the most common opportunistic infections in patients with acquired immunodeficiency syndrome. The need for a reliable experimental model of this infection is crucial not only for achieving a better understanding of the patho-physiology of the disease, but also for developing better methods for evaluating new therapeutic regimens. The purpose of the present study was to investigate the role of CD4+CD25+ T regulatory lymphocytes in mice infected with Toxoplasma gondii. T regulatory (Treg) cells have been shown to play an important role in our immune system in controlling the activity of other T lymphocytes. These cells are differentiated from other T lymphocyte populations based on the co-expression of CD4 and CD25 and expression of the Foxp3 gene. The results of several recent studies have suggested that certain pathogens may be able to increase their survival in the host by exploiting T reg cell activity. T regulatory cells have been shown to control the persistence of the protozoan parasite, Leishmania major, in mice; however, this population of cells plays only a limited role during murine infection with Trypanosoma cruzi. In the present study we have investigated the role of Treg cells during murine infection with the ME49 strain of T. gondii. In vivo depletion of Treg cells was accomplished by injecting mice with a monoclonal antibody (Mab) isolated from the 7D4 rat hybridoma cell line. This Mab is specific for the interleukin-2 receptor chain (also known as CD25). Female Swiss Webster mice of approximately 6-7 weeks of age were depleted of Treg cells by intraperitoneal injection of 400µg of Mab, mice were injected once 7days prior to infection, and a second time 1 day prior to infection, with 20 tissue cysts of T. gondii. Mouse weight and tissue cyst numbers were monitored to evaluate the impact of Treg depletion on the outcome of infection. Our results suggest that depletion of Treg cells has little measurable impact during the acute stage of infection with the ME49 strain of T. gondii. Further studies will be required to determine what role, if any, these cells play in the chronic stage of murine toxoplasmosis.
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Nissen, Jesper Klintø. "Control of regulatory T cell lineage differentiation by Foxp3." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609792.
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Salisbury, Emma. "Forward genetic analysis of natural T regulatory cell development." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/18844.
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Natural (n) T regulatory (Treg) cells generated in the thymus are essential throughout life for the maintenance of T cell homeostasis and prevention of autoimmunity. T cell receptor (TCR)/CD28-mediated activation of Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NFB) and Jun N-terminal kinase (JNK) pathways is known to play a key role in nTreg development but many of the predicted molecular interactions are based on extrapolations from non-Treg cell TCR stimulation with non-physiological ligands. For the first time, this work provides strong genetic evidence of a scaffold function for the Caspase Recruitment Domain (CARD) of the TCR signalling protein CARD-MAGUK1 (CARMA1) in nTreg development in vivo. I report two, new, N-ethyl-N-nitrosourea (ENU)-derived mutant mice, Vulpo and Zerda, with a profound block in the development of nTregs in the thymus as well as impaired inducible (i) Treg differentiation in the periphery. Despite independent heritage, both mutants harbour different point mutations in the CARD of the CARMA1 protein. vulpo and zerda mutations do not affect expression levels of CARMA1 but still impair signalling through the TCR due to defective downstream B cell CLL/Lymphoma 10 (Bcl-10) protein recruitment by the mutated CARD of CARMA1. Phenotypic differences observed between Vulpo and Zerda mutants suggest a role for the CARD of CARMA1 independent of Bcl-10 activation of downstream pathways. I conclude that this forward genetic approach demonstrates a critical role for the CARD function of CARMA1 in Treg development in vivo.
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Cook, Katherine. "The Regulatory T-cell response to Helicobacter pylori infection." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.664309.
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Helicobacter pylori is a Gram-negative bacterium that infects the human stomach and can cause peptic ulcer disease CPUD) and gastric adenocarcinoma. Around 50% of the world's population is infected with H. pylori, but only about 10-15% of infected people go on to develop clinical symptoms, with around 1 % developing gastric cancer. There is evidence that H. pylori may also provide protection against some disease including gastric reflux and more controversially extra-gastric conditions such as asthma and allergy. The anti-inflammatory regulatory T-cell (Treg) response is increased during H. pylori infection and patients with the greatest Treg responses are less likely to have PUD. The experiments presented in this thesis aimed to increase understanding of the Treg response to H. pylori infection and its role in health and disease. Blood samples and gastric biopsies were collect from patients attending the Queens Medical Centre, Nottingham. In vivo and in vitro models were utilised to investigate aspects of the Treg response to H. pylori infection. The results show that the CCR6/CCL20 axis is involved in Treg recruitment to the human gastric mucosa. In vivo models were developed that will help to further investigate the importance of this axis in Treg migration during H. pylori infection. The protective role of H. pylori-associated Tregs in EAE, a mouse model of MS was investigated. Finally, work was begun to assess the role of H. pylori virulence factors in determining the Treg response to infection.
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Huynh, Alexandria. "Mechanisms of regulatory T cell lineage homeostasis and stability." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467375.
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Defined by the transcription factor Foxp3, regulatory T cells (Tregs) are a lineage of CD4+ T lymphocytes critical for the maintenance of immune homeostasis and tolerance. A lack of functional Tregs in both mice and humans leads to a fatal systemic autoimmune disease, underscoring their importance as mediators of tolerance to self antigen. One notable distinction between conventional T cells (Tconv) and Tregs is their differential control of the phosphatidylinositol 3-kinase (PI3K) pathway: PTEN, the primary negative regulator of PI3K, is expressed at high levels constitutively in Tregs, preventing the downstream activation of PI3K targets. Regulation of signaling through PI3K has previously been described to play an important role in the maintenance of homeostasis in Tconv, but has not been well characterized in Tregs.
Here, we show that control of PI3K in Tregs is essential for the maintenance of in vivo lineage homeostasis and stability. Mice lacking expression of Pten specifically in Foxp3+ Tregs developed an autoimmune/lymphoproliferative disease characterized by excessive TH1 responses, B cell activation and renal failure. Diminished control of PI3K activity in Tregs led to reduced expression of the high-affinity interleukin-2 (IL-2) receptor subunit CD25 and accumulation of Foxp3+CD25- cells in vivo. The downregulation of CD25 expression on PTEN- deficient Tregs preceded the eventual loss of Foxp3 expression in these cells, representing the total destabilization of the Treg lineage and accumulation of “exFoxp3 cells” in vivo. Collectively, these data demonstrate that control of PI3K signaling by PTEN is critical to maintain in vivo Treg homeostasis, function and stability.Medical Sciences
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Danby, Robert David. "A study of regulatory T cells in allogeneic haematopoietic stem cell transplantation." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:341878ee-8c3e-4eef-ab16-b1b04e34bf4d.
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Allogeneic haematopoietic stem cell transplantation (alloHSCT) is an established therapy for many haematological disorders. Unfortunately, the new donor-derived immune system may damage host cells (graft-versus-host disease (GvHD)), causing significant morbidity and mortality. Since regulatory T cells (Tregs) can modulate immune responses, it was hypothesised that Treg numbers in the haematopoietic stem cell grafts and/or peripheral blood may influence the development of GvHD and other transplant-related complications. In this project, a prospective observational clinical study of putative Tregs in human alloHSCT was performed in Oxford. Flow cytometry and methylation-specific qPCR assays were developed to quantify putative Tregs and lymphocyte populations within the grafts and post-transplant blood samples. Although low CD4(+)CD25(+)FOXP3(+)CD127(-/dim) T-cell numbers were not associated with increased incidence of GvHD, low proportions of CD25(+)FOXP3(+)CD127(-/dim) cells in the graft (as a percentage of total CD4(+) T cells) were independently associated with poor engraftment, increased non-relapse mortality and inferior overall survival. Similarly, falling CD4(+)CD25(+)FOXP3(+)CD127(-/dim) T-cell counts over the first three months post-transplant were associated with higher non-relapse mortality and inferior overall survival. In view of these novel findings, strategies that increase CD4(+)CD25(+)FOXP3(+)CD127(-/dim) T cells in alloHSCT may improve clinical outcomes. One possible route for increasing Tregs is through cellular therapy. This project therefore tested the hypothesis that CD4(+)CD25(+)FOXP3(+) Tregs can be produced in vitro from conventional CD4(+) T cells. In the presence of TGFβ and Azacitidine, FOXP3 was expressed in the majority of activated CD4(+) T cells. These cells also had a demethylated FOXP3 TSDR enhancer which is specific to natural Tregs. However, most of these cells produced pro-inflammatory cytokines, for example, TNFα. Therefore, under these conditions, FOXP3 expression was not sufficient to produce a Treg phenotype. It is proposed that current focus for generating Tregs for human clinical trials should be directed towards improving isolation and expansion of ex vivo isolated Tregs.
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Huang, Anfei [Verfasser]. "Progranulin Prevents Regulatory NK Cell Cytotoxicity Against Antiviral T Cells / Anfei Huang." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/123423341X/34.
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Meredith, Tobias. "The regulatory effects of CD161 and MAIT cells." Thesis, Federation University Australia, 2020. http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/176644.
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Mucosal associated invariant T (MAIT) cells are connected with the potential regulation of anti-tumour responses, although their role in this regulation is poorly defined. In cancer, the relative frequency of MAIT cells has an impact on patient outcome, although how this impact is mediated is not known. Therefore, we have carefully modulated the frequency of MAIT cells within cultures and assessed the effect this has on the anti-tumour functions of important immune cells such as NK and conventional T cells. We identified that changes in MAIT cell frequency can significantly impact the ability of NK cells to become activated and produce proinflammatory cytokines. Interestingly, changes in MAIT cell frequency do not impact conventional T cell activation, but can alter pro-inflammatory cytokine expression. We also identified trends that suggest alterations in MAIT cell frequency may suppress a broad range of cytokines produced within the PBMC pool. The thesis also examined the potential regulatory impact of the cell surface molecule CD161 on T cells (particularly MAIT cells). Several distinctive characteristics have been identified that provides a broader understanding of the effect ligating and blocking this molecule can have. We have demonstrated that interaction with CD161 can promote activation and affect cytokine and perforin expression by MAIT cells. Conventional T cells are also affected, specifically their cytokine expression and activation. Lastly, we also performed several pilot studies, which identified changes in the expression of some genes of interest (e.g. IL-13, IL-5) and raised the possibility that the products of these genes could also be affected. Taken together, our research indicates that MAIT cell frequency can have significant effects on the anti-tumour roles of other immune cells. Additionally, we have furthered the understanding of which anti-tumour functions CD161 interaction can affect. CD161 has the potential to be used as an immunotherapeutic target in cancer patients, but more knowledge is required to determine the host of potential functions CD161 may affect. We suggest that further study is required, particularly in determining the effect CD161 ligation and blocking can have on cytokine output on a range of cells, including MAIT cells.Doctor of Philosophy
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Berglund, David. "Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-220873.
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Solid organ transplantation has evolved from being an experimental procedure to a life-saving treatment for patients with end-stage organ failure. The risk of losing a transplant due to acute rejection is very low with the use of modern immunosuppressive protocols and the short-term results are impressive. However, long-term outcomes are suboptimal and transplant recipients are at increased risks for severe complications such as cancers, opportunistic infections and cardiovascular events. The previous struggle to achieve short-term survival has turned into a search for new strategies to improve patient and transplant longevity. Regulatory T cells (TRegs), a subset of T cells, occur naturally in the immune system and have the capacity to down regulate immune responses. Under normal conditions they maintain self-tolerance and prevent excessive immune activation. Functional TReg defects lead to a massive autoimmune response and are not compatible with life. Preclinical data support that TRegs can be used as a cell therapy to prevent transplant rejection, with the potential to minimize the need for traditional immunosuppression and improve the long-term outcome. This thesis aims to enhance the translation of TReg cell therapy to clinical organ transplantation. In particular, strategies for isolation and expansion of TRegs from uremic patients awaiting kidney transplantation have been assessed. A non-invasive imaging technique to study T cell products after intravenous administration was developed, for use in future clinical trials. The performance of a novel cell purification technique was investigated to potentially improve the clinical production of TRegs. The thesis demonstrates that TRegs can be isolated and expanded from uremic patients to display potent suppressive properties in vitro. The mode of isolation and expansion affect the functional characteristics, where cells purified with cytometry based techniques and expanded with mature dendritic cells were the most advantageous. T cells can be labeled using the radioactive tracer [111In]oxine with preserved viability and subsequently followed in vivo with SPECT/CT for more than 1 week after intravenous administration. The use of microfluidic switch technology offers a novel way of purifying TRegs at high speed, purity and viability, under conditions compatible with clinical use.
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Uttenthal, B. J. "T cell receptor-transduced regulatory T cells : functional studies in models of graft-versus-host disease." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1379030/.
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Alloreactive immune responses directed against malignant cells in recipients of allogeneic haematopoietic stem cell transplants are able to cure patients with haematological cancers. However, such immune responses may cause severe morbidity when directed against healthy recipient tissue, resulting in graft-versus-host disease (GvHD). Naturally occurring regulatory T cells (Tregs) are CD4+ T cells characterized by their expression of the transcription factor Foxp3. Whilst adoptively transferred polyclonal Tregs suppress GvHD in several murine models, their lack of specificity may compromise beneficial immunity against malignancy or infection. The generation of MHC class I-restricted, alloantigen-specific Tregs would allow them to recognize antigen presented directly on GvHD target tissues, concentrating their sites of activation at these tissues and potentially reducing non-specific immune suppression. I have generated ‘converted’ Tregs through retroviral transfer of genes encoding Foxp3 and specific MHC class I-restricted T cell receptors (TCRs) into conventional CD4+ T cells. I used the 2C-TCR, which recognizes the MHC class I molecule H-2Ld, expressed in Balb/c and other H-2d mice, in complex with the ubiquitously expressed peptide p2Ca; and the MH TCR, which recognizes the MHC class I molecule H-2Db, expressed in B6 and other H-2b mice, in complex with the male peptide WMHHNMDLI. In vitro, Foxp3 2C-TCR-transduced B6 CD4+ T cells are hyporesponsive to stimulation and are able to suppress the alloreactive proliferative response of B6 CD4+ and CD8+ T cells to Balb/c splenocytes, consistent with the acquisition of regulatory function. When adoptively transferred to lethally irradiated Balb/c recipients of MHC-mismatched B6 bone marrow and conventional T cells, Foxp3 2C-TCR-transduced B6 CD4+ T cells reduce early proliferation of donor T cells, weight loss and GvHD score in the recipients. Similarly, CD4+ T cells transduced with Foxp3 and the MH-TCR are able to suppress allogeneic responses both in vitro and in vivo. However, while both the 2C-TCR and the MH TCR confer specificity to their cognate antigens in vitro, antigen specificity of suppression is not evident in these in vivo models. In this thesis I show that the endogenous TCR of transduced CD4+ T cells contributes to this lack of specificity, a finding that has important implications for the use of class I-restricted TCRs alongside Foxp3 in CD4+ T cells to direct regulatory activity.
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Jain, Nitya. "Multifaceted Regulation of Peripheral T Cell Tolerance and Autoimmunity by FOXP3+ T Regulatory Cells: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/416.
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Adaptive immunity requires T cell responses to foreign pathogens to be counterbalanced with the need to limit collateral destruction of the host’s own tissues. Further, the presence of a substantial pool of lymphocytes capable of recognizing selfantigen in the periphery poses a threat to the maintenance of peripheral tolerance and prevention of autoimmunity. Regulatory T cells (Treg) that can suppress potentially self-reactive T cells are critical regulators of peripheral tolerance as well as initiation of immune responses. Treg cells employ several context-dependent mechanisms to establish regulation. In this thesis, we describe two distinct pathways of regulation used by Treg cells involving negative costimulation by CTLA-4 and immunomodulation by the morphogen, TGFβ.
CTLA-4 is a co-inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. CTLA-4 expression is induced in conventional T cells following activation, whereas it is constitutively expressed in regulatory FOXP3+CD4+ regulatory T cells. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both, is not known. We present evidence here that in addition to a critical CTLA-4 function in regulatory T cells, CTLA-4 in conventional T cells is also necessary for controlling the consequences of abnormal T cell activation. CTLA-4 expression in activated conventional T cells only in vivois unable to compensate for the impaired function of CTLA-4-less regulatory T cells that results in systemic lymphoproliferation, but it can prevent the aberrantly activated T cells from infiltrating and fatally damaging non-lymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell homeostasis: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells can prevent the harmful accumulation of inappropriately activated pathogenic T cells in vital organs.
In addition, we have identified Disabled-2 (Dab2), a TGFβ signaling intermediate, as a FOXP3 target gene that is expressed exclusively in Treg cells and is critical for in vitro and in vivo regulation by Treg cells. During T cell development, DAB2 is also expressed in a Foxp3-independent manner in thymic precursor cells, and acts as a sensor of TGFβ signals that is required for programming normal TGFβ responsiveness in T cell progenies. Naïve CD4+ T cells that differentiate from Dab2-deficient precursors favor Th17 cell generation at the expense of FOXP3+ Treg cells as a result of altered sensitivity to TGFβ. Importantly, retinoic acid can restore TGFβ signaling capacity of naïve CD4+ T cells generated from Dab2-deficient precursors, emphasizing the cooperative nature of retinoic acid and TGFβ signaling pathways in promoting Treg cell development and maintenance.
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Lei, Hong. "Human natural regulatory T cells subsets." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16958.
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Regulatorische T-Zellen (Treg) eröffnen neue immuntherapeutische Wege zur Kontrolle unerwünschter Immunreaktionen, jedoch wirft die Heterogenität dieser Zellen die Frage auf, welche Treg-Population für die klinische Anwendung. Darauf basierend werden in dieser Arbeit drei Fragestellungen bearbeitet: i) Bestimmung der Häufigkeit von Tregs und deren Subpopulationen in verschiedenen Altersgruppen bei Empfängern einer Organtransplantation (Tx) und einer gesunden Kontrollgruppe; ii) Vergleich der Suppressorkapazität verschiedener Treg-Populationen und in vitro-Expansion der Zellen unter Erhaltung ihrer Funktionalität; iii) Klärung der Differenzierungsmerkmale von Tregs und deren Verknüpfung mit konventionellen T-Zellen (Tconv) mittels Analyse des T-Zell-Rezeptor- (TCR) Repertoires. Sowohl bei gesunden Probanden als auch bei Tx-Empfänger konnte eine altersabhängige Verschiebung von naiven (TregN) hin zu dominant zentralen Gedächtnis-Zellen (TregCM) beobachtet werden, Treg von Tx-Empfängern hatten mehr Effektor-Memory-Zellen (EM) und sie waren mehr aktiviert. In Bezug auf die Kontrolle der frühen Tconv zeigen TregCM eine erhöhte Suppressorkapazität im Vergleich zu TregN. Außerdem sind im Gegensatz zu TregN nur TregCM dazu in der Lage, Apoptose bei Responderzellen zu induzieren. Der Grund hierfür könnte in der stärkeren Expression von CTLA-4 auf TregM liegen. Die Expansionskultur führte zur phänotypischen Veränderung der TregN, deren Umwandlung in TregCM mit einer verbesserten Suppressoraktivität verbunden ist. Die Daten legen nahe, dass das Expandieren mit gesamt Treg für die Adoptive-Treg-Therapie optimal sind, da sie der größte Anteil von ihnen die hochpotenten TregCM sind. TCR-Studien mittels Next Generation Sequencing zeigen weiter, dass TregM aus TregN entstehen, anstatt aus Tconv, in einem Antigen-gesteuerten Prozess. Diese Daten belegen erstmalig neue Erkenntnisse hinsichtlich der Unterschiede der TCR-Repertoires von TregM und Tconv beim Menschen.Regulatory T cells (Treg) offer new immunotherapeutic options to control undesired immune reactions, but the heterogeinetiy of Treg raises the question which Treg population should be used for clinical translation Thus, this project involves three main parts: i) investigating Treg frequency and subsets distribution with age in healthy donors and transplant (Tx) patients; ii) comparing the suppressive capacity of Treg subsets and expanding them in vitro without losing functionality; iii) clarifyjing the differiation relationship of Treg subsets and their relation to conventional T cells (Tconv) by T cell receptor (TCR) repertoire analysis. From both healthy donors and Tx patients, an age-dependent shift from naïve Treg (TregN) to the dominant central-memory Treg (TregCM) was observed,; However,Treg in Tx patients contained more effector-memory EM cells, , and they were pre-activated due to the exposure to allo antigens,. Regarding control of early Tconv activation, TregCM showed enhanced suppressive capacity compared to TregN; furthermore, only TregCM could induce apoptosis of responder cells while TregN could not, which may result from thehigherexpression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) on TregM. Following in vitro expansion of the Treg subsets, however, TregN converted mainly into TregCM phenotype with enhanced suppression activity. The poor proliferation capacity of TregEM might indicate EM as the terminal differential stage. These data suggest that expansion with total Treg is optimal for adoptive Treg therapy as the majority of them are the highly potent TregCM. Lastly, TCR repertoire study by next generation sequencing (NGS) indicate that TregM derived from TregN rather than Tconv in an antigen-driven process. The highest similarity of the TCR repertoires was observed between TregCM and TregEM. These data reveal new insights for the first time into the distinct TCR repertoires of Treg subsets and Tconv in human by NGS technology.
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Chen, Ye. "Induced regulatory T cells in transplantation tolerance." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:cffc275b-d32c-495e-a1da-55421a57e7e7.
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Induced regulatory T cells (iTreg) play an important role in the induction of tolerance to self and non-self antigens. Harnessing their suppressive potential has therapeutic implications for the treatment of autoimmune conditions and transplant rejection. Although the role of TGFβ-conditioned iTreg in natural and therapeutic tolerance is indisputable, their mechanism of action as well as factors that influence their function and stability in vivo remain unclear. Here it is shown that TGFβ-conditioning of T cells in the absence of any Foxp3 expression is insufficient for conferring a suppressive phenotype in vivo, whilst Foxp3 expression is sufficient to enable naïve T cells to become suppressive both in vitro and in vivo. Graft antigen was found to enhance the number of iTreg-derived Foxp3+ cells localising to the draining lymph nodes of recipients, and this was associated with histone modifications at the Foxp3 locus that suggested a stabilisation or 'affirmation' of Foxp3 expression. Finally, iTreg were shown to 'out-compete' naïve T cells in forming clusters with dendritic cells. Activated inflammatory T cells could also 'out-compete' naïve T cells. However, unlike activated T cells, iTreg did not activate interacting DCs to the same extent, and this may potentially be a mechanism of their action in vivo.
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Marshall, D. J. "The role of multiple cell types in the development of regulatory T-cells." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1417081/.
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FoxP3 expressing regulatory T-cells (Treg) are essential for preventing autoimmunity by the immune system. The dynamics and signalling requirements for Treg development in the thymus are not well understood but are thought to integrate TCR, co-stimulatory and cytokine signalling. Previous studies have been hampered by the difficulty of distinguishing peripheral homeostasis from de novo thymic generation of Treg. To circumvent this problem, we used mice bearing both a FoxP3 reporter allele (FoxP3GFP) and in which Zap70 expression is controlled by a Tet-inducible transgene (TetZap70), induced by administration of antibiotic doxycycine (dox). Zap70 deficient thymocytes are arrested at the CD⁴+CD⁸+ double positive stage of development. Induction of Zap70 expression by dox therefore restores positive selection and allows analysis of de novo Treg development independently of existing peripheral Treg. In timecourses of Zap70 induction of TetZap70 FoxP3GFP mice, we found that Treg develop after day 4 and remained in the thymus until day 10, at which time GFP+ Treg were first detected in peripheral lymphoid organs. To investigate the requirement for TCR signals for Treg development we used a pulse of the tetracycline analog methacycline, which resulted in a tight 48h window of Zap70 induction. Remarkably, confining Zap70 expression to the first two days of thymic development was sufficient for normal development 4 days later. Using the TetZap70 FoxP3GFP mice we also investigated the temporal requirement for TGFβ, IL-2 and CD40 signalling during Treg development. Neither TGFβ nor CD40 signalling were required for de novo thymic Treg development. Using blocking antibodies and the addition of cytokine-antibody complexes revealed an essential role for IL-2 as well as a semi redundant role for IL-15. Blockade of IL-2 had no effect on induction of FoxP3 or the number of Treg induced during development. However, induction of CD25 by FoxP3+ Treg was entirely IL-2 dependant. Using mixed bone marrow chimeras we show evidence supporting a hematopoietic source of thymic IL-2. We therefore propose a model of thymic Treg development in which TCR signals alone are sufficient to induce FoxP3 expression but that continued development of Treg is reinforced by IL-2.
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Heil, Luke. "THE ROLE OF CD8 T CELL IMMUNODOMINANCE AND REGULATORY T CELLS IN NEONATAL IMMUNITY TO INFLUENZA VIRUS." UKnowledge, 2019. https://uknowledge.uky.edu/microbio_etds/22.
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Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Efforts to improve influenza infection outcomes in neonates typically center on prevention, although current vaccines fall short of complete protection and can only be administered in humans after 6 months of life. We propose that as the neonatal immune system responds differently than the adult immune system, interventions that are efficacious or tolerable in adults cannot be guaranteed to perform the same in neonates. T cell vaccines that target conserved influenza virus epitopes have been proposed for conferring protection to multiple influenza virus strains, but if T cell vaccines will be used in infants and adults, neonates must be able to respond to the same T cell antigens as adults. Mouse pups responded to influenza virus peptide PA224-233 but not NP366-374 during influenza virus infection in contrast to the codominant adult response. Mice infected as pups also generated diminished T cell memory compared to mice infected as adults and displayed skewed immunodominance during secondary infection. Adult bone marrow derived dendritic cells (BMDCs) improved viral clearance when loaded with influenza virus and promoted NP366-374-specific CD8+ T cell responses in infected pups. BMDC peptide vaccination could stimulate PA224-233-specific but not NP366-374-specific CD8+ T cell responses in pups, but, PA224-233 vaccination offered no protection to pups during lethal infection. These data suggest that altered immunodominance must be considered when stimulating CD8+ T cell responses in adults and neonates.
Immaturity and active suppression of immune responses are both factors in neonatal vulnerability to disease. Specifically, active suppression of neonatal immunity by regulatory T cells (Tregs) has been proposed as a driving factor in diminished neonatal immunity, but removing these cells can compromise viral defense or increase deleterious inflammation. Mice that lacked Tregs displayed compromised anti-influenza antibody responses and decreased lymph node responses during influenza virus infection. A high proportion of pup Tregs also expressed Gata3. Transgenic pups with a Treg specific Gata3 knockout displayed an increase in Tbet expression in both conventional and regulatory T cells and an increase in IFNγ producing CD4+ T cells in the lungs during infection. These data suggest that Tregs are required for effective humoral responses to influenza virus and that Gata3 expression influences Treg suppressive function in neonates.
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George, Mariam M. B. S. "Zinc regulates tolerogenic dendritic cell phenotype and skews regulatory T cell- Th17 balance." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439305564.
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Burocchi, Alessia. "Modulation of regulatory T cell suppression in tumors through OX40." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.576669.
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Tumor cells develop numerous mechanisms to escape from the control exerted by the immune system. One of these strategies is the accumulation of regulatory T cells (Treg) within the tumor, which keep effector T cells (Teff) and dendritic cells (DC) in an inactive state. An efficient approach to overcome the inhibitory potential of Treg focuses on OX40, a costimulatory molecule constitutively expressed by Treg and induced in activated Teff. The treatment of mouse transplantable tumor models with the mAb OX86, the agonist of OX40, induces tumor rejection by acting on both these T cell subsets. In this study we investigated the fine cellular mechanisms at the basis of this process, dissecting the effects of OX86 on Treg and on CD4+Foxp3•CD44highCD62L,owOX40+ effector memory T cells (Tem), which represent the most abundant Teff subset in the tumor. Upon OX40 stimulation, Treg are "contra-suppressed" and down-modulate the expression of the transcription factor interferon regulatory factor 1 (IRFl), thus reducing the secretion of IL- 10. Conversely OX86 provides activating stimuli to Tern, which up-regulate CD40L and in turn promote the maturation of DC. OX86 shifts the tumoral milieu from tolerogenic to immunogenic, favoring the activation and migration of DC from the tumor to the draining lymph node (dLN) and the subsequent new CTL induction. The relevance of OX40 in Treg biology goes beyond the modulation of their suppressive abilities. OX40 increases the sensitivity of Treg to IL-2, facilitating the phosphorylation of STAT5 through high level of the mirl55 and low level of SOCS 1. The overexpression of miR155 endowed Treg of higher suppressive functions, further enhancing tumor growth. These data clearly remark the key roles exerted by OX40 in influencing Treg and Teff behavior. Understanding how to manipulate OX40 signaling will provide great advantage in the development of efficient therapy for both tumors and autoimmune diseases.
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Sharif-Paghaleh, Ehsan. "In vivo imaging of regulatory T cell mediated transplant tolerance." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/in-vivo-imaging-of-regulatory-t-cell-mediated-transplant-tolerance(4ee28e3c-431f-430f-9484-d22f030787b1).html.
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Regulatory T cells (Tregs) were identified several years ago and are key in controlling autoimmune diseases and limiting immune responses to foreign antigens. These cells have been used successfully in animal models first and more recently in the clinic to prevent Graft vs Host disease and transplant rejections. However, their locations in vivo, their migratory abilities and their in vivo survival have not been extensively investigated. Imaging of the human sodium/iodide symporter via Single Photon Emission Computed Tomography (SPECT) has been used as a reporter gene to image various cell types in vivo. It has several advantages over other imaging techniques including high sensitivity, it allows non-invasive whole body studies of viable cell migration and localisation over time and lastly it may offer the possibility to be translated to the clinic. The study presented in this thesis addresses whether SPECT/CT imaging can be used to visualise the migratory pattern and survival of Tregs in vivo. At first, CD4+ T cells were directly radiolabelled and were subsequently imaged in vivo to demonstrate that T cells can be imaged using NanoSPECT/CT. Then Treg lines derived from CD4+CD25+FoxP3+ cells \ were/ retrovirally transduced with a construct encoding for the human Sodium Iodide Symporter (NIS) and the fluorescent protein mCherry. NIS expressing self-specific Tregs were specifically radiolabelled in vitro with Technetium-99m pertechnetate (9 mTcC)4~) and exposure of these cells to radioactivity was shown not to affect cell viability, phenotype and Treg function. In addition adoptively transferred Treg-NIS cells were imaged in vivo in C57BL/6 (BL/6) mice by SPECT/CT using 99mTcO4". After 24 hours NIS expressing Tregs were observed in the spleen and their localisation was further confirmed by organ biodistribution studies and flow cytometry analysis. Later, Treg lines with direct or indirect alloantigen specificity were imaged in skin transplant models using the same technique. It was observed that adoptively transferred Tregs migrate to the site of transplant at earlytime points and then migrated to various lymph nodes. The data presented here suggests that SPECT/CT imaging can be utilised in preclinical imaging studies of adoptively transferred Tregs without affecting Treg function and viability thereby allowing longitudinal studies within disease models. Moreover, new insight into pattern of migration of Tregs was identified.
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Mair, Iris. "Investigating mechanisms of regulatory T cell function in inflammatory disease." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28705.
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Regulatory T cells (Treg) play a crucial role in controlling immune homeostasis. Several inflammatory diseases including multiple sclerosis and inflammatory bowel disease have been associated with dysfunctional and/or reduced numbers of Treg. While several mechanisms of action have been discovered by which Treg can exert their function, disease-specific Treg requirements remain unknown. The Treg pool consists of highly diverse subpopulations, indicating that there is a potential to optimise Treg-targeted therapies if disease-relevant mechanisms can be established. Microarray data from our lab suggests a marked upregulation of the integrin αv as well as the IL-33 receptor ST2 in Treg retrieved from the inflamed central nervous system (CNS) during experimental autoimmune encephalomyelitis compared to peripheral lymphoid organs. These two molecules were further investigated within this PhD project with the aim to understand their role in Treg function during chronic inflammatory disease. αvβ integrins have been reported to be needed for effector T cell migration to inflamed sites through binding of extracellular matrix components and are involved in TGF-β activation by a variety of cell types. Conditional knockout mice lacking the integrin αv specifically in Foxpγ+ Treg were generated to address the role of αv integrins on regulatory T cells in inflammatory disease. αv-/- Treg showed a deficiency in activating latent TGF-β, but were able to suppress responder T cell proliferation in vitro as well as in vivo. αv-/- Treg were also able to migrate to the inflamed CNS during EAE and resolve disease. However, αv-/- Treg were detected at significantly lower numbers and proportions in the inflamed gut during a curative T cell transfer model of colitis; this led to a quantitative impairment in the ability of αv-/- Treg to cure colitis when compared to wild-type (WT) Treg. Whether this is a deficit in migration, survival, proliferation, or Foxp3 stability, remains to be investigated. IL-33 acts as an alarmin and is best studied as a cytokine released upon tissue damage that induces a potent type 2 immune response by acting on a multitude of immune cells. Expression of the IL-33 receptor ST2 on Treg has recently been associated with positive metabolic parameters in visceral adipose tissue, protection from gut inflammation, and tissue-restorative function in other inflamed tissues such as injured muscle or lung. This project showed that in steady state, ST2+ Treg expressed high levels of several markers which have been associated with potent regulatory function. When stimulated in vitro, ST2+ Treg showed a better survival and expansion rate compared to their ST2- counterparts, even more so in the presence of IL-33. T-bet deficiency in Treg resulted in an increased ST2+ Treg pool, and T-bet-associated cytokine IFN-γ was found to antagonise IL-33-induced expansion of the ST2+ Treg pool in a T-bet-independent manner. When ST2+ and ST2- Treg were tested for their respective suppressive capacity in vivo, ST2+ Treg were able to suppress responder T cell expansion despite being found only at low numbers in secondary lymphoid organs compared to ST2- Treg. However, in a curative model of T cell transfer colitis, ST2+ Treg were less capable of controlling the ongoing immune response than ST2- Treg. A possible explanation for the superiority of ST2- Treg in this setting can be found in the fact that injected ST2- Treg acquired a distribution of ST2 expression reminiscent of WT Treg over the course of disease. On the other hand, an increased starting pool of ST2+ Treg as occurs in T-bet-/- Treg significantly enhanced the capacity of Treg to control colitis compared to WT Treg. In conclusion, both ST2- and ST2+ Treg are likely to have a distinct, non-redundant role in suppressing T cell activation in secondary lymphoid organs and controlling ongoing inflammation in peripheral tissue, respectively.
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Franchini, Fanny. "Immune regulatory networks in inflammation-driven cancer." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:2314081e-8c3f-43c7-9ea6-edf43430a43c.
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The incidence of colorectal cancer (CRC) is increasing and the prognosis for patients with advanced or metastatic disease is relatively poor. Immunotherapies hold great promise, but deploying them effectively in CRC patients will require further knowledge of the complex cellular and molecular interactions that occur between intestinal tumours and the host immune system. The objective of this study is to understand the mechanisms by which lack of immune cell regulation in the gut can drive the formation of colon adenocarcinomas. In addition, this work aims to identify new mechanisms involved in progression to metastatic disease. Using mouse model systems, we found that aberrant activity of Treg cells deficient in IL-10 can promote inflammation-driven CRC. IL-10 deficient Tregs have increased capacity to drive tumourigenesis compared to their CD4+ effector T cell counterparts. RNA sequencing revealed specific upregulation of several genes, including a newly-described cytokine, in tumour-promoting Tregs. We explored cytokine regulation and the tumour microenvironment, and show that the inflammatory cytokine IL-6 and TGFÎ2 are necessary for tumour formation in this model. Moreover, disease is associated with a marked stromal cell signature that is induced as a consequence of Treg deficiency in IL-10 production. Gp38+ stromal cells are dominant producers of IL-6, and potent ECM modellers. Furthermore, tumours driven by IL-10 deficient Tregs express high amounts of the pro-mesenchymal transcription factor Sox4. Using combined in vitro and in vivo analyses, we confirm that Sox4 is involved in tumour growth and characterise its expression in CRC patients. Collectively, our findings suggest that Tregs and stromal cells act together to foster a microenvironment that promotes disease progression, notably through the expression of Sox4 in tumour cells. These findings open an exciting avenue to explore the phenotype of tumour-promoting Tregs and to study Sox4 function in metastatic disease.
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Schreiber, Taylor Houghton. "Balancing Effector and Regulatory T Cell Responses in Cancer and Autoimmunity." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/654.
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Activation of immunity to self-antigens is the goal in cancer immunotherapy, whereas blocking such responses is the goal in autoimmune disease. Thus, it is not surprising that investigation into cancer immunotherapy might also produce insights for the treatment of autoimmune disease. Heat shock protein, gp96, based therapies lead to the robust activation of CD8+ cytotoxic T cells that can slow tumor growth in 60-70% of mice, but only lead to the elimination of tumors in 30-40% of animals. The primary goal of the current studies was to understand why vaccination with a secreted gp96 vaccine was not efficacious in a larger proportion of animals, and identify combination therapies that enhanced the anti-tumor activity of gp96-Ig vaccination. It was found that in mice bearing established tumors, some mice responded well to vaccination with gp96-Ig, and that the induction of CD8+ T cells was found to correlate with tumor rejection; indicating that the proportion of mice that failed to reject tumors had established mechanisms of tumor-mediated suppression of anti-tumor immunity. The mechanism of this suppression was found to differ between various tumor models, so combination therapy sought to amplify CD8+ T cell responses directly, rather than by indirectly inhibiting suppressive factors induced by established tumors. It was found that antibody-based therapies leading to the stimulation of TNFRSF25, a powerful T cell co-stimulatory receptor, caused synergistic expansion of tumor-specific T cells when given in combination with gp96-Ig vaccination and led to enhanced rejection of multiple tumor types. Interestingly, TNFRSF25 agonistic antibodies were also found to directly stimulate the proliferation of natural CD4+FoxP3+ regulatory T cells. This activity was found to be beneficial in the prevention of allergic lung inflammation when administered prior to antigen challenge. These studies have therefore identified the conditions required for successful tumor elimination following gp96-Ig vaccination, and discovered that a TNFRSF25 agonistic antibody may be used to enhance anti-tumor immunity induced by gp96-Ig. These studies have also identified TNFRSF25 stimulation as the most powerful, and physiologically relevant, method to selectively induce Treg proliferation in vivo ever discovered, with important consequences for the treatment of autoimmune inflammation.
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Chan, Ping-lung, and 陳秉隆. "Roles of TLR5 and ICOS on the human allogenic CD40-activated B cell-induced CD4hiCD25+ regulatory T cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47149735.
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Carretero-Iglesia, Laura. "Autologous regulatory myeloid cell therapy in transplantation." Nantes, 2014. http://archive.bu.univ-nantes.fr/pollux/show.action?id=57eee07a-2290-4c76-b10e-0603a68039b7.
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The aim in organ transplantation is to induce specific long-term allograft tolerance. Current therapies control short-term allograft rejection but are inefficient against late graft failure. Moreover, they carry important side-effects, rendering patients vulnerable to other diseases. New therapies are nowadays being developed. The use of in vitro modified cell types as a strategy to induce donor-specific tolerance has proven to be effective to prolong allograft survival in a variety of animal models. Myeloid cells play a key role in transplantation. They are involved in both, tolerance and rejection. Therefore, the in vitro modification of myeloid cells for their use in cell therapy has gained interest those last years. The work developed during this thesis aimed at generating three regulatory myeloid cell types (tolerogenic dendritic cells, regulatory macrophages and myeloid-derived suppressive cells). In vitro, we studied their capacity to avoid T cell activation and the mechanisms underlying their suppressive activity. In vivo, we tested the potential of autologous regulatory myeloid cells to prolong allograft survival when injected in a mouse skin transplant model one day before transplantation and the in vivo mechanisms induced after their injection. We believe that the results obtained during this thesis will help to progress towards an efficient cell therapy and tolerance induction in the transplantation settingL'objectif en transplantation d'organes est d'induire une tolérance spécifique du greffon à long terme. Les thérapies actuelles sont efficaces pour contrôler le rejet aigu du greffon mais sont inefficaces pour prévenir le rejet chronique. De plus, elles peuvent induire à des effets secondaires importants, rendant les patients sensibles à d'autres maladies. De nouvelles thérapies sont ainsi en cours de développement. L'utilisation de différents types cellulaires modifiés in vitro comme stratégie pour l'induction d'une tolérance spécifique d'antigène a été démontré efficace pour prolonger la survie de l'allogreffe dans plusieurs modèles animaux. Les cellules myéloïdes jouent un rôle important en transplantation. Elles sont impliquées dans la tolérance, ainsi que dans le rejet de la greffe. La modification in vitro des cellules myéloïdes pour leur utilisation en transplantation a suscité un intérêt ces dernières années. Le travail développé pendant cette thèse a eu pour objectif la génération de trois types de cellules régulatrices myéloïdes (cellules dendritiques tolérogènes, macrophages régulateurs et cellules myéloïdes suppressives). In vitro, nous avons étudié leur capacité suppressive sur l'activation des lymphocytes T et les mécanismes impliqués dans cette suppression. In vivo, nous avons testé leur potentiel à prolonger la survie de l'allogreffe après injection autologue dans un modèle de greffe chez la souris ainsi que les mécanismes qu'elles induisent. Nous supposons alors que les résultats obtenus pendant cette thèse pourront aider à développer une thérapie cellulaire efficace pour l'induction d'une tolérance en transplantation
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Hoffmann, Markus [Verfasser]. "Regulatory T cell-mediated suppression of Th9 cell development and effector function / Markus Hoffmann." Mainz : Universitätsbibliothek Mainz, 2014. http://d-nb.info/104816490X/34.
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Oldham, Kimberley Anne. "The recruitment and role of effector and regulatory T cells in renal cell carcinoma." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3263/.
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Immunotherapy for renal cell carcinoma (RCC) has yielded some clinical responses. However this approach frequently fails, possibly due to inefficient migration of T-cells to tumour tissue or immunosuppressive mechanisms within the tumour environment. To aid development of T-cell therapy for RCC I investigated how T-cells are recruited to this tumour, which T-cell subsets infiltrate, and how they function. Analysis of the expression of all 19 chemokine receptors on matched TIL and PBMC demonstrated that CCR5, CXCR3 and CXCR6 were expressed at significantly higher levels on tumour-infiltrating T-cells than memory T-cells in PBMC, suggesting a role for these receptors in recruitment to RCC. Immunohistochemistry showed the corresponding ligands were present in RCC, and transwell assays confirmed the ligands induce migration of TIL. I demonstrated Foxp3\(^+\)CD25\(^{hi}\)CD127\(^{low}\) Tregs were enriched within the tumour, and also expressed high levels of CCR5, CXCR3 and CXCR6, as well as CCR6. They lacked expression of IL-2 and IFN-\(\gamma\) post-stimulation, consistent with a regulatory phenotype. Functional characterisation of Foxp3\(^-\) TIL demonstrated they can function ex vivo, however their high expression of the inhibitory molecule PD-1 may indicate exhaustion in vivo. Double positive CD4\(^+\)CD8\(^+\) T-cells were also enriched in TIL and had a similar functional profile to CD8 T-cells.
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Hirani, S. "The characterisation of human umbilical cord blood regulatory T cell subsets." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344048/.
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Umbilical cord blood (CB) is recognised to be a valuable alternative to bone marrow (BM) as a source of hematopoietic stem cells (HSC). The occurrence of Graft vs. Host Disease (GvHD) after CB transplantation has been reported to be less severe in comparison to BM transplants. In addition to the naive state of immune cells, the action of immuno-suppressive cells such as regulatory T cells (Treg) may contribute to the positive aspects observed in CB transplants. This study investigated the phenotypic and functional characteristics of CB Treg and their potential for expansion in culture. In addition, the allogeneic response of CB and AB CD4+ cells was compared. Two main subsets of Treg have been described: resting (CD45RA+FOXP3low) and activated (CD45RA-FOXP3high). Results presented here showed that CB contained mostly resting Treg whereas AB contained mostly activated Treg. In addition, freshly isolated CB Treg were less capable of inhibiting the proliferation of responses in comparison to AB Treg. CB Treg acquired an activated Treg phenotype and potent suppressive activity after expansion, and expanded CD25+ cultures maintained Treg characteristics for longer in comparison to CD25+ cells expanded from AB. Importantly, unlike AB Treg, expanded CB Treg suppressed the proliferation of autologous and allogeneic responders equally. Finally, ‘putative Treg’ were induced from CB CD25- cells following allogeneic stimulation, the putative Treg were CD4+FOXP3+CD25+CTLA-4+ and were capable of suppressing the proliferation and cytokine responses to primary and subsequent allogeneic challenges. In conclusion, Treg subsets from CB display different phenotypic and functional properties to AB Treg. These properties of CB Treg may clarify the cellular interactions in clinical settings in which CB is currently used and highlight potential future uses.
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Walter, Gina. "Do activated monocytes impair regulatory T cell function in rheumatoid arthritis?" Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/do-activated-monocytes-impair-regulatory-t-cell-function-in-rheumatoid-arthritis(bec96e89-858a-42a3-87cf-6167ee9d633e).html.
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Rheumatoid arthritis (RA) is a chronic inflammatory immune disease affecting the joints. CD4+CD25+ regulatory T cells (Tregs) are abundantly present in the inflamed joints of patients with RA, but inflammation still persists. The notion that Tregs are terminally differentiated suppressor cells has recently been disputed by studies showing that Tregs can display a significant degree of plasticity and even convert into IL-17-producing cells under inflammatory conditions. Therefore, the overall hypothesis of this thesis was that the pro-inflammatory environment impairs Treg function in RA by converting them into IL-17-producing cells. We show in this thesis that frequencies of CD25+CD127low Tregs with a CD45RO+ memory phenotype were increased at the site of inflammation in RA. These Tregs displayed a regulatory phenotype, with increased expression of the Th17 marker CD161. Furthermore, CD14+ monocytes with an activated phenotype were found in high numbers in the RA joint. Monocytes and Tregs could be found in close proximity in human tissue suggesting that they interact in vivo. We next studied the effects of in vitro-activated monocytes on Treg phenotype and function. Activated monocytes increased the percentages of IL-17+, IFNγ+, TNF-α+, and IL-10+ memory (CD45RA-) Tregs. Tregs from these co-cultures showed no loss in Treg markers or suppressive capacity, and were rather enhanced in their suppressor functions. Finally, Tregs from the peripheral blood of patients with RA showed a similar phenotype and cytokine expression profile compared to Tregs from healthy controls. RA Tregs were capable of suppressing autologous effector T cell proliferation and cytokine secretion. However, Tregs from some patients showed a hampered ability to suppress monocyte-derived chemokines and cytokines. Together, these data suggest that Treg function is not globally impaired in patients with RA and that Tregs exposed to a pro-inflammatory environment, such as occurs in the inflamed rheumatic joint, do not lose their regulatory function.
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Whatcott, Andrew. "Assessing the impact of immunosuppressive drugs on regulatory T cell therapy." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d3e538bc-0558-4f12-8be4-5f77d79c4323.
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Immunosuppressive drugs have facilitated the progression of solid organ transplantation from experimental therapy to routine practice, however transplant recipients are still susceptible to chronic rejection and co-morbidities. The emergence of regulatory T cells (Treg) as a key regulator of the immune system, together with an abundance of evidence from experimental transplant models, has led to clinical trials asking whether Treg can improve transplant outcomes. However, given that Treg cellular therapy will only be acceptable if introduced into current immunosuppressive regimens, a critical question is how Treg will respond in the presence of concomitant immunosuppression. Whilst in vitro data are available, very few credible experiments have been done asking whether individual immunosuppressive drugs have a positive, a neutral or a detrimental impact on the Treg function in vivo. Thus the aims of this thesis were firstly to generate sufficient numbers of adaptive Treg for extensive experimental use and secondly to evaluate their ability to control transplant rejection in vivo in the presence of biologically valid doses of individual, clinically relevant immunosuppressive drugs. Importantly, the model chosen was the heterotopic heart transplant model in lymphoreplete mice to avoid possible artefacts that can occur in cell reconstituted lympho-depleted mice. The model also has the added advantage that by dealing with an intact immune system, it perhaps represents a small step closer to the clinical situation. Generating sufficient numbers of stable Treg was necessary for planned in vivo experiments. Incubating CD4+ T cells with anti-CD44 antibody, prior to driving them with bone-marrow derived dendritic cells, enriched for a stable population of Treg and importantly yielded sufficient numbers of cells for in vivo experiments. It is frequently stated that alloantigen-driven Treg are more efficacious than activated autologous nTreg, however there was no difference in rejection kinetics in either a skin or heart allograft model when comparing alloantigen-driven Treg with nTreg. As generating alloantigen-driven Treg is less efficient than nTreg, pursuing the former as a potential therapy might therefore be unnecessary. This could have a considerable impact on the logistics and the practicality of clinical Treg cellular therapeutics. The timing of Treg administration is an important consideration to maximise efficacy. Pre-transplant administration led to the longest graft survival times, suggesting that this is the most effective time for cell delivery. Preclinical models provide a useful tool to ask how immunosuppressive drugs will affect adoptively transferred Treg. The data presented in this thesis suggest that combining Treg with Rapamycin, Mycophenolate Mofetil (MMF) or Tacrolimus did not completely prevent Treg function. However, Methylprednisolone (MP) did prevent Treg function, suggesting it cannot be used with adoptively transferred Treg. Overall, these results provide important data for the design of immunosuppressive regimens for future clinical trials assessing the efficacy of Treg in transplant recipients.
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Powell, Michael D. "Insights Into the Regulatory Requirements for T Follicular Helper Cell Development." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/89085.
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During the course of an immune response, CD4+ T helper cells differentiate into a number of subsets including: T helper 1 (TH1), TH2, TH17, and T follicular helper (TFH) populations. The functional diversity of CD4+ T effector cells results in a coordinated, pathogen-specific immune response. For example, the production of IFNγ by TH1 cells is vital for the clearance of intracellular pathogens, while TFH cell engagement with cognate B cells is required for germinal center (GC) formation and the generation of pathogen- and vaccine- induced antibody production. The development of CD4+ subsets is contingent on extracellular signals, in the form of cytokines, and downstream transcriptional networks responsible for promoting the unique gene expression profile for each subset while simultaneously suppressing alternative cell fates. However, the exact composition of, and stage-specific requirements for, these environmental cytokines and transcription factor networks in the governance of TFH cell differentiation remain incompletely understood. The work in this dissertation seeks to understand how cell-extrinsic cytokine signals and cell-intrinsic transcription factor activities are integrated to properly regulate TFH cell development. Here, we demonstrate that in response to decreased IL-2 and constant IL-12 signaling, T helper 1 (TH1) cells upregulate a TFH-like phenotype, including expression of the TFH lineage defining transcription factor Bcl-6. Intriguingly, our work established that signals from IL-12 were required for both the differentiation and function of this TFH-like population. Mechanistically, IL-12 signals are propagated through both STAT3 and STAT4, leading to the upregulation of the TFH associated genes Bcl6, Il21, and Icos, correlating with increased B cell helper activity. Conversely, exposure of these TFH-like cells to IL-7 results in the STAT5-dependent repression of Bcl-6 and subsequent inhibition of the TFH phenotype. Finally, we describe a novel regulatory mechanism wherein STAT3 and the Ikaros zinc finger transcription factors Ikaros and Aiolos cooperate to regulate Bcl-6 expression in these TFH-like cells. Collectively, the work in this dissertation significantly advances our understanding of the regulatory mechanisms that govern TFH cell differentiation, setting the basis for the rational design of novel immunotherapeutic strategies and increasingly effective vaccines.Ph. D.
Specialized cells called T helper cells serve as a critical interface between the innate (first line of defense) and adaptive (specialized and long-term) immune systems. During the course of an infection, T helper cells are responsible for orchestrating the immune-mediated elimination of invading viruses, bacteria, and parasites. This wide breadth of functionality is achieved through the formation of distinct T helper subsets including T helper 1 (TH1), TH2, TH17, and T follicular helper (TFH) populations. Individual subsets have distinct developmental requirements and have unique functions within the immune system. For example, TFH cells are required for the production of effective antibodies that recognize invading pathogens, leading to their subsequent elimination. This naturally occurring process is the basis for a number of modern medical therapies including vaccination. Conversely, aberrant generation of antibodies that recognize host tissues can result in the onset of various autoimmune diseases including lupus, multiple sclerosis, and crohn’s disease. Due to the importance of TFH cells to human health, there is intense interest in understanding how these cells are formed. It is recognized that the generation of these therapeutically important immune cells is mediated by numerous cell-extrinsic andintrinsic influences, including proteins in their cellular environment called cytokines, and important proteins inside of the cell called transcription factors. However, as this is a complicated and multi-step process, many questions remain regarding the identity of these cytokines and transcription factors. The work in this dissertation seeks to understand how cellextrinsic cytokine signals and cell-intrinsic transcription factor activities are integrated to properly regulate TFH cell development. Collectively, this body of work significantly advances our understanding of the regulatory mechanisms that govern TFH cell differentiation, setting the basis for the rational design of novel immunotherapeutic strategies and increasingly effective vaccines.
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Hu, Mingjing. "Human regulatory T cell physiology - Lessons learnt from newborns and adults." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/18396.
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Human Regulatory T (Treg) cells play a critical role in the immune homeostasis. Hence, understanding Treg cell physiology is of vital importance. Various soluble factors, including IL-10 and short chain fatty acids (SCFAs), contribute to the transplacental immune programming by shaping the fetal immune system, specifically Treg cells. Therefore, this thesis aims to provide further evidence for the Treg cell transplacental programming, and to explain how SCFAs contribute to this process. We demonstrated that the absence of maternal gut microbiota caused significantly reduced fetal thymus size and fewer thymic Foxp3+ Treg cell numbers, which could be rescued by supplementation of acetate. Moreover, the fetal-maternal correlation of serum acetate implied that maternal acetate likely crossed the placenta. TCR sequencing data also suggested that fetal antigen receptor immunity was not inherited, but rather driven by local immunomodulatory factors. Taken together, it indicated that maternally acquired metabolites (acetate) play an important role in shaping fetal thymic development and output, hence exerting their influences on fetal immunity. In addition to the context of pregnancy, this thesis extends the knowledge of SCFAs to both neonate and adult immune cells in vitro. We are the first to demonstrate the effectiveness of SCFAs in Treg cell differentiation via histone acetylation inhibition in vitro in humans. We also proved the tolerogenic effects of SCFAs on other immune cells in humans, including MoDCs and different T cell subsets. These results highlight the essential role of SCFAs in immune tolerance, particularly in Treg cell physiology. Collectively, this study provides theoretical evidence for a non-pharmaceutical approach. Since diet is closely interlinked with the composition of gut microbiota and SCFAs production, dietary interventions may alleviate or treat allergies and autoimmune diseases via modulating Treg cells.
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Strainic, Michael George Jr. "THE ABSENCE OF C3AR AND C5AR SIGNAL TRANSDUCTION PROMOTES T REGULATORY CELL DIFFERENTIATION AND REGULATES IMMUNOLOGIC TOLERANCE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1363707372.
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