Dissertations / Theses: 'Immunometabolism, T cells, autoimmunity'

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Tänzer, Aline. "Molecular Mechanisms of Immunometabolic Dysfunction in Multiple Sclerosis." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20482.

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Multiple Sklerose (MS) ist eine chronische neuro-degenerative Erkrankung des zentralen Nervensystems, die durch auto-immun-bedingte Prozesse charakterisiert ist. T Zellen wurden als wesentliche pro-inflammatorische Mediatoren mit der Pathogenese der MS assoziiert. In gesunden Individuen passen Immunzellen ihren Metabolismus, wie die mitochondriale Atmung und Glykolyse, ihrer jeweiligen Funktion und ihrem inflammatorischen Phänotyp an. Im Krankheitsverlauf der MS ist die Bedeutung der metabolischen Anpassung und der damit verbundenen pro-inflammatorischen Mechanismen von T Zell-Subpopulationen noch nicht eindringlich erforscht. Um dieser Fragestellung nachzugehen wurden Relapsing Remitting MS (schubförmig, RRMS) Patienten und sorgfältig aufeinander abgestimmte gesunde Kontrollprobanden als Teil der Studie Depression und Immunfuktion bei MS rekrutiert (n=62). Den Patienten und gesunden Kontrollprobanden wurde Nüchternblut entnommen, woraus periphäre mononukleäre Blutzellen (PBMC) aufgearbeitet wurden, um anschließend CD4+ und CD8+ T Zellen zu isolieren. Die erzielten Ergebnisse zeigten CD4+ T Zell-spezifische Verringerungen der mitochondrialen Atmung und glykolytischen Aktivität in der MS Patienten Kohorte im Vergleich zur Kohorte der gesunden Kontrollprobanden. Darüberhinaus wurden, zusätzlich zu den umfangreichen phänotypischen Charakterisierungen der PBMCs via Durchflußzytometrie, erhöhte Werte des mitochondrialen Membranproteins CPT1a in CD4+ T Zell-Subpopulationen in der MS Patienten Kohorte detektiert. Die Analyse der CD4+ CD25- CD127+ konventionellen T Zell- Subpopulation ergab leicht erniedrigte Werte von IL7-Rα in MS Patienten. Genexpressionsanalysen, die mit pro-inflammatorischen und metabolischen Genen assoziiert sind, ergaben keine Veränderungen in den T Zell-Subpopulationen der MS Patienten. Die in dieser Studie erzielten Ergebnisse weisen auf Funktionsstörungen bei der metabolischen Anpassung in T-Zell-Subpopulationen bei MS Patienten hin und helfen, den Beitrag des Immunmetabolismus bei der Pathogenese der MS Erkrankung besser zu verstehen.
Multiple Sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system characterized by autoimmune-mediated mechanisms. T cells have been associated as central pro-inflammatory mediators in MS pathogenesis. In healthy individuals, immune cells adapt metabolic programs like mitochondrial respiration and glycolysis based on their function and inflammatory phenotype. However, the relevance of metabolic reprogramming and associated pro-inflammatory mechanisms in T cell subpopulations in MS disease is not well understood yet. To address this question, Relapsing Remitting MS (RRMS) patients and meticulously matched healthy control (HC) participants were recruited as part of the clinical study Depression and Immune Function in MS (n=62). Blood samples, after a period of fasting, were collected and CD4+ and CD8+ T cells isolated from peripheral blood mononuclear cells (PBMC). The results obtained demonstrated decreased mitochondrial and glycolytic activity specific to CD4+ T cells in the MS patient cohort compared to the HC participant cohort. Furthermore, increased CPT1a mitochondrial membrane protein levels were detected in CD4+ T cell subpopulations in the MS patient cohort as assessed in comprehensive flow cytometry PBMC phenotype investigations. The analysis of the CD4+ CD25- CD127+ conventional T cell subpopulation moreover revealed a trend of decreased IL7-Rα expression levels in MS patients. Gene expression measurements of pro-inflammatory and metabolic genes did not reveal alterations in MS patients’ T cell subpopulations. The results obtained in this study allude to dysfunctions in metabolic reprogramming in T cell subpopulations in MS patients and help to better understand the contribution of immunometabolism in the pathogenesis of MS disease.

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May, Kenneth F. "T cell costimulation in anti-tumor immunity and autoimmunity." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085004772.

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Thesis (Ph. D.)--Ohio State University, 2004.
Document formatted into pages; contains xv, 178 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 May 20.

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Chen, Yuling [Verfasser]. "Immunometabolism of inflamm-aging in naive and memory CD4+ T cells / Yuling Chen." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/120204333X/34.

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Thompson, Angus Gordon. "Dendritic cell NFkB function in T cell activation and autoimmunity /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18273.pdf.

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Zancanaro, Krauss Maria Eduarda. "CD4+ T cell metabolism during Trichuris muris infection." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/cd4-t-cell-metabolism-during-trichuris-muris-infection(24eb0cc7-db70-46ea-ba49-e4fe3d5a5d03).html.

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Trichuris trichiura is a gastrointestinal dwelling nematode that infects almost 500 million people worldwide. T. muris occurs naturally in mice and is very closely related the human whipworm, making it a suitable model to dissect the immune response against the parasite. Studies using the Trichuris muris system have identified CD4+ T cells as dictators of the outcome of infection. In wild type mice, infection with a high dose of T. muris eggs leads to resistance and worm expulsion, which are dependent on a Th2 response and the secretion of type 2 cytokines especially interleukin (IL) 13. Chronicity is dependent on a Th1 response and occurs when mice are infected with a low dose of T. muris eggs. It is well established that metabolic changes are essential to promoting T cell activation and effector function. Moreover, during chronic infection the host immune system is continuously exposed to parasite antigen, which represents a metabolic challenge. This thesis has investigated the importance of T cell metabolism during response against T. muris. Data presented here show that low and high dose T. muris infections promote upregulation of the glycolytic pathway in CD4+ T cells. During later stages of chronic infection, CD4+ T cells displayed supressed glycolysis and mitochondrial respiration, and may be due to metabolic modulation imposed by the parasite. Leucine uptake via the amino acid transporter Slc7a5 was previously shown to be required for mTORC1 activation and for T cell effector function. Data presented here show that in early stages following a high dose T. muris infection, mice that lack Slc7a5 in T cells have delayed worm expulsion, impaired production of antibodies, and lower levels of IL-13. Their CD4+ T cells present reduced glycolytic rates when compared to cells from cohoused infected wild type mice. However, at later stages of infection, antibody, IL-13 and glycolytic levels were restored together with worm expulsion. CD4+ T cells from the early stage of infection showed reduced phosphorylation of mTOR, which suggested that impairment of function was mTOR dependent. Indeed, mice lacking mTOR in T cells fail to expel a high dose of parasites. They showed abrogation of IL-13 production, impairment in antibody class switching and their CD4+ T cells failed to upregulate glycolysis. Thus, this thesis shows that mTOR is essential for the proper functioning of T cells during T. muris infection and efficient amino acid transport plays a significant role. Taken together, these data show that metabolic orchestration of T cell function influences the capacity to effectively control helminth infection and that even subtle changes in T cell metabolic control can have a major effect on response phenotype.

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Kissler, Stephan. "How transgenic T cells interpret encounter with peptide antigen." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324380.

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Ratts, Robert Bruce. "The role of chronically stimulated and senscent T cells in autoimmunity." Access limited to abstract only until after 9/25/2007, 2006. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=ETD#206.

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Amorim, Garcia da Rosa Catarina Alexandre. "The role of regulatory T cells in the prevention of autoimmunity." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312209.

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Lee, Priscilla. "Defining pathways that promote and characterize pathogenic T cells in CNS autoimmunity." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1448984666.

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Colamatteo, Alessandra. "Metabolic control of FoxP3 expression in human regulatory T cells." Doctoral thesis, Universita degli studi di Salerno, 2017. http://hdl.handle.net/10556/2686.

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2015 - 2016
Regulatory CD4+CD25+ T (Treg) cells play a central role in the maintenance of immune self-tolerance and homeostasis. Although Treg cells operate through multiple mechanisms, it appears that the expression of the transcription factor Forkhead-box-P3 (FoxP3) is crucial for their function. Here we describe human peripheral Treg (pTreg) cells that develop from CD4+CD25- T (Tconv) cells following suboptimal stimulation via the T cell antigen receptor (TCR). This population of pTreg cells, which we call inducible Treg (iTreg) cells, is characterized by high FoxP3 expression, strong suppressive capacity and an active proliferative and metabolic state. The development of iTreg cells tightly depends on glycolysis, which controls FoxP3 splicing variants containing exon 2 (FoxP3-E2), through the glycolytic enzyme enolase-1. Remarkably, iTreg cells suppressive activity is impaired in autoimmune diseases such as relapsing remitting multiple sclerosis (RR-MS), and associates with the reduction of FoxP3-E2 expression, secondarily to impaired glycolysis and IL-2/IL-2R/STAT-5 signalling. These results suggest a novel mechanism that links glucose metabolism to the induction of specific FoxP3 splicing variants, via enolase-1, that directly impact on human Treg cell function, in health and in autoimmunity. [edited by author]
Le cellule T regolatorie CD4+CD25+ (Treg) svolgono un ruolo centrale nel mantenimento dell’omeostasi e della tolleranza immunitaria. Sebbene le cellule Treg operino attraverso diversi meccanismi, sembra che l'espressione del fattore di trascrizione Forkhead-box-P3 (FoxP3) è fondamentale per la loro funzione. Qui descriviamo le cellule Treg periferiche (pTreg) umane che si sviluppano dalle cellule T CD4+CD25- (Tconv) dopo stimolazione subottimale del recettore delle cellule T (TCR). Questa popolazione di cellule pTreg, chiamata cellule Treg indotte (iTreg), è caratterizzata da un'elevata espressione di FoxP3, da una forte capacità soppressoria e da uno stato proliferativo e metabolico attivo. Lo sviluppo delle cellule iTreg dipende fortemente dalla glicolisi, che controlla le varianti di splicing di FoxP3 contenenti l'esone 2 (FoxP3-E2), attraverso l'enzima glicolico enolasi-1. In particolare, l’attività soppressoria delle cellule iTreg è compromessa nelle malattie autoimmuni come la sclerosi multipla recidivante-remittente (RR-MS) e si associa alla riduzione dell'espressione di FoxP3-E2, secondariamente alla compromissione della glicolisi e della via di segnalazione IL-2 / IL-2R / STAT-5. Questi risultati suggeriscono un nuovo meccanismo che collega il metabolismo del glucosio all'induzione di specifiche varianti di splicing di FoxP3, attraverso l'enolasi-1, che ha un impatto diretto sulla funzionalità delle cellule Treg, sia in condizioni fisiologiche che in corso di autoimmunità. [a cura dell'autore]
XXIX n.s.

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Jain, Nitya. "Multifaceted Regulation of Peripheral T Cell Tolerance and Autoimmunity by FOXP3+ T Regulatory Cells: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/416.

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Adaptive immunity requires T cell responses to foreign pathogens to be counterbalanced with the need to limit collateral destruction of the host’s own tissues. Further, the presence of a substantial pool of lymphocytes capable of recognizing selfantigen in the periphery poses a threat to the maintenance of peripheral tolerance and prevention of autoimmunity. Regulatory T cells (Treg) that can suppress potentially self-reactive T cells are critical regulators of peripheral tolerance as well as initiation of immune responses. Treg cells employ several context-dependent mechanisms to establish regulation. In this thesis, we describe two distinct pathways of regulation used by Treg cells involving negative costimulation by CTLA-4 and immunomodulation by the morphogen, TGFβ. CTLA-4 is a co-inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. CTLA-4 expression is induced in conventional T cells following activation, whereas it is constitutively expressed in regulatory FOXP3+CD4+ regulatory T cells. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both, is not known. We present evidence here that in addition to a critical CTLA-4 function in regulatory T cells, CTLA-4 in conventional T cells is also necessary for controlling the consequences of abnormal T cell activation. CTLA-4 expression in activated conventional T cells only in vivois unable to compensate for the impaired function of CTLA-4-less regulatory T cells that results in systemic lymphoproliferation, but it can prevent the aberrantly activated T cells from infiltrating and fatally damaging non-lymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell homeostasis: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells can prevent the harmful accumulation of inappropriately activated pathogenic T cells in vital organs. In addition, we have identified Disabled-2 (Dab2), a TGFβ signaling intermediate, as a FOXP3 target gene that is expressed exclusively in Treg cells and is critical for in vitro and in vivo regulation by Treg cells. During T cell development, DAB2 is also expressed in a Foxp3-independent manner in thymic precursor cells, and acts as a sensor of TGFβ signals that is required for programming normal TGFβ responsiveness in T cell progenies. Naïve CD4+ T cells that differentiate from Dab2-deficient precursors favor Th17 cell generation at the expense of FOXP3+ Treg cells as a result of altered sensitivity to TGFβ. Importantly, retinoic acid can restore TGFβ signaling capacity of naïve CD4+ T cells generated from Dab2-deficient precursors, emphasizing the cooperative nature of retinoic acid and TGFβ signaling pathways in promoting Treg cell development and maintenance.

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Li, Ming 1957. "Generation of CD8+ T cell immunity with help from CD4+ T cells." Monash University, Dept. of Pathology and Immunology, 2002. http://arrow.monash.edu.au/hdl/1959.1/8476.

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Cambrook, Helen Elizabeth. "Investigating the role of T-bet in CD4+ T cell driven central nervous system autoimmunity." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17608.

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Self-reactive CD4+ helper T cells (Th) are key causal agents in the pathogenesis of many autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a CD4+T cell model of the demyelinating autoimmune disease multiple sclerosis (MS). It has been shown that EAE is caused by CD4+ T-cells that produce pro-inflammatory cytokines IFN-γ (Th1) and IL-17 (Th17). As such, understanding how these Th cells are generated and controlled is essential. There is debate as to whether Th1 and Th17 cells act independently in EAE or if there is plasticity between these two subtypes, and whether the capacity to switch from Th1 to Th17 confers pathogenic capacity. T-bet was first described as the master transcription factor for Th1 cells, and is thought to have a critical role in EAE even though IFN-γ, the Th1 archetypal cytokine, has been shown to be redundant. More recent work has shown that T-bet is expressed in multiple immune cell types, and it remains unclear in what cells the expression of T-bet is required for EAE. Considerable efforts have been put into understanding the role of T-bet in EAE pathogenesis, with a view to modulate cells expressing T-bet for therapy. The hypothesis of this work was that T-bet has multifaceted roles in EAE, in initiating and directing an immune response in innate antigen presenting cells such as dendritic cells (DC) as well as programming pathogenic effector CD4+ T cell (Teff) response to antigen. T-bet-/- mice were studied using different models of EAE to dissect the role of T-bet in disease pathogenesis. Active immunisation of C57BL/6 mice with the immunodominant peptide from myelin oligodendrocyte glycoprotein (MOG35-55) showed that T-bet-/- mice developed EAE with an IL-17 dominated profile and critically, T-bet-/- mice were able to produce GM-CSF which has recently been described as a key cytokine for EAE. T-bet-/- cells were not able to transfer EAE in a model of passive transfer EAE, where CD4+ T cells were polarised towards a Th1 profile in vitro. Illustrating that T-bet is required in CD4+ T cells for Th1 mediated EAE. DC driven EAE showed that T-bet-/- DC were able to activate CD4+ T cells in vitro and cause EAE upon co-transfer into host mice with transgenic CD4+ T cells. Thus, it has been shown that T-bet is not required in EAE. This work represents a step further towards understanding the disease mechanisms involved in EAE and suggests T-bet is not an appropriate therapeutic target for the treatment of MS.

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Jha, Vibha. "Cellular regulation of mercury-induced autoimmunity." Diss., Temple University Libraries, 2009. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/60597.

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Microbiology and Immunology
Ph.D.
Etiological agents causing autoimmune diseases largely remain unknown. However, several lines of evidence suggest that environmental factors such as heavy metals (arsenic, lead and mercury) play a crucial role in the development of autoimmune disorders. In our model of mercury-induced autoimmunity, administration of subtoxic doses of HgCl2 to genetically susceptible strains of mice result in an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hypergammaglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of HgCl2 (tolerogenic dose). Previous studies from our lab had demonstrated that CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) control the induction and maintenance of tolerance to mercury. We investigated the therapeutic role of Tregs in our model by utilizing agents that are known to stimulate in vivo expansion of Tregs. We studied two such agents, CD3-specific non-Fc receptor-binding [(Fab’)2 fragment] monoclonal antibody (Anti-CD3) and immune complexes containing recombinant IL-2 and anti-IL-2 monoclonal antibody (IC). In our model, treatment of mice with Anti-CD3 had no effect on Treg population. Administration of Anti-CD3 with the tolerogenic dose prevented induction of tolerance and failed to improve the maintenance period of tolerance. Anti-CD3 in presence of mercury activated the immune-system causing splenomegaly and expansion of B cell population. Overall, in contrast to its protective role in other experimental autoimmune disease models, Anti-CD3 exacerbated mercury-induced autoimmune syndrome. Treatment of mice with IC resulted in selective expansion of Tregs with a modest decrease in IgE levels and autoantibody production. Administration of IC with the tolerogenic dose led to a reduction in autoantibody response, thus IC was able to extend the maintenance period of tolerance to mercury. Lymphocyte Activation Gene-3 (LAG-3) is an inhibitory molecule that maintains lymphocyte homeostatic balance by controlling effector T cell expansion and contributing to the suppressive functions of Tregs. Thus, with the goal to understand the impact of homeostatic balance on Hg-induced autoimmunity, we investigated the role of LAG-3 in our model. Administration of an anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in levels of serum IgE. Additionally, LAG-3-deficient B6.SJL mice exhibited an increased susceptibility to mercury-induced autoimmunity whereas, wild type controls suffered only from a mild disease. Moreover, adoptive transfer of wild-type CD4+ T cells protected LAG-3-deficient mice from mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.
Temple University--Theses

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Isaksson, Magnus. "Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis." Doctoral thesis, Uppsala universitet, Molekylär medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-173427.

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The events that trigger an autoimmune disease remain largely unknown. To study these events animal models are necessary because symptoms of autoimmune diseases are preceded by a long asymptomatic period in humans. Experimental autoimmune encephalomyelitis (EAE) is the best characterized model for cell mediated autoimmunity and an animal model for the human disease multiple sclerosis. EAE is induced in rodents by immunization with myelin antigens (Ags) together with adjuvants. After immunization, T cells are primed in the periphery by Ag presenting cells and subsequently invade the central nervous system where they mediate parenchymal inflammation, resulting in demyelination and clinical symptoms of an ascending paralysis. It is now generally recognised that the main cell type mediating EAE is the T helper type 17 (Th17) cell. Tolerance to EAE can be attained by DNA vaccination, but how the immune response against the myelin Ags is abrogated after DNA vaccination is not known. By employing short interfering RNA technology, induction of the innate immune signalling molecule interferon (IFN) -β was found to be necessary for the protective effect of DNA vaccination in EAE. In addition, DNA vaccination inhibited subsequent autoimmune Th17 cell responses. The Toll-like receptors (TLRs) of the innate immune system have evolved to recognise conserved molecular structures on microbes and signalling through them almost exclusively converge on the molecule MyD88. Signalling via MyD88 was found to be required for induction of EAE since mice deficient in this molecule did not develop disease. Upstream signalling via TLR4 and TLR9 had tolerogenic properties. In studies of Ag presentation in EAE, two major subtypes of dendritic cells (DCs) were examined. Plasmacytoid DCs were found to have a promoting role in the induction of EAE, partly via type 1 IFNs. Myeloid DCs had a redundant role in the induction phase of EAE, neither disease severity nor encephalitogenic Th17 responses were affected by their absence during priming. These studies further demonstrate that the cells and molecules of the innate immune system exhibit a crucial role in controlling the adaptive immune system which mediates tissue damage in autoimmune diseases.

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Yang, Cuihong. "Regulation of autoimmune responses by dendritic cells and regulatory T cells in murine models of systemic lupus erythematosus." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39573527.

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Cao, Duojia. "CD25+CD4+ regulatory T cells in rheumatic disease /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-178-4/.

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Webb, Lindsay M. Webb. "Protein Arginine MethylTransferase 5 (PRMT5) Drives Inflammatory T cell Responses and Autoimmunity." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1540137110161319.

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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 (T_REG) 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 Immunology
Ph.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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Nowakowska, Dominika Joanna. "Phenotype and function of regulatory T cells in Th1- and Th2-mediated inflammatory diseases." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/11779.

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Regulatory T cells (Treg) are critical to the maintenance of immune tolerance, partly by controlling the unwanted activation of effector T cells (Teff) and thereby enhancing the resolution of autoimmune and allergic inflammation. Recent data suggest that Treg can specialize to better control different types of inflammation by using transcriptional machinery which controls differentiation and function of Teff. This thesis addresses questions related to the efficacious use of Treg, notably their ability to adopt distinct phenotypic profiles under different inflammatory contexts and their need to recognize antigen in the inflamed organ. Two differentially mediated mouse disease models were used in this project, namely Th1/Th17-mediated experimental autoimmune encephalomyelitis (EAE) as a model of multiple sclerosis and Th2-mediated allergic airways inflammation (AAI) as a model of asthma. A new model of rMOG-induced AAI was developed to specifically answer the questions on the importance of cell phenotype versus antigen-reactivity for the effective Treg-mediated suppression. It was demonstrated that Treg from the inflamed CNS in EAE had an upregulated expression of Th1 master regulator T-bet and Th1-associated chemokine receptor CXCR3, whereas Treg derived from the inflamed lung in AAI had an increased expression of Th2 master regulator GATA-3, lacked expression of T-bet and displayed decreased levels of CXCR3. This specialized and activated phenotype was restricted to tissue-derived Treg. The importance of appropriate Treg phenotype for effective suppression was suggested by the observed inability of CNS-derived Treg to inhibit AAI. A different Treg subset, TGF-β-induced Treg (iTreg), was shown to express high levels of T-bet and CXCR3, but not GATA-3 upon induction in vitro. iTreg effectively suppressed both Th1 and Th2 types of inflammation and the antigenreactivity was key to this. This thesis demonstrates that Treg are capable of acquiring a distinct phenotype corresponding with a CD4+ T cell response driving inflammatory disease and identifies antigen-reactivity as key to the efficacious suppression of inflammation. It also highlights substantial phenotypic differences between iTreg and naturally-occurring Treg which could be associated with different modes of suppression.

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Mesri, Mehdi. "T lymphocytes-blood retina barrier cells interactions in vitro : the role of adhesion molecules and inflammatory mediators." Thesis, University of Aberdeen, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320782.

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The BRB consists of both capillary endothelial cells (REC) and retinal pigment epithelial cells (RPE). Both cell types have been suggested as potential activators of circulating T cells. In this study, an in vitro model using cultured rat REC and syngeneic T cells was developed. Furthermore RPE and for the purpose of comparative studies, AEC were also successfully cultured. It was demonstrated that activation of T lymphocyte LFA-1 is a critical event governing the adhesion of T cells to RPE and REC as IFN-γ induced up-regulation of RPE and REC ICAM-1 expression did not increase binding of resting T lymphocytes. The enhanced adhesion of activated lymphocytes (but not resting lymphocytes) to normal and IFN-γ treated RPE and REC was inhibited by LFA-1 mAb and to a lesser extent by ICAM-1 mAb but not OX34 (CD2). Treatment of lymphocytes with the anti-VLA-4 mAb resulted in differential effects on binding to AEC and REC. MAb to VLA-4 significantly blocked enhanced adhesion of activated T cells to AEC but not to REC. The results also demonstrated that VLA-4 mAb significantly inhibited unactivated T cell binding to IFNγ+TNFα+LPS stimulated AEC but not REC, suggesting that VLA-4 may also function in an activation-independent manner. It was shown that activation of T cells can enhance their migratory activity across cultured REC monolayers. Migration was decreased by both adhesion receptor-dependent mechanisms i.e., mAb to LFA-1 (but not ICAM-1) and adhesion receptor-independent mechanisms by means of PGE₂. The results of this thesis have shown that activation of LFA-1 is required for functioning of the LFA-1/ICAM-1-mediated lymphocyte adhesion and migration. In addition to the role of adhesion molecules, inflammatory mediator PGE₂, but not NO^o, was found to be important in regulation of T cell adhesion and migration across REC.

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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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Zhang, Jinyu. "The role played by microRNA-155 in the regulation of T cell function." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209317.

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T cells chronically stimulated by their antigen often become dysfunctional and lose effector functions and proliferative capacity. This state of unresponsiveness is referred as T cell exhaustion. In order to investigate this, we developed a laboratory model, which allowed us to stimulate chronically in vivo a monoclonal population of CD4+ T cells. This model is based on the adoptive transfer of TCR transgenic CD4+ T cells specific for the male mHAg into male recipient mice. We found that systemic exposure to the male antigen modified deeply anti-male TcR-transgenic CD4+ T cells, plunging them into a state of functional unresponsiveness. Microarray analysis revealed that, in comparison with naive T cells, transferred T cells displayed a gene expression profile very similar to that of virus-specific exhausted CD8+ T cells. Moreover, like exhausted CD8+ T cells, exhausted CD4+ T cells lost their capacity to secrete IFN-ã as well as to proliferate in response to antigen stimulation, and T cell unresponsiveness was controlled by the engagement of programmed death receptor 1 (PD-1) present at the surface of T cells.

MicroRNAs are key molecules in shaping T cell function. In order to explore the possibility that chronic antigenic stimulation could shape the pool of microRNAs in exhausted anti-male CD4+ T cells that would account for specific changes in protein synthesis, we compared by microarray analysis the specific expression of microRNAs in naive CD4+ T cells and exhausted CD4+ T cells. Ninety five of them were found differentially expressed, among which, microRNA-155 (miR-155) displayed one of the highest changes. To identify the importance of miR-155 in T cell exhaustion, we analyzed miR-155-deficient CD4+ T cells after chronic exposure to systemic antigen. We found that, chronically-stimulated miR-155-/- CD4+ T cells were retained in a deeper state of unresponsiveness than miR-155+/+ CD4+ T cells. Furthermore, inhibition of PD-1/PD-L1 interaction did not promote antigen-dependent expansion of miR-155-deficient CD4+ T cells, nor did it stimulate T cell inflammation of several organs, contrary to what was observed in mice that received miR-155-sufficient CD4+ T cells. Thus, our observations demonstrated that miR-155 deficiency played a dominant role over PD-1-mediated inhibition of T cells and that miR-155 was required for restoring function in exhausted CD4+ T cells.

Next, we explored the mechanism by which exhausted miR-155-/- CD4+ T cells were kept in a deeper unresponsiveness state than miR-155+/+ counterparts. By comparative microarray analysis of gene expression between exhausted miR-155+/+ CD4+ T cells and miR-155-/- CD4+ T cells, heme oxygenase 1 (HO-1) was identified as a specific target of miR-155. Finally, inhibition of HO-1 activity restored the capacity of exhausted miR-155-/- CD4+ T cells to promote autoimmune inflammation in adoptively-transferred recipients.

Taken together, our study identified miR-155-mediated regulation of protein expression as a critical factor for restoring function in exhausted CD4+ T cells. Our results also present regulation of HO-1 expression in T cells as one of the mechanisms by which miR-155 promote T cell-driven inflammation.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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25

BROGGI, ACHILLE. "Migratory and not lymphoid-resident dendritic cells maintain peripheral self-tolerance and prevent Autoimmunity via induction of iTreg cells." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/30034.

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There is evidence that dendritic cells (DCs) induce peripheral tolerance. Nevertheless, it is not known whether immature DCs in general are able to tolerize CD4+ T cells or if this is a prerogative of specialized subtypes. Here, we show that, when autoantigen presentation is extended to all conventional mouse DCs, immature lymphoid tissue resident DCs are unable to tolerize CD4+ T cells. In contrast, this is a prerogative of steady state migratory DCs. The way they contribute to tolerance development is via the induction of autoantigen-specific regulatory T (iTreg) cell conversion. Since only lymph nodes host migratory DCs, iTreg cells develop solely in lymphnodes, and not in the spleen, and are retained inside the lymph nodes.Mechanistically, in cutaneous lymph nodes, DC-derived CCL22contributes to the retention of iTreg cells. The importance of the local generation of iTreg cells is emphasized by their essential role in preventing autoimmunity.

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Chang, Xing. "X-Linked FOXP3 & OTC in immune tolerance and autoimmunity." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1149171466.

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27

Lampropoulou, Vasiliki [Verfasser], and Roland [Akademischer Betreuer] Lauster. "TLR/MyD88 signaling in B cells suppresses T cell-mediated CNS autoimmunity / Vasiliki Lampropoulou. Betreuer: Roland Lauster." Berlin : Universitätsbibliothek der Technischen Universität Berlin, 2012. http://d-nb.info/1021976601/34.

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28

Huber, Johanna Elisabeth [Verfasser], and Dirk [Akademischer Betreuer] Baumjohann. "Human circulating T follicular helper cells during viral infection and autoimmunity / Johanna Elisabeth Huber ; Betreuer: Dirk Baumjohann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1226092527/34.

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29

Nicolaou, Stella A. "K⁺ Channel Trafficking in the Immunological Synapse of Human T Cells in Health and Autoimmunity." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1194547989.

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30

Yang, Cuihong, and 楊翠紅. "Regulation of autoimmune responses by dendritic cells and regulatory Tcells in murine models of systemic lupus erythematosus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39707362.

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31

Castaneda, Adrian Lance. "Selective histone deacetlyase inhibition decreases disease in lupus-prone mice." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/72952.

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Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that acetylates several proteins that are involved in the immune response. HDAC6 inhibition has been shown in various models to decrease inflammation by altering various proteins involved in the dysregulation of B and T cell responses. In our current studies we sought to determine if HDAC6 inhibition would decrease disease in lupus-prone mice using two murine mouse models of SLE: MRL/lpr mice and NZB/W F1 mice. Both mouse models were fed a rodent diet formulated with the selective HDAC6 inhibitor ACY-738 (N-hydroxy-2-(1-phenylcycloproylamino) pyrimidine-5-carboxamide). NZBW mice received 18 weeks of treatment starting at 16-weeks-of-age and had an average of 57.3 +/- 14.6 ng/mL of ACY-738 in the plasma. MRL/lpr mice received 7 weeks of treatment starting at 11-weeks-of-age and had an average of 78.5 +/- 17.3 ng/mL of ACY-738 in the plasma. Controls received either dexamethasone 5x a week or were left untreated. As the mice aged, body weight, urine protein, and blood sera was collected weekly. Spleen cells were isolated following euthanasia for flow cytometry and kidneys were also collected for histological analyses. We found that in both mouse models that mice treated with ACY-738 had reduced splenic weight and IgG immunoglobulin isotypes. MRL/lpr mice that were treated with ACY-738 had a reduction in the number of IL-17+, ROR-gamma-t TH17 cells. NZBW/ F1 mice that received ACY-738 treatment also had a reduction in the TH17 cells and we observed a significant reduction in kidney pathology. Selective HDAC6 targeting may warrant future investigations as a potential therapeutic target for the treatment of SLE.
Master of Science

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32

Brabb, Thea. "The fate of MBP-specific T cells in MBP TCR transgenic mice /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/10853.

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33

Aksoylar, Halil I. "A Critical Role for Gimap5 in CD4+ T Cell Homeostasis and Maintenance of Peripheral Immune Tolerance." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367937122.

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34

Adeegbe, Dennis O. "Allogeneic CD4+CD25+Foxp3+ T Regulatory Cells in Autoimmunity and Transplantation Tolerance: Therapeutic Potential and TCR Repertoire Requirement." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/43.

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CD4+CD25+Foxp3+ T regulatory (Treg) cells are critical in maintaining self tolerance and promoting the acceptance of allogeneic tissue/organ grafts. To be widely applied in clinical settings, there needs to be a readily available source of Treg cells, a requirement that is better met if non-histocompatible donor cells could be utilized in adoptive therapy. Therefore, to investigate the therapeutic potential of fully allogeneic Treg cells to control autoimmune disease or allograft rejection, we utilized IL-2R beta-deficient mice that exhibit rapid lethal autoimmunity due to low production of an ineffective population of Treg cells. We show that adoptive transfer of MHC-mismatched Treg cells into IL-2R beta-/- mice resulted in life-long engraftment of the donor cells, which exhibited skewed reactivity toward host alloantigens, and prevented autoimmunity. When such animals received skin grafts, they exhibited tolerance to those grafts that expressed MHC molecules from which the donor Treg cells were derived. Collectively, these data provide proof-of-principle that effective engraftment by allogeneic Treg cells controls autoimmunity and leads to favorable conditions for long-term acceptance of allografts. Current data indicates that CD4+CD25+Foxp3+ Treg cells exhibit a broad TCR repertoire. However, the relationship between this diversity and capacity to control a similarly diverse population of potentially autoreactive T cells remains to be defined. To investigate this issue, we assessed the TCR repertoire of chimeric donor Treg cells in IL-2R beta-/- mice that were adoptively treated with a diverse polyclonal Treg inoculums. We demonstrate that autoimmune disease was fully prevented by engrafted donor Treg cells in spite of a TCR repertoire that is less diverse than the input cells. However, in settings where the input TCR repertoire is limited by utilizing donor Treg cells that express a single TCR beta chain, control of disease was hampered, correlating with a limited TCR alpha repertoire within the engrafting donor Treg cells. Collectively, these findings suggest that for adoptive therapy, a diverse TCR repertoire of input Treg cell inoculums is an essential requirement for effective control of polyclonal autoreactive T cells but perturbations in the repertoire that results in significant limitation to this diversity may compromise Treg cell efficacy at fully keeping autoaggressive cells in check.

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McNally, Jonathan P. "The rational targeting of the DNA damage response pathway for the selective elimination of encephalitogenic T cells." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428652709.

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36

Ramalingam, Rajalakshmy. "Importance of TGF-beta Signaling in Dendritic Cells to Maintain Immune Tolerance." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/228458.

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TGFβ is an immunoregulatory cytokine that has a pivotal function in maintenance of immune tolerance via the control of lymphocyte proliferation, differentiation and survival. Defects in TGFβ1 expression or in its signaling in T cells correlate with the onset of several autoimmune diseases. However, the early effects of this cytokine on the innate immune system, particularly the dendritic cells (DCs) which play an equally important role in development of immune tolerance, are not well documented in vivo. In the current study, we developed conditional knockout mice with targeted deletion of Tgfbr2 specifically in dendritic cells. DC-Tgfbr2 KO mice developed spontaneous multi-organ autoimmune inflammation with T and B cell activation. Phenotypic analysis of dendritic cells revealed no significant differences in the expression of MHCII and co-stimulatory molecules between control and DC-Tgfbr2 KO mice. However, we found that DCs from DC-Tgfbr2 KO mice were more pro-inflammatory, which exacerbated the severity of disease in a T cell transfer model of colitis. Furthermore, increased IFNγ expression by Tgfbr2-deficient DCs inhibited antigen-specific regulatory T cells (Tregs) differentiation by DCs in the presence of TGFβ. Since DCs play an important role in Treg homeostasis in vivo, we also examined the phenotype of Tregs and observed a significant increase in the frequency and numbers of Foxp3⁺ T cells in both the spleen and MLNs of DC- Tgfbr2 KO mice. Further analysis of these Tregs revealed attenuated expression of Foxp3 and an expansion in the numbers of CD4⁺CD25⁻Foxp3⁺T cells suggesting that the Tregs from KO mice may not be fully immunosuppressive. Adoptive transfer of in vitro differentiated iTregs into 2-3 week old DC-Tgfbr2 KO mice partially rescued the autoimmune phenotype by reducing the frequency of activated T cells and severity of colitis but did not prevent inflammation in other organs. The phenotype of this novel mouse model clearly indicates the importance of TGFβ signaling in DCs in the maintenance of immune homeostasis and prevention of autoimmunity and provides an opportunity to study the pathogenesis of complex disorders such as autoimmune gastritis, pancreatitis, hepatitis and inflammatory bowel diseases.

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37

AL, ANSARI FARAH. "Studies of the autoimmune reactions in the thyroid and peripheral blood of patients with Graves ophthalmopathy with an emphasis on the roles of the CD8+ T cells and the eye muscle antigen calsequestrin." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/19602.

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The mechanism for the association of autoimmunity in the thyroid and orbit in Graves ophthalmopathy (GO) is unclear but is most likely a result of autoimmune attack against a thyroid and orbital tissue shared antigen. In this thesis, a novel approach was taken in relation to the correlation between parameters of thyroid autoimmunity, changes in the peripheral blood T cell populations and the presence of ophthalmopathy in patients with Graves’ disease. Enzyme digestion, flow cytometry, cell culture, cell proliferation assays and enzyme linked immunosorbent assay (ELISA) were used to study % thyroidal and peripheral blood total T cells, CD8+ T cells and CD8+ T-reg cells and thyroid and peripheral blood T cell specificity to the auto-antigens calsequestrin (CASQ1) and collagen XIII (CollXIII). These parameters were correlated with each other, serum titres of the corresponding antibodies and the concentration of CASQ1 protein in the thyroid. Finally, percentages of several cell types and serum CASQ1 antibody levels were correlated with various genotype carriers of those CASQ1 gene single nucleotide polymorphisms (SNPs) that have been described as risk factors for GO. Several observations were found including a positive correlation between % thyroidal CD8+ T cells and % CD8+ T-reg cells in Graves’ disease patients with (GO) but not in those without (GD) ophthalmopathy. Other findings include positive thyroid T cell reactivity to CASQ1 and a positive correlation between thyroidal % CD8+ T cells and CASQ1 serum antibody levels in patients with GO. These results indicate that both CD8+ T cells and CASQ1 play roles in a link between thyroid and orbital autoimmune reactions in GO. This study opens a new area of research into thyroid immunocompetent cell subtypes and related factors in relation to the various orbital antigens and the development of GO and could be the basis for the introduction of future immunomodulatory treatments for the management of this disorder.

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Ishikawa, Yuki. "Functional engraftment of human peripheral T and B cells and sustained production of autoantibodies in NOD/LtSzscid/IL-2Rγ-/- mice." Kyoto University, 2015. http://hdl.handle.net/2433/195963.

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Pilli, Deepti. "The Autoimmune T cell Response Against the Dopamine-2 Receptor in Movement and Psychiatric Disorders." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/22465.

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Autoimmunity and immune dysregulation are associated with a subset of movement and psychiatric disorders. This paradigm is largely supported by the discovery of autoantibodies against neuronal antigens, like the dopamine-2 receptor (D2R). T cells are a prominent cell subset in the immune system, however, their role in these diseases is unknown. Herein, we identified and characterised D2R-specific T cells in movement and psychiatric disorders in children and adults. In children with suspected autoimmune or neurodevelopmental movement and psychiatric disorders (n=24), activated D2R-specific T cells were detected in 8/24 (33%) patients when their peripheral blood was stimulated with a library of D2R peptides and assessed for CD25+CD134+CD4+ T cells via flow cytometry. The D2R-specific T cells recognised three immunodominant regions: aa121-131, aa171-181, and aa396-416. These regions were predicted with computational methods to bind with high affinity to the HLA of D2R-specific T cell positive patients and were associated with elevated levels of pro-inflammatory cytokines that characterise Th1 and Th17 cells, as quantified by a cytometric bead array and an enzyme-linked immunosorbent assay. The eight D2R-specific T cell-positive patients were seronegative for D2R antibodies, as evaluated with the flow cytometry live cell-based assay. These findings on autoreactive T cells in children formed the basis for investigating D2R-specific T cells in adults with isolated dystonia, a movement disorder that is often idiopathic and has been associated with impaired dopamine signalling. In adults with dystonia (n=20), activated D2R-specific T cells were detected in 6/20 (30%) patients via flow cytometry after stimulation with seven immunogenic regions of D2R. A subset of the D2R-specific T cell-positive patients had activated CD39+ Treg cells (2/6) and 1/6 D2R-specific T cell-positive patient concomitantly harboured activated CXCR5+ Tfh cells and D2R antibodies. In summary, this thesis offers new insights into autoreactive T cells against D2R in the movement and psychiatric disorders. Our observations encourage studies to further understand explore T cell dysregulation to better identify novel subsets of movement and psychiatric disorders and have clinical implications in improving diagnosis and treatment.

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Motz, Gregory T. "The Role of Cigarette Smoke Exposure-Induced Activation of the Innate and Adaptive Pulmonary Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1265989482.

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41

Bray, Cara. "Using CRISPR to determine the effects of mutations of PTPN22 in human T cells." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31418.

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The haematopoietic phosphatase PTPN22 is a key regulator in balancing immune responses between self-reactivity and tolerance. PTPN22 downregulates T cell signaling and harbors the non-HLA genetic variation most strongly associated with autoimmune disease in humans, the single nucleotide polymorphism R620W. The effect of this mutation is currently controversial due to confounding results in mouse and human models. The polymorphism is linked to increased susceptibility to autoimmunity in both human and mouse models, although the latter does depend on genetic background. However, mouse data clearly shows that the polymorphism has a loss-of-function effect on T cell signalling, whereas studies in human models largely demonstrate a gain-of-function effect for R620W. A confounding issue in human studies is that they depend on comparison of T cells from distinct individuals, on protein over-expression, or on RNA interference, techniques for which it is difficult to control for genetic and environmental variables, changes in stoichiometry, and off-target effects or incomplete knockdown, respectively. We aimed to create isogenic human cell lines with mutations in PTPN22 at the genomic level to alleviate the complications inherent in analysing human data. In addition to autoimmune pathogenesis, we are interested in the role of PTPN22 in a cancer setting. Because PTPN22 has a strong suppressive effect on T cell responses to weak affinity antigen, which encompass most tumour antigens, we postulated that knocking out PTPN22 may better enable T cells to kill tumour cells. Furthermore, we have shown that PTPN22 knockout (KO) leads to increased IL-2 expression in mouse T cells, and that this effect is protective against TGF-β mediated suppression, a common driver of T cell inhibition in the tumour microenvironment. T cell transfer experiments in mice showed that PTPN22 KO T cells are indeed more effective at reducing tumour size. Based on these findings, we aim to determine whether PTPN22 KO in human cells confers a similar effect on signaling. To investigate the effects of PTPN22 KO on human T cell signaling, we used CRISPR gene-editing to target PTPN22 in a Jurkat cell line. By combining this technique with lentiviral transduction of a specific T cell receptor, we generated human cell lines which are genetically identical, save for specific alterations to PTPN22, and which can be stimulated with strong or weak cognate antigen. We found that PTPN22 KO Jurkat cells develop an enhanced activation phenotype upon stimulation, including increased IL-2 expression. Additionally, PTPN22 KO Jurkat cells show enhanced Erk signalling following stimulation with weak affinity antigen, but this difference is lost as stimulus strength increases. CRISPR technology has presented the opportunity to create novel models of PTPN22 signalling in the context of human T cell lines. The data from these lines suggests that, unlike the R620W mutation, complete loss of PTPN22 has a comparable effect in human and mouse T cells. In conjunction with our previous findings, these results suggest that knocking out PTPN22 may lead to signalling alterations that improve adoptive T cell cancer therapy.

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Oleinika, Kristine. "The role of CD1d-mediated lipid presentation by regulatory B cells in invariant natural killer T cell suppression of autoimmunity." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10025884/.

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Regulatory B cells (Bregs) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The role of CD1d in Breg biology and the specific contribution to iNKT cell function and in suppressing inflammation remains unknown. Combining chimeric mice, cell depletion and adoptive transfer strategies, we show that CD1d lipid presentation by B cells to iNKT cells is critical for the induction of iNKT cells that down-regulate Th1 and Th17 adaptive immune responses and arthritis, whilst dispensable for Breg development. Mice lacking CD1d-expressing B cells developed exacerbated arthritis compared to wild-type mice and failed to respond to α-GalCer treatment. Absence of lipid presentation by B cells led to altered activation of iNKT cells, with disruption of regulatory pathways including those involved in metabolism and cytokine responses. Thus, we have identified a novel mechanism by which Bregs via CD1d, in an IL-10 independent manner, control and restrain excessive inflammation.

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Gebauer, Christina. "The Janus face of immunity : how anti-tumor immunity leads to autoimmunity in paraneoplastic neurological diseases." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30139/document.

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Les syndromes neurologiques paranéoplasiques (SNP) sont des maladies neurologiques rares, associés à une réponse immunitaire efficace contre un cancer sous-jacent exprimant un antigène également exprimé par des cellules du système nerveux central (SNC). Le cancer déclenche alors une réponse auto-immune secondaire qui provoque la destruction des cellules du SNC. Certains travaux récents suggèrent que l'immunité à médiation cellulaire associée à des auto-anticorps reconnaissant des antigènes intracellulaires pourrait jouer un rôle majeur, bien qu'encore mal compris, dans la physiopathologie des SNP. Les exemples de SNP les plus représentatifs sont le syndrome Hu, qui conduit à la perte de diverses populations de neurones du SNC et l'ataxie cérébelleuse subaiguë (PCD en anglais, pour Paraneoplastic Cerebellar Degeneration), caractérisée par la perte sélective des cellules de Purkinje du cervelet. Alors que le syndrome Hu se développe en général chez des patients présentant des tumeurs du poumon à petites cellules qui expriment l'antigène HuD spécifique des neurones, la majorité des patients souffrant de PCD présente un cancer gynécologique qui exprime la protéine CDR2, également exprimée dans les cellules de Purkinje. Afin de mieux cerner la physiopathologie des SNP et de tester l'implication de l'immunité cellulaire, notamment des lymphocytes T, nous avons durant ma thèse développé et analysé deux modèles murins, l'un pour le syndrome Hu et l'autre pour la PCD. Ces modèles reposent sur l'utilisation de souches de souris génétiquement modifiées : la souris CamK-HA, qui exprime l'hémagglutinine (HA) du virus de la grippe dans la plupart de ses neurones du SNC et la souris L7-HA dans laquelle la protéine HA est exprimée exclusivement par les cellules de Purkinje du cervelet. Dans ces souris, une réponse anti-tumorale est provoquée par l'injection de cellules tumorales 4T1 exprimant HA (4T1-HA). Afin le faciliter le suivi des réponses cellulaires contre l'antigène HA, nous avons injecté des lymphocutes T CD4+ et/ou T CD8+ naïfs isolées à partir de souris transgéniques pour des récepteurs de lymphocytes T spécifiques de HA. Nos résultats montrent que seul le transfert in vivo des cellules tumorales 4T1-HA, et non celui des cellules 4T1 témoins, peut conduire à l'activation, la prolifération et la différentiation des deux types de lymphocytes T spécifiques pour l'antigène HA. De plus, nous avons observé que les populations de lymphocytes T CD4+ et CD8+ sont toutes deux requises, non seulement pour une réponse anti-tumorale efficace, mais aussi pour le déclenchement d'une réaction auto-immune collatérale chez la souris CamK-HA. Enfin, nous avons montré qu'il était nécessaire d'injecter en parallèle des anticorps contre le récepteur inhibiteur CTLA-4 chez la souris L7-HA, afin de permettre la migration des lymphocytes T spécifiques de HA dans le cervelet. Chez ces souris L7-HA, nous avons en outre démontré que les lymphocytes T CD8+ cytotoxiques sont les effecteurs principaux de la maladie. Ces nouveaux modèles murins représentent donc des outils précieux pour une meilleure compréhension des mécanismes moléculaires responsables du développement des SNP. De plus, ils pourraient permettre de tester et de valider de nouvelles approches thérapeutiques visant à bloquer la pénétration dans le SNC d'effecteurs immunitaires potentiellement pathogènes, tout en préservant l'efficacité de la réponse anti-tumorale en périphérie
Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural self-antigen that is ectopically expressed in neoplastic tumor cells and naturally expressed in CNS cells. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to autoantibodies against intracellular proteins. However, its precise contribution in the pathogenesis remains unclear. Two illustrative examples of possibly cell-mediated PNDs are the Hu-syndrome, characterized by inflammation and widespread los of neurons, and paraneoplastic cerebellar degeneration (PCD), characterized by the selective loss of Purkinje cells. PCD develops mostly in patients with gynecologic carcinomas that express the Purkinje neuron-specific CDR2 protein whereas most patients with the Hu-syndrome harbor small cell lung cancer expressing the neuron-specific protein HuD. In this context, our study aimed to investigate the impact of anti-tumor cellular immune responses in the development of these PNDs. To this end, we developed two animal models mimicking the Hu-syndrome and PCD. We used a tumor cell line expressing the hemagglutinin (HA) of influenza virus to induce an anti-tumor response in CamK-HA mice, which express HA in CNS neurons and L7-HA mice, which express HA only in cerebellar Purkinje neurons. To promote and track the T cell response against the HA antigen, naïve HA-specific CD8+ and/or CD4+ T cells, originating from TCR-transgenic animals, were transferred into these mice. We demonstrate that HA-expressing tumors, but not control tumors, induce in vivo activation, proliferation and differentiation of naïve HA-specific CD4+ and CD8+ T cells into effector cells. Moreover, the collaboration between these two T cell subsets was needed to control tumor growth and induce CNS inflammation in CamK-HA mice. In L7-HA mice the additional injection of the antibody against the inhibitory receptor CTLA-4 was necessary to allow T cells to enter the cerebellum to cause inflammation and the subsequent destruction of Purkinje neurons. Furthermore, in L7-HA mice we demonstrate that cytotoxic CD8+ T cells are the main effectors driving the disease. Thus, these two new mouse models provide further insights into the cellular mechanisms of PND whereby a potent anti-tumor immunity triggers a cancer-associated autoimmune disease, and may therefore help to develop new therapeutic strategies against PND

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44

Fang, Ping [Verfasser], and Naoto [Akademischer Betreuer] Kawakami. "Visualizing the stimulation of encephalitogenic T cells in gut associated lymphoid tissue as a trigger of autoimmunity / Ping Fang ; Betreuer: Naoto Kawakami." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1202011233/34.

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45

Eriksson, Catharina. "Immunological mechanisms in systemic autoimmunity : autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis." Doctoral thesis, Umeå universitet, Klinisk immunologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-42954.

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Background. Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that, without powerful treatment, may lead to irreversible joint damage. During the past decade, anti-cytokine therapy has become available, e.g., infliximab, a chimeric antibody targeting the pro-inflammatory cytokine TNF that has a central role in the inflammatory process in RA patients. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that may affect all organs and is characterized by a massive antibody production. Chemokines, chemokine receptors and lipoprotein receptor-related protein 1(CD91) are regulators of inflammation in autoimmune diseases and T-cell migration. Objectives. The aim of this study was to get a deeper understanding how TNF blocking treatment influences inflammatory mechanisms and autoantibody formation in RA with special reference to similarities and differences with SLE. Methods. In patients with RA treated with anti-TNF, and in SLE patients (ACR criteria) clinical evaluation was performed and blood samples analyzed. Autoantibodies were analyzed using indirect immunofluorescence, ELISA and multiplex flow cytometry in samples from anti-TNF treated RA patients (n=59) followed longitudinally for 54 weeks, in pre-diseased samples from SLE patients (n=38) and matched population-based controls (n=152). T-cell expression of chemokine receptors and CD91 was analyzed by flow cytometry, whilst serum levels of chemokines were determined using ELISA in anti-TNF treated RA-patients (n=24) followed longitudinally (30 weeks), and cross-sectionally in SLE-patients (n=23). Expression of mRNA for chemokines was analyzed in T-cells from SLE-patients (n=10) using PCR. Results. After treatment with infliximab, RA patients produced ANA, anti-dsDNA and anti-nucleosome antibodies, but not anti-ENA antibodies. Although these antibodies are considered typical for SLE only one patient developed a transient lupus-syndrome. Antibodies against cell nuclear antigens, including ENA, were detected several years before the first clinical symptom of SLE; anti-SSA was the earliest detectable antibody. In RA-patients before infliximab treatment, the T-cell expression of several chemokine receptors was elevated compared with healthy controls. In contrast, only one soluble chemokine, IP-10 was elevated. After treatment the levels of soluble MIP-1β, MCP-1 and IP-10, and the T-cell expression of CCR2 were decreased. In SLE-patients MIP-1β, MCP-1, SDF-1, IP-10 and RANTES in blood were elevated, whilst expression of CXCR5 and CCR6 on T-cells was lower than in healthy controls. T-cell expression of CXCR2 and CCR1 was elevated in active disease (measured as SLEDAI index), whereas the CXCR5 and CCR2 expression was lower in inactive SLE. In SLE patients with nephritis IP-10 was lower and T-cell expression of CXCR3 and CCR3 elevated compared with patients without nephritis. The expression of CD91 was higher on T-cells from patients not responsive to infliximab treatment compared with responders. Conclusion. These findings indicate that anti-TNF (infliximab) treatment in RA-patients has a major impact on the production of autoantibodies and chemokines. The autoantibody profile in infliximab-treated patients was similar to that predating disease onset in SLE patients with the exception of anti-ENA being detectable in SLE, but the development of lupus-syndromes was rare. The expression of CD91 on T-cells may predict responsiveness to infliximab. The expression of chemokine receptors in SLE- patients seemed to be related to disease activity. Anti-nuclear antibodies were detectable years before clinical disease onset in patients who developed SLE suggesting a gradual pathogenic process.

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Michieletto, Michael. "Rôles des facteurs de transcription Foxo3 et Eomes dans la différenciation et les fonctions des lymphocytes T CD4." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30224/document.

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Les Lymphocytes T CD4 (LT CD4) sont des cellules du système immunitaire adaptatif extrêmement plastiques qui, en fonction des signaux présents dans le microenvironnement cellulaire, ont la capacité de se différencier en différentes sous-populations de LT CD4 possédant des fonctions distinctes. Ce processus est hautement régulé par l'expression de facteurs de transcription (FT) clés tels que T-Bet, GATA-3, RORgammaT et Foxp3, nécessaires à la mise en place des lignages Th1, Th2, Th17 et Treg respectivement. Néanmoins, ces protéines n'agissent pas seules, et d'autres facteurs de transcription sont nécessaires pour amplifier, soutenir et maintenir ces différents lignages. Chaque lignage permet de lutter efficacement face à différents types de pathogènes ; toutefois, si la réponse immune n'est pas adaptée, ils peuvent également être responsables du développement de maladies auto-immunes. Afin de mettre en évidence les voies de signalisation et les facteurs de transcription impliqués dans la différenciation des LT CD4 pathogènes, nous avons utilisé le modèle de l'Encéphalomyélite Auto-immune Expérimentale (EAE), un modèle murin de Sclérose En Plaques (SEP). Dans ce modèle, nous avons mis en évidence le rôle clef de deux facteurs de transcription, Foxo3 et Eomes, dans la différenciation des LT CD4. En effet, les souris déficientes en Foxo3 développent une EAE moins sévère que les souris WT, et cette moindre sévérité de la maladie est associée à une proportion réduite de cellules productrices d'IFN-gamma et de GM-CSF in vivo, suite à l'immunisation. L'analyse du transcriptôme des souris Foxo3KO et WT a révélé que la déficience en Foxo3 a pour conséquence une diminution drastique de l'expression du FT Eomes. Bien que cette protéine soit nécessaire à la mise en place des réponses cytotoxiques dans les LT CD8 et les NK, son rôle précis dans les LT CD4 reste peu connu. D'un point de vue moléculaire, nous avons pu prouver, par des techniques d'Immuno-Précipitation de la Chromatine (ChIP) et des analyses de gènes rapporteurs, que le FT Eomes est un gène cible direct de Foxo3 dans les LT CD4.[...]
CD4 T cells are extremely plastic, and depending on the cytokines that are present within the microenvironment, they have the ability to differentiate into several subpopulations. This process is finely regulated by the expression of Master Regulator of each lineage such as T-Bet, GATA-3, RORgammaT and Foxp3, that are mandatory for the differentiation of Th1, Th2, Th17 and Treg cells respectively. However, they do not act alone, and several other transcription factors are required to stabilize, amplify and lock CD4 T cell lineages. Each subpopulation of CD4 T cells is highly specialized in the elimination of particular types of pathogen; however, in case of dysregulation of the immune response, they can also be involved in the development of autoimmune diseases. In order to determine how such properties are acquired by pathogenic CD4 T cells, we used the Experimental Autoimmune Encephalomyelitis (EAE) model which mimic Multiple Sclerosis pathology. In this model, we identified two transcription factors, Foxo3 and Eomes, that are critical for the differentiation of a particular and highly pathogenic subset of CD4 T cell. Indeed, Foxo3-deficient mice develop a less severe disease as compared to WT littermate and this decreased disease severity is associated with a decreased proportion of IFN-gamma and GM-CSF producing cells. Transcriptomic analysis of Foxo3KO versus WT CD4 T cells revealed that the most downregulated gene within Foxo3KO CD4 T cells is Eomes, which is essential for/to the acquisition of cytotoxic functions and production of IFN-gamma by NK and CD8 T cells. At the molecular level, using Chromatin Immuno-Precipitation experiments and Luciferase assays, we showed that Eomes is a direct target gene of Foxo3 in CD4 T cells. Then, in order to determine which of the downregulated gene is responsible for the decreased production of IFN-gamma and GM-CSF, we decided to overexpress Eomes in Foxo3KO CD4 T cells. Eomes overexpression restored IFN-gamma and, to a lesser extent, GM-CSF production by CD4 T cells, thus indicating that Eomes is involved in IFN-gamma and GM-CSF regulation in CD4 T cells.[...]

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Petermann, Franziska Verfasser], de Angelis Martin [Akademischer Betreuer] [Hrabé, Thomas [Akademischer Betreuer] Korn, and Dirk [Akademischer Betreuer] Haller. "IL-23R+ γδ T cells: A population of effector cells that is pre-programmed in the embryonic thymus and enhances autoimmunity by restraining Foxp3+ regulatory T cells / Franziska Petermann. Gutachter: Thomas Korn ; Dirk Haller ; Martin Hrabé de Angelis. Betreuer: Martin Hrabé de Angelis." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1049281152/34.

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Mesquita, Júnior Danilo [UNIFESP]. "Avaliação fenotípica das células T reguladoras CD4+CD25+CD127LOW em pacientes com lúpus eritematoso sistêmico." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9122.

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Made available in DSpace on 2015-07-22T20:49:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-29
O Lúpus Eritematoso Sistêmico (LES) é uma doença inflamatória crônica pertencente ao grupo das doenças reumáticas autoimunes sistêmicas, caracterizando- se por apresentar as mais variadas manifestações clínicas e laboratoriais. Seu mecanismo exato de etiopatogenia ainda permanece obscuro. Observações prévias avaliando o papel das células TREG CD4+ CD25+ nas doenças autoimunes, em que se tem detectado tanto alterações de freqüência como alterações funcionas e fenotípicas em modelos murinos e humanos, sugerem o papel significante dessa população celular na etiopatogenia da autoimunidade. No LES podemos observar a existência de uma complexa rede de interações que caracterizam a doença, em que muitos alvos para intervenção terapêutica podem ser considerados. Atualmente tem-se voltado bastante a atenção para o estudo das células TREG CD4+CD25+, a fim de que possam ser usadas como alvos potenciais para terapia imunomoduladora. Os dados sobre a freqüência e fenótipo das células TREG publicados ate o momento são controversos devido à heterogeneidade de marcadores fenotípicos e estratégias de análises utilizadas. Um alto nível de células efetoras ativadas contaminam as amostras de células selecionadas de acordo com as estratégias clássicas de identificação de células TREG no LES e este fenômeno é ainda mais acentuado quanto maior o grau de atividade da doença. Assim, o presente projeto pretendeu inicialmente validar uma estratégia de análise capaz de identificar e quantificar células TREG utilizando a combinação dos marcadores CD25 e CD127 associados à expressão de Foxp3 em pacientes com LES em atividade ou fora de atividade. Concluiu-se pelo painel CD4+CD25+/highCD127Æ/low como melhor marcador de células TREG em virtude de sua alta associação com Foxp3 tanto em sadios como em pacientes com LES. Num segundo momento avaliamos a freqüência de células TREG e células Tconvonde observamos níveis normais de células TREG e níveis elevados de células Tconv ativadas em pacientes com doença em atividade. Foi nosso objetivo, também, avaliar a expressão de marcadores fenotípicos importantes para biologia das células TREG. Foi avaliada a expressão dos marcadores: CTLA-4, GITR, PD-1, OX40, HLA-DR, CD95, CD45Ra, CD28, CD40L nas células CD4+CD25+/hiCD127Æ/low, em pacientes com LES em fase ativa e inativa. Avaliamos também a relação entre o balanço de células TREG versus células Tconv expressando estes marcadores mediante o calculo da razão de equilíbrio fenotípico TREG/Tconv. Em pacientes com doença ativa observamos níveis diminuídos de células TREG positivas para as moléculas CTLA-4 e CD28 e níveis elevados de células TREG CD40L+. Quando avaliada a razão TREG/Tconv observamos uma alteração no balanço TREG/Tconv positivas para GITR, HLA-DR, OX40, CD40L e CD45RO. Houve queda na razão TREG/Tconv para os marcadores GITR, HLADR, OX40 e CD45RO e ganho para o marcador CD40L em pacientes com LES quando comparado a controles sadios. Além da caracterização fenotípica ampla, o presente estudo tem um ponto original extra, que consiste na definição da população de células TREG a partir do fenótipo CD4+CD127lowCD25+, que tem se mostrado mais específico que o tradicional fenótipo CD4+CD25high altamente contaminado por células Teff. Estas informações, no futuro, poderiam levar a pistas importantes na busca de alternativas mais eficazes de imunoterapia, capazes de restabelecer os mecanismos normais de tolerância imunológica, evitando ou minimizando assim os danos causados pela resposta autoimune.
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that is part of the group of rheumatic autoimmune inflammatory diseases, being characterized by heterogeneous clinical and laboratory manifestations. The exact etiopathogenic mechanism underlying SLE still remains obscure. Previousr observations evaluating CD4+ CD25+ TREG cell function in auto-immune diseases detected alterations on frequency and on phenotypic and functional features in murine and human models that support the significant activity of this cell population on autoimmune pathophysiology. In SLE we can observe the existence of a complex interaction network that characterizes the disease, in which many targets for therapeutic intervention may be considered. The present study has focused on TREG cells, since they may represent putative targets for immunomodulatory therapy in this disease. Published data on frequency and phenotype of TREG cells is controversial due to heterogeneity of phenotypic markers and analytic strategies used. The present project aimed to validate an appropriate strategy to identify and quantify TREG in SLE. The CD4+CD25highCD127 low/- panel was validated as an appropriate strategy for identification of Foxp3+ TREG cells in healthy and in SLE patients. The frequency of TREG cells presented normal frequency in active and inactive SLE. In contrast, the frequency of conventional non-regulatory T cells was increased in patients with active disease. We also evaluated the expression of important phenotypic markers for TREG cells biology, including CTLA-4, GITR, PD-1, OX40, HLA-DR, CD95, CD45RO, CD28 and CD40L in patients with active and inactive disease. In addition we evaluated the relationship between the balance of TREG cells versus conventional non-regulatory T cells expressing these markers by means of deriving the TREG/Tconv rate for each surface marker. In patients with active disease we observe reduced levels of TREG cells expressing CTLA-4 and CD28 molecules, and elevated levels of CD40L+ TREG cells. There was an imbalance in TREG/Tconv for GITR, HLA-DR, OX40, CD40L and CD45RO: samples from active SLE patients depicted a decreased TREG/Tconv ratio for GITR, HLA-DR, OX40 and CD45RO and an increased ratto for CD40L when compared with healthy controls. The knowledge on the role of TREG cells in SLE may bring important contribution in devising therapeutic alternatives for this disease.
TEDE
BV UNIFESP: Teses e dissertações

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Itani, Farah R. "Infection with neuroantigen-encoding Listeria: induction of CD8 T cell responses and suppression of demyelinating disease." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5780.

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Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) with characteristic multifocal lesions or ‘ plaques’ of demyelination mainly in the white matter of the brain ( involving cerebral cortex, cerebellar, brain stem and spinal cord). These MS plaques vary in size and shape, and are composed of infiltrates of lymphocytes and macrophages - which contain myelin debris. CD8 T cells are more prevalent in CNS lesions and display oligoclonal expansion. However, their role in disease remains unclear with studies showing both protective and pathogenic roles for myelin-specific CD8 T cells in the experimental autoimmune encephalomyelitis (EAE) model. Our studies have demonstrated a disease-suppressive function for CNS-specific CD8 T cells in a model where the antigen is exogenously administered in vivo and used for in vitro CD8 activation. My studies focus on probing the nature of the CD8 response elicited by endogenously presented myelin antigens in vivo utilizing a novel approach, infection with Listeria monocytogenes (LM) encoding for myelin proteolipid protein peptide PLP178-191 (LM-PLP). I show that LM-PLP infection preferentially induces PLP-specific CD8, but not CD4, T cell responses. Despite this, infection does not result in autoimmunity. In fact, routinely induced EAE is significantly ameliorated in LM-PLP-infected mice, compared to controls. Disease suppression is dependent on the presence of CD8 T cells, and the effector molecules IFN-g and perforin. CNS T cell infiltration and inflammatory responses are reduced in LM-PLP-protected mice, and CD4 T cells from LM-PLP-protected mice are less inflammatory than those from controls. Importantly, infection with LM-PLP ameliorates already established disease. My studies indicate that myelin-specific CD8 T cells induced by endogenous presentation of antigen attenuate CNS autoimmunity in multiple mouse models of EAE, implicating the potential of this approach as a novel immunotherapeutic strategy.

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Jakobsson, Charlotta. "Suppressive DNA vaccination in Experimental Autoimmune Encephalomyelitis and how it affects gene expression of inflammatory mediators." Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8018.

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Vaccination with DNA encoding the encephalitogenic autoantigen myelin oligodendrocyte glycoprotein (MOG), pMOG91-108, induce a protective immunity against experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. By injection of a DNA vaccine that contains a DNA region encoding short interfering RNA specific for IFNβ (pMOG-IFNβ) the protective effect of the DNA vaccination is totally inhibited. This demonstrates that IFN-β is directly involved in the protective mechanism against EAE.

The objective of this project was to study how molecules involved in the inflammatory process in EAE are regulated by suppressive DNA vaccination. mRNA expression of IL-1β, TGF β, IL-23p40 and Axl receptor tyrosine kinas did not show any significant differences between the groups vaccinated with these DNA vaccines. IL-6 and IFNγ mRNA expression after MOG stimulation in rats treated with pCI, a control vaccine was significantly higher compared to the group vaccinated with vaccine containing pMOG-IFNβ. IL-17 m RNA expression after MOG stimulation in pCl-treated rats was significantly higher compared to the group vaccinated with vaccine containing pMOG-91-108. Of these results the mRNA expression of IL-17 and IL-6 were of interest for the project.

The immune system normally protects the body against infections and T-cells have an important role in this defence system. In MS and EAE, the immune system attacks the myelin and this process is caused by a dysregulation of the T-cells. IL-17-producing Th17 cells mediate EAE. Naïve CD4 T-cells in the presence of IL-6 and TGFβ are differentiated to Th17 cells instead of differentiating into T-helper or regulatory T-cells. These IL-17-producing T-cells are highly pathogenic and essential for the development of EAE. The results showed that pMOG IFNβ vaccine had an effect at the immune response, which resulted in an inhibition of the IL-6 production and that vaccination with pMOG91-108 impairs differentiation of IL-17-producing T-cells.

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Dissertations / Theses on the topic 'Immunometabolism, T cells, autoimmunity'

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