Dissertations / Theses on the topic 'Regulatory T cells; immunology'
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1
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.
2
Sayin, Ismail. "Characterization of human T follicular regulatory cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1560336991188191.
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Emani, Sirisha. "MOLECULAR CHARACTERIZATION OF T REGULATORY CELLS IN FIV-INFECTION." NCSU, 2006. http://www.lib.ncsu.edu/theses/available/etd-01192006-105756/.
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Naturally occurring CD4+CD25+ T regulatory cells (Treg) play important roles in maintaining immunologic self-tolerance in addition to controlling the magnitude of anti-microbial immune responses. However, the capacity of these CD4+CD25+ Treg cells to control immune responses both in vivo and in vitro is not well established. CD4+CD25+ Treg cell-mediated suppression can control autoimmune diseases; transplantation tolerance and graft verses host disease and, in contrast hinder tumor immunity and immunity to infectious agents. As Treg cells have been reported to be involved in several diseases, this study focused on molecular characteristics that enables them to maintain anergy and also resistance to programmed cell death along with the effect of FIV-infection on regulation of the above phenotypic characteristics. Our results show that feline CD4+CD25+ Treg cells are phenotypically and functionally anergic as indicated by elevated levels of the cyclin dependent kinase inhibitors, CdkI¡¦s, (p21cip1,p16ink4, and p27kip1) , and resistance to mitogen-induced proliferation compared to their counter parts CD4+CD25- T cells. Importantly, CdkI¡¦s are constitutively over-expressed only in FIV-infected cats. As expected Treg cells from FIV-infected cats that over-expressed CdkI¡¦s expressed low levels of the cyclins (mainly cyclins D) and phosphorylated retinoblastoma protein (pRb) that are responsible for cell cycle progression. We investigated the role of TGF?Ò signaling and found that TGF?Ò1 plus ConA stimulation was able to convert CD4+CD25- T cells to CD4+CD25+ T cells with functional and phenotypic characteristics including upregulation of CdkI¡¦s and bcl-2. The differential expression of CdkI¡¦s and bcl-2 between the two CD4+ T cell subsets may be linked to TGF?Ò-Smad pathway. Consistent with upregulation of CdkI¡¦s and bcl-2, we found that although natural and TGF?Ò1 converted CD4+CD25+ Treg cells are anergic, they are more resistant to activation induced cell death compared to CD4+CD25- T cells functionally which correlated with increased bcl-2 to bax ratio in Treg cells. Thus, the molecular characterization of this unique population of Treg cells may be essential for understanding their role and function for developing effective therapeutics and vaccination especially against chronic infections such as Acquired Immune Deficiency Syndrome (AIDS).
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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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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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Alexander, Carla-Maria Alana. "T regulatory cells and the germinal center." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1117.
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Germinal center (GC) reactions are central features of T cell-driven B cell responses, and the site where antibody (Ab) producing cells and memory B cells are generated. Within GCs, a range of complex cellular and molecular events occur which are critical for the generation of high affinity Abs. These processes require exquisite regulation not only to ensure the production of desired Abs, but to minimize unwanted autoreactive or low affinity Abs.
To assess whether T regulatory cells (Treg) participate in the control of GC responses, immunized mice were treated with either an anti-glucocorticoid-induced TNFR-related protein (GITR) mAb or an anti-CD25 mAb to disrupt Treg activity. In both groups of treated mice, the GC B cell pool was significantly larger compared with control treated animals, with switched GC B cells composing an abnormally high proportion of the response. With these results indicating Tregs influence on GC dynamics, experiments were conducted to determine if Tregs were located in the GC, which subset of Treg was involved and by which mechanisms were their functions being effected. Within the spleens of immunized mice, CXCR5+ and CCR7- Tregs were documented by flow cytometry and Foxp3+ cells were found within GCs using immunohistology. Studies demonstrated administration of either anti-TGF-β or anti-IL-10R blocking mAb to likewise result in dysregulated GCs, suggesting that generation of inducible Tregs is important in controlling the GC response. Blockade of two Treg methods of suppression, PD-1/PD-L1 pathway and CTLA-4, also resulted in disrupted GCs, indicating the possible use of them for suppression by Treg. Collectively, these findings indicate that Tregs contribute to the overall size and quality of the humoral response by controlling homeostasis within GCs.
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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
8
Okeke, Emeka B. "Regulation of Sepsis and Endotoxic Shock by Regulatory T cells." Wolters Kluwer Health Lippincott Williams & Wilkins, 2013. http://hdl.handle.net/1993/31580.
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One of the major challenges facing clinicians is how to effectively manage excessive host immune response to pathogenic insults resulting in sepsis. This is demonstrated by the fact that despite over half-century research efforts, sepsis and its spectrum of diseases (severe sepsis and septic shock) are still associated with poor clinical outcome. Currently, sepsis is a leading cause of death in intensive care units.
The immune system protects the host against pathogens and is therefore armed with an arsenal of deadly ammunitions (including chemicals, cells and proteins) necessary for the elimination of microbes. It is therefore paramount that the immune system must develop mechanisms necessary to prevent destruction of the host it is designed to protect. A good example of such a mechanism is found in the subset of lymphocytes known as regulatory T cells (Tregs). There is unequivocal experimental evidence of the role of Tregs in the maintenance of immune homeostasis and self tolerance and aberrant Treg function has been linked with several inflammatory diseases. Since sepsis is a disease marked by a hyper-inflammatory state, I investigated the possible role of Tregs in dampening sepsis-induced excessive inflammation.
Using a murine model of lipopolysaccharide (LPS) infusion and bacterial infection, I show that Tregs are essential for survival during sepsis because their depletion leads to acute death to an otherwise non-lethal dose of LPS. This enhanced susceptibility to LPS following Treg depletion was also observed using live E. coli infection. Next, I probed the mechanism by which Tregs protect against LPS challenge. I found that defective Treg function leads to exaggerated activity of two immune cells – CD4+ effector T cells and neutrophils in response to LPS, leading to severe inflammatory response. Hence, this work successfully illustrates the critical role of Tregs in regulating other immune cells and the catastrophic consequences of defective Treg function during an immune response.
Overall, this work highlights the significant role of Tregs in the regulation of bacteria associated inflammatory processes. The findings hold implications for the successful management of sepsis and have potential for use in development of adequate therapeutic intervention for sepsis.October 2016
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Chatila, Wissam M. "MicroRNA expression in regulatory T cells in chronic obstructive pulmonary disease." Thesis, Temple University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3719335.
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COPD is characterized by an abnormal regulatory T cell (Treg) response with a shift towards a Th1 and Th17 cell responses. However, it is unclear if the function of Treg cells is impaired by smoking and in COPD. In addition, the miRNA profile of Treg cells in COPD is unknown and whether miRNA deregulation contributes to COPD immunopathogenesis. We set the objective to study Treg cell function isolated from peripheral blood of patients with COPD versus controls and to compare their miRNA profiles. We also were interested in exploring the function of some of the differentially expressed Treg cell miRNAs. We assessed the Treg cell function by observing their suppressive activity on autologous effector T cells and analyzed their miRNA expression initially by microarray analysis then conducted real time RT-PCR validation for selected miRNAs. In Silico target gene analysis for the validated miRNAs suggested that miR-199-5p is particularly relevant to Treg cell physiology so its function was investigated further using CCD-986Sk and MOLT-4 cells. We found no difference in Treg cell function between COPD and controls but we were able to identify 6 and 96 miRNAs that were differentially expressed in COPD versus control Treg cells. We confirmed that miR-199a-5p was repressed by approximately 4 fold in Treg cells of COPD patients compared to cells in healthy smokers. Importantly, miR-199a-5p had significant overrepresentation of its target genes in the Treg cell transcriptome, with many targets associated with the TGF-β activation pathway. We also confirmed the function of miR-199a5p in an in-vitro loss-of-function cell model running TaqMan® arrays of the Human TGF-β Pathway. These findings suggest that the abnormal repression of miR-199a-5p in patients with COPD compared to unaffected smokers may be involved in modulating the adaptive immune balance in favor of a Th1 and Th17 response.
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Lee, Crystal. "Suppressive activity of CD4+Foxp3+ regulatory T cells in an animal model of spontaneous CD8+ T cell-mediated demyelinating disease." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110761.
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Dr. Fournier's laboratory has generated a mouse strain (L31 mice) that spontaneously develops a CD8+ T cell-mediated demyelinating disease in the central nervous system. In this model of dysregulated costimulation, CD4+ T cells have a regulatory role. A subset of CD4+ regulatory T cells that express the transcription factor Foxp3 have been shown to regulate autoimmune responses. In order to investigate this population's role in disease development, the goal of my M.Sc research project was to functionally characterize the CD4+Foxp3+ regulatory T cell population in L31 mice.We found that regulatory T cells from L31 mice were impaired in their ability to suppress the proliferation of effector T cells in vitro. In part, this was because B7.2 (CD86) expression impeded regulatory T cell suppressive activity. However, regulatory T cells delayed the onset of neurological symptoms in vivo. Although L31 Treg are not suppressive in vitro, our in vivo data suggest that they have a regulatory function in L31 disease development. This dichotomy could provide insights into the mechanisms by which these regulatory T cells control disease development in L31 mice.Le laboratoire du Dr. Fournier a généré une lignée de souris (les souris L31) qui développe de façon spontanée une maladie du système nerveux central qui conduit à la perte de la gaine de myéline et qui est dépendante de la presence de lymphocytes T. Dans ce modèle les lymphocytes CD8+ sont les cellules effectrices de la maladie tandis que les lymphocytes T CD4+ jouent un rôle régulateur. Il a été démontré qu'une sous-population de lymphocytes T CD4+ qui expriment le facteur de transcription Foxp3 est impliquée dans la regulation des réponses auto-immunes. Afin d'étudier le rôle de cette population dans le développement de la maladie neurologique des souris L31, le but de mon projet de recherche était de caractériser de façon fonctionelle cette sous-population de lymphocytes T CD4+ régulateurs des souris L31. Nous avons trouvé que les lymphocytes T régulateurs des souris L31 sont altérés dans leur capacité à supprimer la proliferation de cellules T effectrices in vitro. Ceci est dû en partie à leur expression elevée de la protein B7.2 (CD86). Cependant, les lymphocytes T régulateurs des souris L31 sont capables de prévenir le développement des symptômes neurologiques in vivo. Donc, bien que les lymphocytes T régulateurs des souris L31 ne sont pas suppresseurs in vitro, notre données in vivo suggèrent qu'ils ont une fonction régulatrice dans le développement de la maladie neurologique des souris L31. Cette dichotomie pourrait nous permettre de déterminer les mécanismes utilisés par ces cellules régulatrices pour contrôler le développement de la maladie neurologique auto-immune dans les souris L31.
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White, Todd Christopher. "Therapeutic alteration of T cell development: Modulating diabetogenic and regulatory T cells in the treatment of type 1 diabetes mellitus." Diss., The University of Arizona, 2005. http://hdl.handle.net/10150/280761.
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In this dissertation we investigate the role of avidity in the T cell selection process by examining the impact of signal modulation on T cell and/or NKT cell development. Projects discussed herein (including peptide, anti-CD1d, and hydrocortisone (HC) therapy) examine how changes in avidity can be used to explore potential therapies for Type 1 diabetes mellitus (T1DM). In the case of peptide therapy, we find that fetal thymic organ culture (FTOC), treated with exogenous diabetes related GAD peptides, lose their ability to generate T cell responses to GAD treatment peptides. Also, peptide therapy is shown to inhibit T1DM in vitro (ivT1DM) and in vivo. The abnormally high level of GAD peptides that are presented during peptide therapy treatment are thought to increase avidity between peptide specific T cells and selecting cells during thymic education, leading to increased negative selection of those T cells. In the case of anti-CD1d, FTOC from C57BL/6 (B6) and non-obese diabetic (NOD) mice, when treated with 10 μg/mL of anti-CD1d, show divergent responses to treatment. In response to anti-CD1d, "normal" B6 FTOC shows decreased T cell development and NKT production. Conversely, "poor signaling" NOD mice show no major impact on general T cell development but instead show increases in NKT cell production. Also, treatment with anti-CD1d is shown to inhibit diabetes in our ivT1DM model. These effects are thought to be due to increases in avidity generated through anti-CD1d related increased TCR expression. Changes in avidity caused by anti-CD1d treatment are thought to generate increased negative selection in B6 FTOC, while the same avidity increases are thought to increase positive selection (without increasing negative selection) in "poor signaling" NOD FTOC. In the case of HC treatment, B6 FTOC treated with HC show changes in T cell yield, maturity, and TCR Vβ usage. Research with HC indicates that signal inhibitors have the capacity to change T cell development in a dose and time dependent manner. Based on this work, selection signal inhibitors or enhancers may have the capacity to change T cell development in a fashion that decreases autoimmune T cells and/or enhances regulatory NKT cell development.
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Milward, Kate. "Investigation of the cell biology of human regulatory T cells in the context of transplantation." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:1dc5105f-a74c-4451-a8dd-9b37daf3c01d.
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Regulatory T cells (Tregs), lymphocytes that suppress immunological reactions, are of great interest for our comprehension of basic immunology and as a therapeutic agent to treat immune-mediated pathologies. Understanding the physiology of these cells will help to inform clinical strategies targeting Tregs. In order to study the homing of human Tregs, we utilised genetic engineering to drive expression of fluorescent protein in human Tregs, permitting in vivo cell tracking. We optimised a protocol for lentivirus-mediated transduction of human Tregs during in vitro expansion, to generate high yields of stably-engineered cells. After infusing labelled cells into a humanised mouse model of skin allotransplantation, we detected human Tregs within a human skin graft by PCR and visualised Tregs moving in the graft, in a live mouse, by two-photon microscopy. Through reverse genetic analyses, we explored molecular mechanisms that allow Tregs to respond adaptively to environmental cues. Neuropilin-1 (NRP1), a transmembrane co-receptor, has been implicated in the function of mouse Tregs. Tregs transduced with shRNA to knock down NRP1 were severely impaired in their capacity to suppress cell proliferation in vitro and to prolong allograft survival in a humanised mouse model. qRT-PCR analysis revealed that transcription the gene encoding the anti-inflammatory cytokine IL-10, and the autophagy-associated genes BECN1, COPS4 and MAP1LC3B, was significantly diminished in NRP1-deficient Tregs. We concluded that in human Tregs, NRP1 is necessary for suppressive function, most likely via regulation of NRP1-dependent regulation of cytokine production and metabolism. Having identified a molecular target via which Treg function might be potentiated, we explored methods to target such molecules for cell therapy applications. Tregs engineered to over-express IL-10, but not NRP1, exerted significantly enhanced suppression of cell proliferation in vitro. Thus, relatively straightforward genetic engineering, compatible with generation of therapeutic cell yields, could be exploited to improve the efficacy of Treg cellular therapy.
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Chakraborty, Anish. "Role of Nicotinic Acid Adenine Dinucleotide Phosphate in Memory and Regulatory T Cells." University of Toledo / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1533225900138875.
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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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Oo, Ye Htun. "Recruitment and positioning of regulatory T cells and Th17/Tc17 in inflamed human liver." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1128/.
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The liver is a unique tolerogenic organ with dual blood supply. Both regulatory lymphocytes and effector lymphocytes are present in the normal and inflamed liver along with innate immune cells. The balance between these two subsets of lymphocyte is crucial in maintaining immune homeostasis by adjusting either hepatic tolerance or mounting immunity against invading pathogens. Thus, it is important to understand the intrahepatic regulatory T cells phenotype and role played by distinct chemokine receptors expressed on regulatory T cells as they are major player in controlling hepatic tolerance. At the same time, it would be crucial to explore the role of new subset of Th17/Tc17 effector lymphocytes characteristic and their positioning in inflamed liver. This thesis demonstrates the crucial role of chemokine receptors in recruitment and positioning of both intrahepatic regulatory T lymphocytes and IL-17 secreting Th17/Tc17 effector lymphocyte in both normal and inflamed human liver.
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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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Fields, Maria. "Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1408709850.
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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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Ward, Stephen Thomas. "The selective recruitment of regulatory T cells to human colorectal cancer." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5514/.
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Regulatory T cells (Treg) are enriched in tumour tissue relative to other compartments. Anti-tumour immunity is promoted through their depletion. It is hypothesised that Treg are recruited to human colorectal cancer (CRC) via a specific combination of chemokine receptors and integrins, blockade of which reduces tumour Treg recruitment, ameliorating the anti-tumour immune response. A systematic examination was conducted of receptors expressed by CRC-isolated Treg and the cognate ligands expressed by CRC. The effects of receptor inhibition were tested in murine models of colorectal cancer. Human CRC-infiltrating Treg exhibit a specific chemokine receptor signature, expressing significantly higher levels of CCR5 than conventional T cells. CRC expresses the ligands for CCR5 at significantly higher levels than distal tissue. Isolated Treg migrated towards CCR5 ligands in vitro and suppressed allogeneic T cell proliferation. CCR5 inhibition in murine models of CRC led to delayed tumour growth but had no effect on tumour Treg infiltration compared with vehicle control. CCR5 inhibition is unlikely to provide any significant reduction in the infiltration of Treg into human CRC. Given the effects CCR5 inhibition had on tumour growth, CCR5 antagonists command further investigation into their potential role as novel therapeutic agents in the treatment armoury against human CRC.
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Gammon, Joshua Marvin. "Controlled delivery of a glutamate receptor modulator to promote regulatory T cells and restrain autoimmunity." Thesis, University of Maryland, College Park, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10012602.
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Autoimmunity occurs when the immune system incorrectly recognizes and attacks self-molecules. Current therapies involve broad immunosuppressants that are not curative and leave patients immunocompromised. Dendritic cells (DCs) are a target for new therapies because DCs influence the differentiation of immune effector cells. N-Phenyl-7-(hydroxyimino)cyclopropa[ b]chromen-1a-carboxamide (PHCCC), a glutamate receptor enhancer, modulates DC cytokine profiles to polarize T cells toward regulatory phenotypes (TREG) that are protective in multiple sclerosis (MS). However, PHCCC treatment is limited by poor solubility, a short half-life, and toxicity. We hypothesized that controlled delivery of PHCCC from nanoparticles would alter DC function with reduced treatment frequency. PHCCC nanoparticles attenuated DC activation and promoted TREGs while reducing toxicity 30-fold. In mouse models of MS, these particles delayed disease and reduced severity compared to an equivalent dosing schedule of soluble drug. This outcome demonstrates controlled delivery of metabolic modulators can promote tolerance, suggesting a new route to improve autoimmune therapy.
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Vas, Jaya. "REGULATORY ROLES FOR NATURAL KILLER T CELLS AND TOLL-LIKE RECEPTORS IN MERCURY-INDUCED AUTOIMMUNITY." Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/20283.
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Microbiology and ImmunologyPh.D.
The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar antibody production and immune system activation. Regulatory components of the innate immune system such as NKT cells and TLRs can also modulate the autoimmune process. We examined the interplay among environmental chemicals and NKT cells in the regulation of autoimmunity. Additionally, we studied NKT and TLR ligands in a tolerance model where pre-administration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. We also studied the effect of Sphingomonas capsulata, a bacterial strain that carries both NKT cell and TLR ligands, on metal-induced autoimmunity. Overall, NKT cell activation by synthetic ligands enhanced the manifestations of metal-induced autoimmunity. Exposure to S. capsulata exacerbated autoimmunity elicited by mercury. Although the synthetic NKT cell ligands that we used are reportedly similar in their ability to activate NKT cells, they displayed pronounced differences when co-injected with environmental agents or TLR ligands. Individual NKT ligands differed in their ability to prevent or break tolerance induced by low-dose mercury treatment. Likewise, different NKT ligands either dramatically potentiated or inhibited the ability of TLR9 agonistic oligonucleotides to disrupt tolerance to mercury. Our data suggest that these differences could be mediated by the modification of cytokine profiles and regulatory T cell numbers. The mechanisms by which a heavy metal with an elementary chemical structure induces autoimmunity are unknown. Herein we show that mercury administration results in release of endogenous ligands that activate TLR7, an innate immune receptor implicated in the development of systemic autoimmunity. Moreover, our results suggest that fine specificity of autoantibodies recognizing RNA-containing snoRNPs could be a consequence of TLR7 activation.
Temple University--Theses
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Schwele, Sandra. "Human cytomegalovirus-specific regulatory and effctor T cells are clonally identical." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/16003.
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Die Mehrzahl der im Thymus generierten CD4+CD25high regulatorischen T-Zellen (Treg) besitzt hohe Affinität gegenüber körpereigenen Antigenen. Es ist bekannt, dass T-Zell Rezeptoren (TCR) auf Treg Zellen in der Peripherie zusätzlich auch fremde Antigene verschiedener Pathogene wie Parasiten, Bakterien und Viren erkennen. Wenig ist bekannt über das klonale T-Zell Rezeptor Repertoire dieser Treg Populationen und ihre Beziehung zu CD4+CD25low effektor T-Zellen (Teff) im Menschen. In dieser Studie analysieren wir humane TCR auf expandierten Treg and Teff Zellen mit definierter Antigen Spezifität für Haupthistokompatibilitätskomplex (MHC) Klasse II restringierte „fremde“ Epitope des Cytomegalovirus (CMV). Bemerkenswerterweise fanden wir, dass der gleiche TCR Vb-CDR3 Klon in beiden funktionell unterschiedlichen Subpopulationen in vitro dominant expandiert ist. Im Unterschied zu ihren klonal-identischen Teff Gegenspielern, exprimieren die suppressiven Treg Zellen kaum CD127 und IL-2, aber hohe Mengen an IFNg und IL-10. Zusammen mit der signifikant erhöhten FOXP3 Expression, trotz unvollständiger foxp3-DNA Demethylierung, lassen sich die CMV-spezifischen CD4+CD25high Treg Zellen einem induzierten Treg (iTreg) Phänotyp zuordnen mit Ähnlichkeit zum beschriebenen Tr-1 Phänotyp. Darüber hinaus konnten wir die klonale TCR Identität auch in frisch isolierten CD4+CD25low und CD4+CD25high Subpopulationen bestätigen, was die Entstehung von CMV-spezifischen Treg Zellen bereits in vivo nahe legt. Periphere CD25high Treg Zellen supprimieren die anti-virale Immunantwort in Patienten mit häufigen CMV-Reaktivierungen, was auf ihre Bildung als Reaktion chronischer Antigenexposition interpretiert werden kann. Unsere Ergebnisse beweisen erstmals direkt, dass aus dem gleichen humanen T-Zell Klon Teff und Treg Zellen mit identischer Spezifität entstehen können und lassen vermuten, dass die Treg Induktion in der Peripherie durch häufige Antigenexposition vorangetrieben wird.The majority of thymically arised regulatory CD4+CD25high T cells (Treg) show high affinity to self-antigens. It has been proposed that T-cell receptors (TCR) on Treg cells in the periphery also recognize foreign-antigens from pathogens, such as bacteria and viruses. Studies in mice have shown that peripheral Treg cells can be generated not only from naïve T cells but also from effector T cells (Teff). However, in humans the clonal TCR-repertoire of these Treg populations and their relation to effector CD4+CD25low Teff is not sufficiently known up to date. Here, we analyzed human TCRs derived from expanded Treg and Teff cells with defined specificity to MHC class-II restricted “foreign” epitopes of Cytomegalovirus (CMV). Remarkably, we found that both functionally distinct subsets share the same dominant TCR-CDR3 clones in vitro. In contrast to their Teff counterparts, the Treg cells express low CD127 and IL-2, but high IL-10 upon antigen stimulation. Therefore, together with increased FOXP3 expression, but incomplete foxp3 DNA-demethylation, human CMV-antigen specific Treg cells exhibit an induced phenotype (iTreg) in vitro with similarity to recently described Tr-1 phenotype. Moreover, the clonal identity was confirmed in freshly isolated CD4+CD25low and CD4+CD25high subsets, suggesting their generation occurred already in vivo. Peripheral CD25high Treg cells suppress the anti-viral immune response in patients with frequent CMV-reactivations, implying their development as reaction on chronic antigen-exposure. Our results demonstrate directly for the first time, that the same human T-cell clone can possess the phenotype of Teff and Treg cells with specificity to identical foreign epitopes and suggest that Treg-induction in the periphery is supported by frequent antigen-exposure.
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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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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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Sassano, Emily. "Role of regulatory T cells in in vitro human culture systems." Honors in the Major Thesis, University of Central Florida, 2007. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/1046.
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This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucf.edu/Systems/DigitalInitiatives/DigitalCollections/InternetDistributionConsentAgreementForm.pdf You may also contact the project coordinator, Kerri Bottorff, at kerri.bottorff@ucf.edu for more information.Bachelors
Burnett College of Biomedical Sciences
Molecular and Microbiology
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LaCasse, Collin James. "NEGATIVE MODULATION OF REGULATORY T CELLS AND PROMOTION OF THE TUMORICIDAL ACTIVITY OF DENDRITIC CELLS IN CANCER: A DOUBLE-EDGED STRATEGY." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/146077.
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Cancer is one of the most pervasive health problems in the world today. Despite major advances in its treatment in recent decades, conventional therapies have seen limited success. Aggressive, drug-resistant cancer cells can reemerge after treatment, resulting in relapse. Immunotherapy, a strategy that utilizes a patient's own immune system to specifically destroy cancer cells, is a potential solution to this problem. Immunotherapy, however, is limited by multiple mechanisms of cancer-induced immunosuppression. One of the most important of these mechanisms is the induction of Treg, which are capable of suppressing multiple arms of the anti-cancer immune response. In the current study, we evaluated strategies to hinder the deleterious function of Treg on cancer immunotherapy. First, we determined that imatinib mesylate could inhibit Treg function in vivo and in vitro and increase the efficacy of dendritic cell-based immunization against an imatinib-resistant lymphoma. Then, searching for further methods to inhibit Treg, we found that Th-1 cells were capable of inhibiting Treg function and synergizing with a tumor lysate vaccine to treat leukemia. This process was dependent on IFN-γ secretion by the Th-1 cells. While investigating the influence of Th-1 on Treg and the resulting immunomodulatory effects of these cells in vivo, we discovered that they were capable of promoting the non-conventional direct tumor killing function of DC. We determined that Th-1 induce the cytotoxic function of bone marrow-derived DC generated with GM-CSF and IL-4 by a mechanism dependent on IFN-γ. Finally, because our results indicate that the antigen presenting function of KDC may depend upon their cytotoxic ability, and since DC generated with IL-15 have been reported to be more efficient APC than those generated with IL-4, we evaluated their ability to also function as direct tumor cell killers. We found that while IL-15 DC can indeed kill tumor cells, only LPS and not IFN-γ was capable of inducing this capability. These findings contribute to both arms of anti-cancer immunity by impairing immunosuppression with imatinib and Th-1, and promoting anti-tumor immunity with KDC. This double-pronged approach may contribute to further strategic advances in the field of cancer immunotherapy.
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Kinder, Jeremy M. "Reproductive Benefits Conferred by Genetically Foreign Cells that Persist in Mothers and Offspring." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479816425343745.
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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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Li, Chun. "The Role of Non-Classical Regulatory T Cells in HIV-1 Infection." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10701.
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Regulatory T cells represent a specialized subpopulation of T lymphocytes that may modulate spontaneous HIV-1 disease progression by suppressing immune activation or inhibiting antiviral T cell immune responses. While effects of classical \(CD25^{hi}FoxP3^+CD4^+\) regulatory T cells during HIV-1 infection have been analyzed in a series of recent investigations, very little is known about the role of non-classical regulatory T cells that do not express intracellular FoxP3. Here I evaluated two groups of non-classical Treg cells. One is phenotypically identified by the surface expression of HLA-G, an HLA class Ib molecule. The other Treg cell population is characterized by the surface expression of latency-associated peptide (LAP), a membrane-bound form of \(TGF-\beta\). Both HLA-G and LAP-expressing T cells are present in small proportions in peripheral blood of healthy individuals. I performed a systematic study on the phenotypic and functional profile of HLAG- and LAP- expressing regulatory T (Treg) cells in patients with different stages of HIV-1 infection. I found that HLA-G-expressing Treg cells were highly susceptible to HIV-1 infection, and were significantly reduced in individuals with progressive HIV-1 disease courses. Moreover, the proportion of \(HLA-G^+\) CD4 and CD8 T cells was positively correlated with CD4 T cell count and inversely correlated with markers of HIV-1 associated immune activation. Mechanistically, this correlation corresponded to a substantially increased ability of \(HLA-G^+\) Treg cells to inhibit bystander immune activation, while only minimally affecting functional properties of HIV-1-specific T cells. In contrast, no significant change in \(LAP^+\) Treg cell frequencies was found in progressive HIV-1 infection, and these frequencies were not correlated with immune activation. This observation was consistent with functional analysis, which indicated that \(LAP^+\) Treg cells did not suppress bystander activation. These investigations indicate an important role of \(HLA-G^+\) Treg cells for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection, and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression. In the meantime, \(LAP^+\) Treg cells do not appear to play an important role in determining HIV-1 disease outcome.
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Tritt, Michael. "Studying the role of naturally-occurring regulatory T cells in a model of type 1 diabetes." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101804.
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Treg cells counter-balance autoreactive immune cells in healthy individuals. In the absence of Treg cells, multi-organ immune diseases manifest. Thus, Treg cell defects are suspected to contribute to T1D. Currently, it remains unclear whether Treg cell defects are responsible for the manifestation of T1D. Thus, we hypothesized that Treg cell defects results in T1D. We observed that T reg cells are present in normal frequencies in the thymus and peripheral immune system of diabetes-prone mice. Furthermore, thymic and peripheral T reg cells are operative and mediate regulation by suppressing effector T (Teff) cells in the pancreatic lymph nodes and pancreas. Specifically, regulation corresponded with increased frequencies of Treg cells and reduced in diabetogenic T cells in both sites, and controlled insulitis. However, as the immune response against beta cells of the pancreatic islets progresses in prediabetic mice, peripheral Treg cells wane in function and cannot sustain sufficient Teff cell regulation in the pancreatic lymph nodes and pancreas. In summary, this study characterizes areas of T reg cell immunoregulation of T1D; and highlights a Treg cell dysfunction, not a quantitative Treg cell defect, manifesting in the peripheral immune system prior to diabetes onset but following T cell activation, which contributes to the escape of autoreactive T cells.
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Tong, Alexander Andrew. "LYMPHOCYTE TRAFFICKING, HOMING AND FUNCTION: INSIGHTS INTO THE IN VIVO BEHAVIOR OF REGULATORY T AND NATURAL KILLER CELLS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1499374450217703.
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Rosenblum, Joshua Michael. "Novel Roles for Chemokines in Acute Cardiac Allograft Rejection." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244063137.
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Chatila, Wissam M. F. "MicroRNA Expression in Regulatory T Cells in Chronic Obstructive Pulmonary Disease." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/333572.
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Microbiology and ImmunologyPh.D.
COPD is characterized by an abnormal regulatory T cell (Treg) response with a shift towards a Th1 and Th17 cell responses. However, it is unclear if the function of Treg cells is impaired by smoking and in COPD. In addition, the miRNA profile of Treg cells in COPD is unknown and whether miRNA deregulation contributes to COPD immunopathogenesis. We set the objective to study Treg cell function isolated from peripheral blood of patients with COPD versus controls and to compare their miRNA profiles. We also were interested in exploring the function of some of the differentially expressed Treg cell miRNAs. We assessed the Treg cell function by observing their suppressive activity on autologous effector T cells and analyzed their miRNA expression initially by microarray analysis then conducted real time RT-PCR validation for selected miRNAs. In Silico target gene analysis for the validated miRNAs suggested that miR-199-5p is particularly relevant to Treg cell physiology so its function was investigated further using CCD-986Sk and MOLT-4 cells. We found no difference in Treg cell function between COPD and controls but we were able to identify 6 and 96 miRNAs that were differentially expressed in COPD versus control Treg cells. We confirmed that miR-199a-5p was repressed by approximately 4 fold in Treg cells of COPD patients compared to cells in healthy smokers. Importantly, miR-199a-5p had significant overrepresentation of its target genes in the Treg cell transcriptome, with many targets associated with the TGF-b activation pathway. We also confirmed the function of miR-199a5p in an in-vitro loss-of-function cell model running TaqMan® arrays of the Human TGF-b Pathway. These findings suggest that the abnormal repression of miR-199a-5p in patients with COPD compared to unaffected smokers may be involved in modulating the adaptive immune balance in favor of a Th1 and Th17 response.
Temple University--Theses
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Hooper, Kirsten Mary. "PGE2 AND IL-27: NOVEL PROINFLAMMATORY MECHANISMS INVOLVING DENDRITIC CELLS AND TYPE 1 REGULATORY T CELLS." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/432693.
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Microbiology and ImmunologyPh.D.
Interleukin-27 (p28/EBI3) is an immunomodulatory cytokine expressed by activated antigen presenting cells. Although first discovered to be involved in Th1 cell differentiation, further studies demonstrated the immunosuppressive functions of IL-27 including inhibition of Th2 and Th17 differentiation, development of a tolerogenic phenotype in dendritic cells (DC), and promoting type 1 regulatory T cells (Tr1). The anti-inflammatory effects of IL-27 have been demonstrated in vivo in murine models of parasitic infections and autoimmune diseases. Despite the prevalence of studies detailing the induction of IL-27 expression and the role of IL-27 in Tr1 differentiation, little is known about factors that negatively regulate IL-27 expression and Tr1 differentiation. Prostaglandin E2 (PGE2), a lipid mediator abundant at inflammatory sites, was shown to act as a proinflammatory agent in models of inflammatory/autoimmune diseases primarily by promoting CD4 Th1/Th17 differentiation. Here we describe a novel proinflammatory mechanism for PGE2 through the inhibition of IL-27 production in conventional dendritic cells (cDC) and the inhibition of Tr1 differentiation. PGE2 inhibits IL-27 production in bone marrow-derived DC and macrophages, as well as in splenic cDC, through EP2/EP4 receptors, induction of cAMP, and downregulation of IRF1 expression and binding to the p28 IL-27 ISRE site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1 or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, EPAC, PI3K, or MAPKs. We observed similar inhibition of p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. In addition to the inhibition of IL-27 production in APCs, PGE2 also directly affects Tr1 differentiation by reducing IL-27-induced CD4+CD49b+LAG-3+Foxp3- Tr1 cells and IL-10 production. The inhibitory effect is mediated by EP4 and induction of cAMP in differentiating CD4 T cells. IL-27-induced Tr1 differentiation and function depends primarily on the sustained expression of c-Maf in addition to AhR and Blimp-1. PGE2 significantly reduced expression of c-Maf without affecting AhR and only marginally reducing Egr-2/Blimp-1 expression. The effects of PGE2 on Tr1 cells are independent of STAT1/STAT3 signaling and of IL-21 signaling. In addition, the effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. The effects of PGE2 on both IL-27 production and IL-27-induced Tr1 differentiation represent novel proinflammatory mechanisms of PGE2.
Temple University--Theses
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Sugiyarto, Gessa. "Characterising the preferential suppression of potent anti-tumour CTL responses by regulatory T cells." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/379016/.
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Chia, Julius Ebua. "The Role of IL-4 Receptor Alpha signalling on Foxp3 T Regulatory cells in Listeriosis and Tuberculosis." Doctoral thesis, Faculty of Health Sciences, 2021. http://hdl.handle.net/11427/32563.
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T regulatory cells are critical in the maintenance of self-tolerance, immune homeostasis and regulation of the immune system. Cytokine signalling is a dominant component of environmental signals which controls the function of Forkhead box P3 (Foxp3) regulatory T cells. This thesis addressed the hypothesis that interleukin-4 receptor alpha (IL-4Rα) signalling on T regulatory cells (T reg) play a role in the stability of T reg cells. Loss of IL-4Rα signalling on T reg cells may shift the immune balance from a Foxp3+ T reg to a Th1 effector function essential for Th1 disease outcome. Regulatory cells have a major function to dampen cytokine production; however, this role can be detrimental for host-protective immune responses in diseases such as tuberculosis. Here, we used two Th1 models of intracellular pathogens Listeria monocytogenes (Lm) and Mycobacterium tuberculosis (Mtb), to understand the role of IL-4Rα signalling on Foxp3+ T regulatory cells. Infection studies with L. monocytogenes demonstrated an impairment of T reg responses, with a decreased bacterial burden and diminished pathology both in the liver and spleen at 7 days post-infection, ultimately translated in better survival. Mechanistically, enhanced Th1 signature with the characteristic T-bet transcriptional factor and increased effector T cells producing IFN-γ, IL-2 following ex-vivo stimulation with PMA/Ionomycin, and heat-killed Lm (HKLM) were observed in Foxp3creIL-4Rα-/lox mice. Furthermore, CD8+ T cells of Foxp3creIL-4Rα-/lox mice showed increased cytotoxicity (Granzyme-B secretion) with higher proliferation capacity (Ki-67), better survival (Bcl-2) and decreased apoptosis (activated caspase3), suggesting contribution towards the observed protection against listeriosis. Subsequently, we investigated the role of IL-4Rα on Foxp3 T reg cells in Mycobacterium tuberculosis infection. To our surprise, in contrast to Lm infection, survival Survival of Mtb-infected Foxp3creIL-4Rα-/lox mice was similar to littermate control following infection with an intermediate dose of Mtb (H37Rv). We observed no differences in acute and chronic stages of infection in bacterial burden and histopathological scores in Foxp3creIL-4Rα-/lox mice when compared to littermate control animals in acute and chronic stages of infection. Importantly, Mtb infected FoxP3creIL-4Rα-/lox mice, exhibited significantly enhanced CD4+ T effector functions with increased pro-inflammatory cytokine secretion upon stimulation ex-vivo.
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Goodman, Wendy Ann. "IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278433711.
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Li, Ka-Kit. "The role of CD8+ regulatory T cells in anti-tumour immune responses in hepatocellular carcinoma." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/7940/.
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Tumour specific effector T-cells can be detected in the blood and tumours of patients with hepatocellular carcinoma (HCC) but fail to mount effective immune responses. Attempts to amplify anti-tumour immune responses using immunotherapy show promise, but are hampered by the presence of suppressive regulatory T-cells (Treg) that inhibit anti-tumour immune responses. Many different subsets of Treg have since been identified including regulatory T-cells expressing the surface marker CD8 (CD8⁺Treg). A set of experiments was designed in an attempt to increase our understanding on how CD8⁺Treg may disrupt anti-tumour response and by what mechanisms they are induced. CD8⁺Treg was analysed by isolation of liver-derived T-cells from human HCC. Monocyte-derived dendritic cells (moDC) matured with tumour tissue conditioned medium were used to assess they potential to induce CD8⁺Treg. CD8⁺Treg infiltrating HCC demonstrated a suppressive phenotype. The co-culture of naïve CD8⁺T-cells with tumour-conditioned moDC induces a population of CD8⁺Treg through an IDO dependent mechanism. This population of induced T-cells was able to suppress via the CD39-adenosine pathway. The findings of the mechanisms involved in the induction of CD8⁺Treg by DC and the involvement of CD39 in the suppressive capacity of these novel T-cells, may guide the development of future immunotherapeutic in HCC.
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St-Pierre, Jessica. "The role of CD4⁺ Foxp3⁺ naturally-occurring regulatory T cells in the host immune response to Plasmodium chabaudi AS /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111941.
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Naturally-occurring CD4+Foxp3+ regulatory T cells (nTreg) play a central role in maintaining immune self-tolerance as well as modulating immunity towards pathogens. Pathogens may establish chronic infections in immunocompetent hosts by engaging nT reg in order to promote immunosuppression. The goal of the research described here is to test the hypothesis that nTreg modulate protective immunity to malaria, and consequentially affect susceptibility to the parasite. To investigate this question, the functional dynamics of CD4+Foxp3 + nTreg cells were evaluated in mice infected with blood-stage Plasmodium chabaudi AS. Adoptive transfer of nTreg to infected wild-type C57BL/6 (B6) mice or infection of transgenic B6 mice over-expressing Foxp3 resulted in increased parasitemia and reduced survival compared to control mice. Moreover, while resistant B6 mice exhibited decreased splenic nT reg frequencies at day 7 post infection, susceptible A/J mice maintained high numbers of nTreg at this time. Investigation of the effects of nTreg regulation on immune cell function in P. chabaudi AS-infected mice revealed that increased nTreg frequencies led to decreased malaria-specific lymphoproliferation and increased systemic levels of IL-10. Unlike B6 mice, increased splenic nTreg frequencies in infected A/J mice correlated with decreased effector T cell proliferation and IFN-gamma secretion, decreased B cell and NK cell proliferation as well as deficient IFN-gamma secretion by NK cells. Finally, nTreg proliferated within infected sites in both B6 and A/J mice, albeit to a greater extent in susceptible A/J mice. Altogether, these results demonstrate that nTreg suppressed anti-malarial immunity, and in turn promoted parasite growth and persistence.
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Albanese, Alexandre. "Functional impact of the protective Idd3 allele on regulatory T cells and protection from type-1 diabetes." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101698.
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NOD.B6 Idd3 congenic mice, whose Idd3 locus originates from the autoimmune resistant C57BL/6 mouse, demonstrate a drastic reduction in diabetes onset. In this study we demonstrate that NOD.B6 Idd3 mice show halted disease progression and also show reduced levels of TH1 cells in their peripheral immune system. In vitro , CD4+ CD25- effector T (TEFF ) cells from congenic mice display increased proliferation and IL-2 production compared to wild type NOD mice. However, unfractionated NOD.B6 Idd3 CD4+ T cells maintain a higher TREG:T EFF ratio and proliferate less than their NOD counterparts, suggesting increased immunoregulation. In vivo, the Idd3 locus does not appear to reduce the number of islet-reactive cells or increase the systemic frequency of TREG cells in the immune system of pre-diabetic mice. Instead, reduced infiltration of TEFF cells in the pancreas of NOD.B6 Idd3 mice suggests increased suppression of autoimmune cells at the site of inflammation in vivo. Consistent with this hypothesis, tolerance mechanisms in the NOD.B6 Idd3 mouse are much better at suppressing the proliferation of islet-reactive T EFF cells in the pLN. Furthermore, using a novel strain of BDC.Idd3 mice, which contain islet-reactive TCR transgenic CD4+ T cells and which are homozygous for the B6-derived Idd3 allele, we demonstrate that TEFF cells containing the protective Idd3 allele do not possess reduced diabetogenic potential in vivo. Using an adoptive transfer model for type-1 diabetes, we demonstrate that CD4+CD25+ TREG containing the protective Idd3 allele are intrinsically better suppressors than TREG cells of NOD genotype. Collectively, our data show that the protective Idd3 allele favours immunoregulation in the pancreatic lesion by enhancing TREG cell function. Although the precise mechanism of this protection remains unknown, these findings may ultimately help develop therapeutic strategies to reduce or prevent the autoimmune destruction of pancreatic beta islet cells in type-1 diabetes patients.
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Severin, Mary E. "MicroRNAs Targeting TGFß Signaling Underlie the Regulatory T Cell Defect in Multiple Sclerosis." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1440075697.
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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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Allan, Sarah E. "Defining the biological role of FOXP3 in human CD4+ T cells." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/1122.
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The involvement of regulatory T cells (Tregs) in immune homeostasis is now recognized as one of the fundamental mechanisms of immune tolerance. While several different types of Tregs cooperate to establish and maintain immune homeostasis, much current research is focused on defining the characteristics of the CD4⁺CD25⁺ Treg subset, as these cells can mediate dominant, long-lasting and transferable tolerance in many experimental models.
The aim of this research was to characterize the biological role of a protein known as forkhead box P3 (FOXP3) that was initially identified as an essential transcription factor for the development of mouse CD4⁺CD25⁺ Tregs, in human CD4⁺ T cells. Following confirmation that, like mouse Tregs, human Tregs also expressed high levels of FOXP3, several approaches were used to investigate the role of this protein in human CD4⁺ T cells. 1) Characterization of endogenous FOXP3 expression in CD4⁺ T cell subsets revealed that this protein is not a Treg-specific marker as was previously thought. Instead, low-level and transient expression was found to be typical of highly activated non-regulatory effector T cells. 2) To generate large numbers of Tregs suitable for cellular therapy, the capacity of ectopic FOXP3 expression to drive Treg generation in vitro was explored. It was found that high and constitutive expression mediated by a lentiviral vector, but not fluctuating expression driven by a retroviral vector, was sufficient to generate suppressive cells. Over-expression strategies were also used to characterize a novel splice isoform unique to human cells, FOXP3Δ2 (FOXP3b). 3) To further probe the requirements of FOXP3 to induce suppressor function, a system for conditionally-active FOXP3 ectopic expression was developed. These studies established that FOXP3 acts a quantitative regulator rather than a “master switch” for Tregs, and that there is a temporal component to its capacity to direct Treg phenotype and function.
In summary, this research has significantly expanded the understanding of the biological function of FOXP3 in human CD4⁺ T cells. Based on the potential of these cells to be manipulated for therapy, this work contributes to the field of immunology on both academic and clinical research fronts.
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Lawrie, Sarah. "Characterization of differentially activated human B cells and effects of their soluble products on regulatory T cell suppressive function: assay development and design." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110653.
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B cell depletion therapy with rituximab significantly decreases new disease activity in multiple sclerosis (MS) patients; however, these benefits do not correlate with a reduction in circulating or cerebrospinal fluid antibody levels. These findings implicate antibody-independent, pro-inflammatory roles of B cells in MS. Furthermore, in other autoimmune diseases, such as systemic lupus erythematosus (SLE), B cell depletion reportedly resulted in increased function of circulating regulatory T (Treg) cells. Since MS patients have been found to exhibit deficient Treg function, we hypothesized that activated B cells in MS patients can abnormally suppress the function of Treg cells. Therefore, B cell depletion with rituximab allows for restored Treg function, and the prevention of new autoimmune disease activity. In particular, we postulated that the abnormal pro-inflammatory cytokine profile secreted by MS B cells was responsible for defective Treg function. To begin studying the potential relationship between B and Treg cells, I optimized and validated an in vitro human B cell activation assay, as well as a human Treg suppression assay in healthy controls, to subsequently determine the effects of supernatants from differentially activated B cells on Treg suppressive function.Human B cells were isolated using magnetic-activated cell sorting (MACS), then stimulated with B cell crosslinking antibody (X), CD40 ligand (40), a combination of the two (X40), or CpG-nucleotides. Their supernatants were collected and responses found to support previously published findings. Treg and T responder (Tresp) cells were isolated using both MACS and fluorescence-activated cell sorting (FACS) techniques; then stimulated in coculture with and without B cell supernatants; and proliferation was determined by either standard beta scintillation counting (3H-TdR) or carboxyl-fluorescein succinimidyl ester (CFSE) dilution of Tresp cells. We found that Treg cells isolated using the MACS technique contain high numbers of contaminating CD4+CD25neg Tresp cells; are non-proliferative when stimulated alone; and do not robustly suppress Tresp cell proliferation. In contrast, FACS-isolated Treg cells have higher purity and are suppressive of Tresp cell proliferation and cytokine secretion. Suppression could be modulated by treating cells with either IL-10 to promote suppression, or Pam3Cys to decrease suppression, establishing the dynamic range of the suppression assay. When supernatants from B cells activated with CpG-nucleotides or CD40 ligation were added to the suppression assay, we did not find any significant changes. As such, this may reflect a more subtle biology than can be captured within this assay and still requires further investigation.La thérapie au rituximab visant la déplétion des lymphocytes B diminue la sévérité de la sclérose en plaques (SP) de façon significative. Cependant, ces avantages ne sont pas accompagnés d'une réduction du niveau d'anticorps présents dans le sérum ou dans le liquide céphalo-rachidien. Ces résultats suggèrent certains rôles des lymphocytes B dans la SP indépendants de la production d'anticorps et qui seraient pro-inflammatoires. Dans le lupus érythémateux disséminé (LED), la déplétion des lymphocytes B entraine une hausse des fonctions des lymphocytes T régulateurs (Treg) circulants. Puisque les patients atteints de la SP démontrent un fonctionnement déficient de leurs Treg, nous émettons l'hypothèse que l'activation des lymphocytes B chez ces patients pourrait avoir un impact négatif sur le fonctionnement des lymphocytes T régulateurs. Ainsi, la déplétion des lymphocytes B grâce au rituximab permettrait le rétablissement du fonctionnement des Treg et préviendrait de nouvelles maladies auto-immunes. Notamment, nous avons postulé que les lymphocytes B des patients atteints de la SP produisent un profil anormal de cytokines pro-inflammatoires, et que ceci serait responsable de la dysfonction des Treg. Pour commencer l'étude de la relation entre les lymphocytes B et Treg, j'ai optimisé et validé un test d'activation de lymphocytes B humains in vitro, ainsi qu'un test de suppression des Treg humain chez des contrôles sains afin de déterminer les effets des surnageants provenant de lymphocytes B activés différemment sur la suppression de fonctions chez les Treg.Des lymphocytes B humans ont été isolés à l'aide d'un tri cellulaire magnétique (MACS), et ont été stimulés avec un anticorps lié aux récepteurs des lymphocytes B (X), CD40 ligand (40), une combinaison des deux (X40), ou avec des nucléotides CpG. Les surnageants recueillis démontrent des réponses cellulaires similaires aux résultats publiés auparavant. Les lymphocytes T régulateurs et lymphocytes T répondeurs ont été isolés en combinant MACS et un tri cellulaire fluorescent (FACS), puis ont été stimulés en culture ensemble avec ou sans surnageants de lymphocytes B. La prolifération a été déterminée par soit l'incorporation de la thymidine tritiée, ou par d'ester de 5,6-carboxyfluorescéine diacétate succinimidyl (CFSE). Nous avons trouvé que les lymphocytes T régulateurs isolés en utilisant la technique MACS contiennent un grand nombre de lymphocytes T répondeurs CD4+CD25neg, ne prolifèrent pas lorsqu'ils sont stimulés seuls, et n'étouffent pas la prolifération des lymphocytes T répondeurs. En revanche, les cellules Treg isolées par FACS sont d'une plus grande pureté et inhibent de la prolifération des lymphocytes T répondeurs ainsi que leur sécrétion de cytokines. Cette suppression peut être modulée en traitant les lymphocytes avec IL-10 afin de promouvoir la suppression, ou avec Pam3Cys afin d'atténuer la suppression, établissant une gamme dynamique au test de suppression. Lorsque les surnageants des lymphocytes B activés à l'aide de nucléotides CpG ou de CD40 ligand ont été ajoutés au test de suppression, nous n'avons trouvé aucun changement significatif. À ce titre, ceci pourrait refléter une biologie plus subtile qui ne peut être captée au sein de ce test, exigeant une enquête plus approfondie.
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Ayala-Fontanez, Nilmarie. "Paradoxical onset of psoriasis after IL-6 receptor blockade." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1436396399.
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Gurung, Prajwal. "Regulation of immune responses by apoptotic cells." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/974.
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Billions of cells die everyday as a result of normal tissue turnover, infection, trauma or injury. These dead cells are taken up, processed and presented to T cells by antigen presenting cells resulting in tolerance or immunity. Apoptotic cells induce tolerance; however, the precise mechanisms are still unknown. Previous studies have shown that direct infusion of apoptotic cells induce tolerance mediated by TRAIL-expressing CD8+ T cells. We hypothesized that immunologic tolerance induced by apoptotic cells is dependent on the activation status of apoptotic cells and mediated by direct killing of target cells by TRAIL-expressing CD8+ T cells. Three different experimental systems were used to elucidate the mechanisms by which apoptotic cells regulate immune responses.
Using a classical system of tolerance induction, we examined the immunological consequence of intravenous (i.v.) delivery of ex vivo-generated naïve or activated apoptotic cells. Naïve apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154 in the tolerogenic or immunogenic nature of the naïve or activated apoptotic cells, respectively, as tolerance resulted after i.v. injection of either naïve or activated apoptotic CD154-/- cells, while co-injection of an agonistic anti-CD40 mAb with naïve apoptotic T cells induced robust immunity.
The infusion of large numbers of apoptotic cells has limited physiological relevance, so the investigation of the influence of apoptotic cells on the immune system turned to another experimental tolerance model where soluble peptide antigen is injected systemically to induce the peripheral deletion of a population of antigen-specific T cells. Using this system, we investigated how apoptotic cells generated in vivo leads to T cell tolerance. Following adoptive transfer of OT-II cells, wild-type mice injected with soluble OVA323-339 became unresponsive to subsequent CFA/OVA immunization. Interestingly, Trail-/- or Dr5-/- mice developed robust immunity; even though all strains displayed peripheral deletion of OVA-specific T cells. Subsequent investigation found the mechanism of action of the CD8+ T cells was TRAIL-mediated deletion of the OVA-responsive T cells in a TCR-specific manner.
The experimental systems used above have some clinical relevance but are still not physiologic. To study the impact of apoptotic cells in a physiologic setting, we took advantage of the medical condition sepsis, which is accompanied by massive apoptosis of multiple immune cell populations. Thus, the final set of experiments in this thesis examined the tolerance induced during sepsis using a clinically-relevant cecal-ligation and puncture (CLP) model that included a secondary bacterial infection. CLP-treated WT mice had a reduced ability to control the secondary bacterial infection, which was paralleled by suppressed T cell responses, compared to sham-treated WT mice. In contrast, CLP- and sham-treated Trail-/- and Dr5-/- mice were able to similarly control the bacterial infection and generated bacterial antigen-specific T cell responses. The ability of CLP-treated wild-type mice to control the secondary infection and generate T cell immunity could be restored by the administration of a blocking anti-TRAIL mAb. These results suggest the importance of TRAIL in the induction of sepsis-induced immune suppression, such that TRAIL neutralization may be a potential therapeutic target to restore cellular immunity in septic patients.
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Hung, Hau Yee. "Characterization of the CD4+CD25+regulatory T cells in an animal model of spontaneous demyelination in the central nervous system." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66868.
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CD4+ T cells have been suggested to play an immunoregulatory role in a transgenic mouse model of CD8+ T cell-mediated CNS demyelinating disease. Among the various CD4+ regulatory T cells, we characterized the CD4+ CD25+ Foxp3+ T cell subset to investigate its potential involvement in regulating disease development in these mice. Our results indicated that in their peripheral lymphoid organs, this population is expanded. This expansion is unrelated to autoimmunity and is not due to an increased thymic generation. Instead, these cells have undergone polyclonal expansion. Furthermore, they harbor typical Treg phenotypes and are in an activated status, but yet display significantly impaired suppressive activities against CD4+ and CD8+ T cell response in vitro. Therefore, this population may not be the regulatory CD4+ T cell subset that controls disease development in this model, and these results challenge the dogma that Foxp3 expression in mice is always associated with suppressive activities.Il a été suggéré que les lymphocytes T CD4+ contrôlent le développement d'une maladie de démyélinisation du système nerveux central, causée par des cellules T CD8+ pathogéniques, dans un modèle de souris transgéniques. Parmi les différentes sous-populations de lymphocytes T CD4+ régulatrices, on a caractérisé la sous-population de cellules T CD4+ CD25+ Foxp3+ dans ce modèle transgénique pour étudier leur rôle potentiel dans la régulation de la maladie. Notre étude démontre que cette population est augmentée dans les organes lymphoïdes de ces souris. Cette augmentation est indépendante de la maladie et elle n'est pas due à une génération augmentée de ces cellules dans le thymus. Par contre, cette population a subi une expansion polyclonale. De plus, elle présente un phénotype typique des Treg, et elle manifeste un état d'activation. Cependant, elle possède un potentiel de suppression des réponses cellulaires T diminué in vitro. Ces données soulèvent le rôle de ces cellules régulatrices in vivo et le dogme que l'expression du Foxp3, dans la souris, est inconditionnellement associée aux activités suppressives.
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Schiering, Chris. "Identification of the cellular and molecular mechanisms of IL-23 driven intestinal inflammation." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:b33533f6-c7e1-4c77-9fd2-a3b174fb9bde.
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IL-23 is an essential mediator of chronic intestinal inflammation in experimental models of colitis. Polymorphisms in the IL23R locus are associated with IBD susceptibility in humans. The biological activity of IL-23 has been linked to Th17 cells but little is known about the cellular and molecular mechanism by which IL-23 drives intestinal inflammation. The work presented herein has identified that direct IL-23 signalling into CD4+ T cells was not only required for the accumulation of Th17 cells in the intestine but also modulated their phenotype. Through direct cell intrinsic effects on T cells, IL-23 drove the emergence of an IL-17A+IFN-γ+ population of T cells that co-expressed RORγ and T-bet. Interestingly, we found that expression of RORγ but not T-bet by T cells was required for the development of intestinal inflammation. Furthermore, colitis induced by T-bet deficient T cells was dependent on IL-17A, and showed a unique inflammatory phenotype, thus demonstrating that pathogenic intestinal Th17 responses can develop independently of T-bet. In addition, using transcriptional profiling we identified a core set of genes that is regulated by direct cell-intrinsic IL-23 signals into intestinal CD4+ T cells. This revealed a previously unrecognised role for IL-23 in suppressing Th2 associated genes, such as GATA3 and IL-33R. Functional experiments demonstrated that expression of GATA3 in CD4+ T cells limited their colitogenic potential, suggesting that IL-23-mediated inhibition of GATA3 might contribute to the development of intestinal inflammation. Finally, we described a novel function for IL-33 as a factor that promotes Foxp3+ iTreg differentiation in vitro and in vivo through direct effects on T cells. This activity of IL-33 was inhibited in the presence of IL-23, providing a mechanistic link for the known role of IL-23 in restraining iTreg generation. Collectively, these data suggest that IL-23 promotes acquisition of a pathogenic effector T cell phenotype through multiple mechanisms. This indicates that therapeutic blockade of IL-23 is likely to reduce pro-inflammatory mediators while also facilitating the expansion of regulatory pathways that might help to re-establish intestinal homeostasis.
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Mexas, Angela Marie. "CD4+CD25+ REGULATORY T CELLS ARE INFECTED AND ACTIVATED PHENOTYPICALLY AND FUNCTIONALLY DURING ACUTE INFECTION WITH FELINE IMMUNODEFICIENCY VIRUS." NCSU, 2007. http://www.lib.ncsu.edu/theses/available/etd-11022007-103144/.
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HIV-induced AIDS may be mediated by the activation of immunosuppressive CD4+CD25+ T regulatory cells (Tregs). Tregs have been shown to regulate CD4+ and CD8+ immune responses to HIV and FIV antigens in vitro. We tested the hypothesis that Tregs become infected and activated during the acute stage of FIV infection leading to the suppression of CD4+ T helper cell responses. Cats were experimentally infected with FIV-NCSU-1 and blood and lymph node biopsies were collected at 1 week intervals following inoculation. Real-Time PCR was used to determine plasma viremia and relative number of FIV copies in CD4+CD25+ and CD4+CD25- T cell subsets. Flow cytometry was used to assess the absolute numbers of each cell type and the expression of activation markers. Real-time RT-PCR was also used to assess relative increases in FoxP3 and TGF- mRNA levels over time. Treg suppression of IL-2 production in CD4+ T helper cells was assessed by ELISPOT assays and inhibition of cellular proliferation was assessed by incorporation of tritiated thymidine and CFSE. Our results show that peak viremia levels correlate with maximal infectivity in lymph node CD4+CD25+ populations. FIV-gag-mRNA levels are higher in CD4+CD25+ T cells than CD4+CD25- lymph node T cells. Activation of FoxP3 and increased expression of TGF1 in CD4+CD25+ cells correlates with peak plasma viremia and FIV-gag-mRNA levels in CD4+CD25+ T cells. Regulatory function can be detected in CD4+CD25+ T cells during the acute phase of FIV infection. Our findings support the hypothesis that early activation of immunosuppressor function in Treg cells may limit an effective anti-FIV response contributing to the establishment of the chronic infection and the immunodeficiency caused by this virus.
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Rowe, R. K., G. I. Ellis, J. L. Harrison, A. D. Bachstetter, G. F. Corder, Eldik L. J. Van, B. K. Taylor, F. Marti, and J. Lifshitz. "Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge." SAGE Publications, 2016. http://hdl.handle.net/10150/614986.
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Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.