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Blish, Catherine Anne. "Modulation of T cell function and T cell receptor repertoire during the induction of peripheral tolerance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/8323.
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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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Tunbridge, Helen. "Defining spatiotemporal patterns regulating T cell function in peripheral tolerance induction." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.691166.
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In the Tg4 murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, disease burden can be reduced by repeated doses of self-peptide, resulting in the conversion of pathogenic T H1 cells into tolerant IL-10-secreting regulatory cells. This work sought to identify whether there are any differences in the spatiotemporal organisation of signalling intermediates in these two cell types using live cell imaging of T cells transduced with GFP-tagged signalling intermediates. Pattern classification of distributions found at the T:B cell interface was used to identify any altered localisation. The distribution of all sensors tested have already been established in a model of foreign antigen (5C.C7 transgenic mouse) and the function of these interface structures inferred from the roles of proteins that congregate there. Thus we can relate structure to function and better understand the effects of altered localisation of proteins in tolerance.
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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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Divekar, Rohit Dilip Zaghouani Habib. "Two aspects of peripheral immune tolerance systemic and mucosal tolerance mechanisms /." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6868.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on April 1, 2010). Vita. Thesis advisor: Habib Zaghouani. "May 2008" Includes bibliographical references.
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Yuschenkoff, Victoria Nicole. "Tolerance Induction to a Foreign Protein Antigen: Analysing the Role of B Cells in Establishing Peripheral Tolerance." eScholarship@UMMS, 1995. http://escholarship.umassmed.edu/gsbs_diss/298.
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Tolerance to self proteins is largely dependent upon the deletion of immature, self-specific T and B cells in the thymus and bone marrow. Although highly efficient, the elimination of these self-reactive lymphocytes is dependent on the expression of their target antigen in these primary lymphoid organs. Many proteins, however, such as hormones, are developmentally regulated and expressed at different stages of life, while other proteins are expressed outside the thymus and marrow. To ensure self-tolerance, other mechanisms must exist to inactivate or prevent the activation of mature, potentially self-reactive lymphocytes and maintain peripheral tolerance.
T cell activation requires direct recognition of a specific protein fragment, presented on the surface of an antigen presenting cell (APC), as well as the interaction between various T cell and APC surface molecules. In the absence of the costimulatory signals provided by these ligand-pair interactions and lymphokines, antigen recognition leads to T cell inactivation and tolerance to the protein. Since many autoimmune disorders appear to be based upon the aberrant activation of mature T lymphocytes, it is important to identify and understand the mechanisms of peripheral tolerance.
The obvious importance of the APC in initiating the T cell immune response has led our lab to examine one of the many antigen-processing cells, the B lymphocyte. Our studies have shown that B cells are highly efficient APC and can present antigen at very low doses to cultured T cell lines. In addition, we have found that we can induce tolerance, as measured by a reduced antibody response to an immunogenic form of the protein, in naive, normal mice by targeting a foreign protein to their B cells for antigen processing and presentation. Tolerance in the treated mice can be traced to a lesion in the T cell compartment of the animals, thus suggesting that B cells can act as tolerizing APC for peripherally expressed antigens. To further explore this idea and find more direct evidence for the role of B cells in establishing peripheral tolerance, we developed a model system that would more closely resemble in vivo conditions.
This thesis tests and provides additional evidence for the hypothesis that B cells are tolerizing antigen presenting cells for peripherally expressed protein antigens. Tolerance to the foreign protein human μ chain, is induced in normal recipient mice by the transfusion of splenocytes from transgenic mice that express the membrane-bound form of μ on their B cells. Tolerance is antigen-specific since the transfused recipients' antibody production to the irrelevant protein chicken IgG is not compromised. Only viable transgenic spleen cells are tolerogenic and even when human μ chain is accessible to other APCs for presentation, tolerance can be induced by the transfusion of live μ transgenic splenoctyes. These data suggested that the transfused μ chain-expressing B cells are the tolerizing APCs which was confirmed by experiments that compared the tolerizing abilities of purified B and T cells from the transgenic mice. Adoptive transfer experiments showed that the recipients' T cell response to human μ was impaired but an analysis of the isotypes produced by tolerized mice did not indicate that either helper T cell subset was specifically compromised. Splenocytes from human μ chain-secreting transgenic B cells also induce tolerance to human μ in nontransgenic mice. Although human μ chain-expressing B cells were not detected in transfused mice, the presence of measurable levels of human IgM in the sera of mice transfused with μ chain-secreting spleen cells suggests that the transfused transgenic B cells persist in their new host. In addition, the tolerizing ability of both resting and activated membrane-bound μ chain B cells was compared. Lipopolysaccharide (LPS)-activated transgenic spleen cells do not tolerize, nor do they prime for antibody to human μ, thus suggesting that the induction of costimulatory molecules on the transgenic B cells inhibits tolerance induction. To more specifically address this, human μ chain-expressing mice were bred to transgenic mice that express the costimulatory molecule, B7-1 (CD80), on their B cells. Double transgenic splenocytes, in which the B cells bear both human μ and B7-1, did not induce tolerance to human μ chain, a result that supports the idea that activated B cells are not tolerogenic. Together the data in this thesis show that resting B cells can process and present a foreign endogenous antigen in a tolerogenic manner to the immune system and suggest a role for the B cell in the maintenance of peripheral tolerance.
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Wang, Lei [Verfasser], and Ludger [Akademischer Betreuer] Klein. "Mechanisms of central and peripheral T cell tolerance to an antigen of the central nervous system / Lei Wang ; Betreuer: Ludger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1128074060/34.
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Zheng, Xincheng. "Two-signal requirement for the development of T lymphocytes." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1109258062.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xvi, 156 p.; also includes graphics (some col.) Includes bibliographical references (p. 127-156). Available online via OhioLINK's ETD Center
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Falk, Johannes. "D-Aminosäuren-substituierte Peptidepitope induzierten T-Zell-Toleranz in vivo." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/14968.
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In dieser Arbeit wurde die Induktion spezifischer, immunologischer T-Zelltoleranz als therapeutische Strategie bei Autoimmunerkrankungen im Mausmodell untersucht. Da davon ausgegangen werden muss, dass viele der Autoimmunkrankheiten durch T-Zellen vermittelt sind, ist die Induktion spezifischer T-Zelltoleranz eine besonders interessante Therapiestrategie. Spezifische T-Zelltoleranz kann mittels Injektion des entsprechenden Peptidantigens induziert werden. Insgesamt sind zur Induktion einer solchen Toleranz, zumindest beim Menschen, relativ hohe Dosen an Peptidantigen notwendig. Die Produktion dieser Peptidantigene ist teuer. Bei unvorsichtiger Gabe kann es zur Anaphylaxie kommen. Es sollte also von Vorteil sein, die zu applizierende Menge an Peptid möglichst gering, dabei aber effizient zu halten. Vermutlich werden Antigene in Form von Peptiden schnell von unspezifischen Peptidasen und Proteasen in nicht-immunogene Fragmente gespalten und ausgeschieden, was wiederum eine hohe Dosierung erforderlich macht. Im Anfang der vorliegenden Arbeit stand die Hypothese, dass eine Stabilisierung des zu applizierenden Antigens zum Schutz vor Fragmentierung (und damit Wirkungsverlust) eine geeignete Methode sein könnte, Toleranzinduktion effektiver bzw. kostengünstiger zu gestalten. Bezüglich einer Stabilisierung von Peptiden zeigte sich, dass Peptide, welche aus rechtsdrehenden (D-)Aminosäuren zusammengesetzt sind, nur verzögert durch Proteasen/Peptidasen abgebaut werden. Wir setzten deshalb in dieser Arbeit D-Aninosäuren-substituierte Peptid-Varianten des Ovalbumin323-339-Peptidepitops (OVA323-339) ein und betrachteten die Wirkung dieser Peptide in vitro sowie in vivo auf spezifische DO11.10 T-Zellen. Basierend auf dem Peptidantigen OVA323-339, wurde zunächst ein minimales Epitop definiert, welches bei etwa gleicher Potenz um 6 Aminosäuren verkürzt werden konnte. Anschließend wurde eine Substitutionsanalyse durchgeführt, in der die ursprüngliche Aminosäuresequenz durch Austausch einiger L-Aminosäuren mittels D-Aminosäuren verändert wurde. Diese neu synthetisierten Peptide wurden zunächst auf ihre Fähigkeit überprüft, die OVA323-339 spezifischen DO11.10 T-Zellen in vitro zu aktivieren. Parallel konnte gezeigt werden, dass diese synthetisierten Peptidepitope in vitro eine deutlich verlängerte Serumhalbwertszeit aufwiesen. Im Weiteren wurde versucht, durch systemische Injektion von 300µg D-Peptid-Varianten in BABLB/c Mäusen T-Zelltoleranz zu induzieren. Die ex vivo restimulierten Lymphknoten-Zellen dieser Mäuse präsentierten je nach appliziertem Peptid eine reduzierte Proliferationsbereitschaft und IL-2 Sekretion. Die hier induzierte Toleranz konnte bis zu 60 Tagen post injectionem sowohl für das OVA323-339 als auch für einige der eingesetzten D-Peptide nachgewiesen werden. Auch nach Reduktion der Peptiddosis auf nur 100µg/Maus, waren die verkürzten und D-Aminosäuren-substituierten Peptide immer noch in der Lage sicher Toleranz zu induzieren. Die induzierte Toleranz durch D-Peptide war dabei der durch das Ausgangspeptid OVA323-339 induzierten Toleranz vergleichbar stark. Mit der Hilfe eines Transfermodells in unmanipulierte Mäuse, wurde das Verhalten der spezifischen T-Zellpopulation in vivo beobachtet. Durch den Transfer konnten in den Empfängermäusen (Balb/c) definierte T-Zellpopulationen bekannter Größe erzeugt werden. Mit dem Antikörper KJ1-26.1, der spezifisch den DO11.10-T-Zellrezeptor erkennt, konnten die transferierten Zellen in Geweben der Empfängermaus per FACS-Analyse nachgewiesen und deren Verhalten ex vivo studiert werden. Die intravenöse Injektion der serumstabilisierten Peptidanaloge führte in den transferierten Mäusen je nach Peptid zu einer funktionellen Nichtreaktivität (Anergie) als auch zur Deletion der für das Ausgangs(L-)Peptid spezifischen DO11.10 T-Zellen. In den oben genannten Versuchen ergaben sich Hinweise dafür, dass die D-Peptide ebenso effektiv sind wie das wesentlich längere Ausgangspeptid OVA323-339. Zukünftige Experimente werden weitere Aufschlüsse über einen möglichen Vorteil des Einsatzes von D-Peptiden in der Toleranzinduktion erbringen.Induction of antigen-specific peripheral T cell tolerance in autoimmune diseases is an interesting therapeutically strategy. It can be induced by systemic injection of high-dose antigen. Investigations in induction of peripheral T cell tolerance in autoimmune mouse models revealed promising results. But it was also shown that the induced T cell tolerance spontaneously reverses after a period of time. This is probably due to a short in vivo half-life of the administrated peptide antigens. Since durable tolerance is required for this strategy to be of therapeutic value the administrated antigen-dose has to be of a very high and has to be injected repeatedly, and therefore bears an increased risk of anaphylactic reactions or exacerbation of the autoimmune disease. Because of these restrictions and also the high costs of peptide-production and purification, it is not surprising that this therapy didn t really find its way in to the clinical practice. The discovery that Peptides assembled partly or totally from D-amino acids are much more stable to proteolysis then natural L-peptides and therefore show an increased stability, lead to a wide interest of pharmacologists and immunologists. In former investigations it was shown that D-peptides used as vaccines elicited high levels of neutralizing antibodies so that there is no doubt about their immunogenic potency in vivo. It is also known that a single T cell receptor recognizes a wide range of peptide analogues that closely mimic the natural antigen. These observations led to our hypothesis, that the induction of peripheral T cell tolerance by systemic administration of D-Peptide substituted antigen variants should be possible and could be much more effective than the induction by the wild-type L-peptide. To verify our hypothesis we have chosen the well known OVA323-339 antigen which is recognized by T cells through the presentation in the I-Ad context. In a first step we performed a truncation analysis of OVA323-339 to identify a minimal epitope in it. We were able to demonstrate that the sequence OVA327-337 is as well potent as the original and 6 amino acids longer OVA323-339 sequence. The potency of new defined epitopes was tested by stimulating the OVA323-339 -specific DO11.10 T cells in vitro. In a stepwise performed substitution analysis we attempted to insert some D-amino acids in this novel peptide epitope. The DO11.10 cells only tolerated a few D-amino acid substitutions into the original sequence with the effect of now showing reduced proliferation. Performing an analysis of their half-life in vitro we identified two peptides as interesting candidates for the in vivo tolerance induction experiments. In the in vivo part of this work we induced peripheral tolerance by injecting the novel peptides into BALB/c mice. To monitor the behaviour of the tolerated T cells we also performed adoptive transfer experiments by transferring DO11.10 cells into naive BALB/c mice. With the help of the KJ26-1 antibody which specifically recognizes the DO11.10 T cell receptor it became possible to detect the transferred T cells ex vivo. Our results demonstrate that induction of peripheral T cell tolerance through injection of D-peptides is possible and long lasting (up to 60 days). Even with a dose reduction we found a stable T cell tolerance under ex vivo restimulation with the original peptide. Summarizing we were able to show that D-peptides are at least as effective as the natural occurring L-peptides inducing tolerance. Much more, the transfer experiments revealed that the kind of induced T cell tolerance (i.e. anergy and/or deletion through activation induced cell death) is antigen dependent and probably differs due to the agonistic potency of the given antigen.
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Chen, S. K. "Induction and maintenance of tolerance generated by temporary blockade of CD4 and CD8 on peripheral T cells in murine allo- and xenografts." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597534.
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Herein, I demonstrate that immunological tolerance can be induced in major histocompatibility complex (MHC) mismatched allogeneic heart and skin graft recipients and in concordant xenogeneic heart and skin graft recipients. Tolerance induction was achieved via temporary blockade of CD4 and CD8 co-signalling pathways mediated by non-depleting monoclonal antibodies. Basically, tolerance was demonstrated with four experimental models: 1) mouse heart allograft; 2) mouse skin allograft; 3) rat-to-mouse heart xenograft; and 4) rat-to-mouse skin xenograft. The tolerance induced to heart allograft was further investigated and was found to be specific, stable and transferable. The induced donor specific suppressive regulatory cells were CD4+: these could drive naive alloreactive cells to become new tolerant cells. Thus the population of tolerant cells can be numerically amplified via serial adoptive transfers. Tolerance may spread to linked antigens co-expressed with the original tolerogen. Tolerance, once established, was self perpetuating. To induce peripheral T cell tolerance, direct control of the pathway of T cell activation itself is more effective than control of the pathway of antigen presentation from antigen presentation from antigen presenting cells (APCs). Inhibition of direct antigen presentation via class II MHC had no effect on prolongation of allograft survival. Inhibition of indirect antigen presentation via class II MHC prolonged allograft survival, but did not lead to tolerance. AT cell may be activated to be aggressive, or suppressive, presumably depending upon their signal transduction at the time of antigen stimulation. Evidence provided here showed that the mature immune system can be reprogrammed to accept non-self organ graft as "self". Importantly the induced tolerance was an actively operational state. This is a demonstration that in principle, natural immune regulatory mechanisms may be exploited to induce permanent tolerance and may be developed for clinical use to avoid the need for prolonged immunosuppressive drug therapy.
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Ferreira, Cristina da Conceição Varandas. "Naive T cell survival : analysis of transgenic monoclonal T cell populations." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250701.
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Sutherland, Andrew Peter Robert St Vincents Clinical School UNSW. "BAFF regulation of peripheral T cell responses." Awarded by:University of New South Wales. St Vincents Clinical School, 2005. http://handle.unsw.edu.au/1959.4/22788.
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The activation and effector function of CD4+ T cells are critical points of regulation during an antigen specific T cell response. Dysregulation of these processes can lead to the development of human diseases, encompassing both immunodeficiency and autoimmunity. Members of the TNF superfamily have recently emerged as important regulators of T cell responses, with their overexpression causing autoimmune inflammation in animal models. As overproduction of the novel TNF superfamily ligand BAFF is associated with several autoimmune conditions, we sought to examine the potential role of BAFF as a regulator of T cell activation and effector function. We initially demonstrated BAFF costimulation of T cell activation in vitro. Generation of specific monoclonal antibodies identified BAFF-R as the only BAFF receptor present on T cells, and showed that it was expressed in an activation-dependent and subset-specific manner. Impaired BAFF costimulation in BAFF-R deficient mice indicated that BAFF-R was crucial for mediating BAFF effects in T cells. Analysis of T cell responses in vivo revealed that BAFF transgenic mice have increased T cell priming and recall responses to protein antigens, and showed a corresponding increase in the DTH model of Th1 cell-dependent inflammation. In addition, Th2-dependent allergic airway responses are suppressed in BAFF transgenic mice. Crossing to a B cell deficient background revealed that the proinflammatory effects of BAFF on T cell priming and DTH rely on the presence of B cells, while the suppressive effects during allergic airway inflammation are B cell independent. These data demonstrated that BAFF regulated the outcome of T cell responses in vivo and identified BAFF dependent crosstalk between T and B cells. Stimulation of B cells with BAFF induced the upregulation of MHC class II and ICOS-L both in vitro and in vivo. Induction of these cell surface molecules was associated with an increased capacity to induce T cell proliferation, however this effect was independent of ICOS-L expression. Thus it was demonstrated that BAFF regulated T cell activation and effector function both directly, via stimulation of BAFF-R, and indirectly, by altering the function of B cells. These data suggest that BAFF dependent alterations in T cell function may be an additional causative factor in the association between elevated BAFF levels and the generation of autoimmunity.
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Eriksson, Sabina. "Studies of peripheral tolerance in AIRE deficient mice." Thesis, Linköpings universitet, Molekylär genetik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-69269.
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Autoimmune Polyendocrine Syndrome Type 1(APS I) is a monogenic autosomal recessive autoimmune disorder which is the result of mutations in the autoimmune regulator (AIRE) gene. Symptoms of the disease include circulation of multiple organ specific autoantibodies, which leads to the breakdown of several tissues, including the adrenal cortex and the parathyroid glands. The patients also develop a number of non-endocrine disorders. This study has investigated the peripheral tolerance mechanisms controlled by the AIRE gene in Aire deficient mice, an animal model of the disease. The B cell Activating Factor (BAFF), which is a cytokine involved in B cell survival and growth, is elevated in Aire-/- mice, resulting in an increased release of autoantibodies and B cell proliferation. Therefore the BAFF level differences between TCR-/- and B6 mice was studied, and the results showed significantly higher levels of BAFF in TCR-/- mice. This is not in accordance with earlier studies. ICOS and ICOSL are involved in the activation of follicular T helper cells. The expression of ICOSL on different subpopulations of DC from mice was studied to evaluate the possible influence of AIRE expression on the T cells in the spleen. The results showed that ICOSL is significantly higher expressed in peripheral 33D1+ DCs in Aire-/- mice, showing that AIRE has a role in the over-activation of the follicular T helper cells, which can lead to autoantibody production and inflammation. These results show that AIRE is involved in peripheral tolerance.
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Lute, Kenneth D. "Costimulation and tolerance in T cell immunotherapy." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141850521.
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Thalhamer, Theresa. "B cell signalling in mechanisms of central and peripheral tolerance." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1375/.
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Moreover, significant differences were found in the ratio of FcγRIIb1/FcγRIIb2 expression between the cohorts of healthy controls and RA and SLE patients. The RA and SLE patients expressed relatively higher levels of the FcγRIIb2 isoform which promotes antigen-processing suggesting that these B cells may play some role in priming autoreactive responses in such individuals. Thus, as these inflammatory disorders constitute spectrum diseases, such defects in the regulation of B cell responses could be one of the contributing factors aggravating autoimmune disease development in some subgroups of patients.
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Wong, Ryan. "Breaking T-cell tolerance in chronic lymphocytic leukaemia." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/45673/.
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CLL is an incurable B-cell malignancy associated with profound tumour cell-mediated immune dysfunction. It therefore represents a challenging disease for the successful application of immunotherapeutic strategies aimed at promoting anti-tumour T-cell responses. In this study, extensive immunophenotypic analysis of T-cells from the blood of CLL patients was performed, in order to better characterise their dysfunctional status within the disease. Analysis of CLL patient blood samples revealed a skewing of T-cells towards a highly differentiated effector memory phenotype as well as the expression of markers associated with exhaustion/senescence (CD28- and CD57+) and immunosuppressive molecules (PD-1 and CD200). In addition this study revealed the expansion of CD8+ T-cells in a subset of CLL patients leading to an inversion in the normal CD4:CD8 ratio. The presence of an inverted CD4:CD8 ratio was subsequently shown to be associated with a shorter time to first treatment and reduced progression-free survival. Characterisation of T-cells identified several molecules that could be targeted therapeutically in order to break T-cell tolerance in CLL patients and potentially restore normal immune responses. Investigation of the immunosuppressive molecules PD-1 and CD200 showed that they are over expressed in CLL patients, suggesting that they may be involved in maintaining T-cell tolerance in the disease. However, blockade of PD-1-PDL-1 and CD200-CD200R signalling pathways failed to enhance T-cell responses from CLL patients in vitro. Investigation of an alternative approach to enhance T-cell responses in CLL involved the use of a bi-specific antibody targeting CD19 and CD3 called blinatumomab. In vitro testing showed that blinatumomab can induce T-cell activation, promoting the release of pro-inflammatory cytokines and granzyme B secretion from both CD4+ and CD8+ T-cells. In addition, blinatumomab was shown to mediate T-cell dependent killing of CLL cells requiring the formation of T-cell:CLL cell conjugates. Finally this study provided clear evidence that blinatumomab can break T-cell tolerance in CLL and strongly advocates the progression of blinatumomab into clinical trials as a novel therapeutic agent in CLL.
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Qureshi, I. F. "The role of Lck in peripheral T cell responses." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1446049/.
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The signalling mechanisms that control differentiation of naive T cells to effector and memory cells are unclear. A key event in T cell activation by antigen is the phosphorylation of tyrosine based activation motifs in the TCR CD3 complex by the Src-family kinases, Lck and Fyn. Elucidating the exact signalling mechanisms involved in the generation of memory T cells and effector function is fundamental and has important implications particularly in therapeutics, such as in developing treatments for diseases and infection. Lck knockout mice have no T cells, and so we were unable to study the role of Lck in the peripheral T cell compartment. Using mice that express an inducible Lck transgene in T cells, which were bred to the class I MHC restricted F5 TCR transgenic line, we have investigated the role of Lck-mediated TCR signaling in antigen-specific CD8 T cell responses. Stimulation of lymphocytes in vitro showed that the response of F5 T cells to peptide is 10-100 fold less sensitive in the absence of Lck, suggesting that the threshold of triggering is raised, however once cells were activated they underwent a similar program of division. Using an in vivo model where F5 T cells are transferred with flu virus into Rag1"A recipients, we demonstrated that Lck is required for the activation and subsequent generation of functional effector F5 CD8 T cells. The ability to generate functional Cytotoxic T lymphocytes (CTL) was impaired, shown by the reduced killing of target cells in vitro and in vivo. We have also shown defects in the production of IL-2, TNFct and Granzyme B, which appear to be Lck dependent. However there is a less stringent requirement for Lck in the production of IFNy, showing varying levels of Lck requirement for eliciting effector function. In summary we have shown that Lck contributes to multiple stages of memory cell formation. It is required for the priming, expansion and differentiation of F5 CD8 memory T cells, but is not required for their survival.
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Hochweller, Kristin. "The roles of CD40 and OX40 during the induction of T cell tolerance versus T cell immunity." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/14081.
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Tolerance induction is thought to be the result of peptide presentation by resting DC, which are lacking full costimulatory potential. The precise signals that drive a T cell towards tolerance, rather than a productive immune response, are not well defined. This project has addressed this issue by asking three questions: A. Can exogenous ligation of defined costimulatory receptors convert a tolerogenic signal into an immunogenic one? B. How does expression of the costimulatory pairs CD40-CD154, OX40L-OX40, and RANK-RANKL on DC or T cells respectively differ during induction of T cell tolerance versus immunity? C. Can we mimic tolerance induction by giving antigen-loaded DC lacking CD40? It was found that agonistic antibodies to CD40 and OX40 converted a tolerance signal to an immunogenic one, preventing the induction of tolerance. CD154, OX40 and RANKL are expressed on T cells under conditions leading to either tolerance or immunity. Up-regulation/induction of CD40, OX40L and RANK on DC, however, was only observed during the induction of T cell immunity. The administration of antigen-loaded CD40-deficient DC mimicked tolerance induced by soluble peptide. Collectively, the results suggest that the CD40-CD154 interaction provides an important checkpoint in the decision between T cell tolerance and immunity. Investigating the process of tolerance induction may provide a rational basis for therapeutic targeting of costimulatory pairs in adverse immune reactions in humans.
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Zeidan, Joumana. "Novel findings on the impact of HIV infection: Interplay between T cell development and peripheral T cell homeostasis." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104565.
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A hallmark of HIV infection is the gradual decline in CD4 T cells leading to AIDS and failure of the immune system. Depletion of CD4 T cells has been attributed to direct viral cytopathogenicity and hyperimmune activation which all lead to accelerated apoptosis. More recently, impaired thymic function has been shown to contribute to the numerical decline of CD4 T cells. The thymus is the primary source of de novo T cells that bear a broadly diverse T cell receptor (TCR) repertoire. In adults, the thymus produces every day approximately 50 million new T cells termed recent thymic emigrants (RTEs). Following their exit from the thymus, RTEs join the naive T cell compartment and upon antigen encounter differentiate into effector and memory T cells.Abstract
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Stockner, Kaija. "Influence of Lck abundance on thymic selection, peripheral T cell activation and the formation of T cell memory." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9702.
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Selection of the T cell repertoire in the thymus is governed by the need to create a repertoire of peripheral T cells that can respond to any foreign antigen in the context of self-major histocompatibility complex (MHC), while enforcing central tolerance to self-antigens. Perturbations in signalling molecules, that reduce the affinity of thymic selection, can lead to the production of a peripheral repertoire with increased autoimmunity, as has been shown for mutations in the Zap-70 kinase. Upstream of Zap-70 is Lck, the most proximal tyrosine kinase required for T cell receptor (TCR) triggering upon TCR engagement by peptide:MHC. In order to study how Lck influences T cell activation, a transgenic mouse model (LckVA), in which Lck is expressed constitutively from a T cell specific transgene and mice have very low expression of Lck (~5% of WT) in both the thymus and periphery, was used. It has been shown that Lck is critical for successful T cell development, yet the results of this thesis show that even 5% of WT levels of Lck are sufficient for selection of thymic T cells on both polyclonal and F5 TCR transgenic backgrounds. Previous studies utilising mice expressing an inducible Lck transgene, which also had reduced Lck expression in the periphery, showed Lck to be critical in determining the activation threshold of T cells. In contrast, peripheral T cells in LckVA mice had similar activation thresholds to wild type T cells, as measured by in vitro upregulation of early activation markers. Further analysis of LckVA peripheral T cells revealed differential influences of low expression of Lck on downstream signalling pathways upon TCR engagement. For example, ERK signalling was impaired, while calcium flux and proliferation were enhanced in LckVA T cells. Finally, LckVA T cells were altered in their ability to differentiate, showing enhanced production of cytokines and retaining the capacity to form memory cells.
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Sharif-Paghaleh, Ehsan. "In vivo imaging of regulatory T cell mediated transplant tolerance." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/in-vivo-imaging-of-regulatory-t-cell-mediated-transplant-tolerance(4ee28e3c-431f-430f-9484-d22f030787b1).html.
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Regulatory T cells (Tregs) were identified several years ago and are key in controlling autoimmune diseases and limiting immune responses to foreign antigens. These cells have been used successfully in animal models first and more recently in the clinic to prevent Graft vs Host disease and transplant rejections. However, their locations in vivo, their migratory abilities and their in vivo survival have not been extensively investigated. Imaging of the human sodium/iodide symporter via Single Photon Emission Computed Tomography (SPECT) has been used as a reporter gene to image various cell types in vivo. It has several advantages over other imaging techniques including high sensitivity, it allows non-invasive whole body studies of viable cell migration and localisation over time and lastly it may offer the possibility to be translated to the clinic. The study presented in this thesis addresses whether SPECT/CT imaging can be used to visualise the migratory pattern and survival of Tregs in vivo. At first, CD4+ T cells were directly radiolabelled and were subsequently imaged in vivo to demonstrate that T cells can be imaged using NanoSPECT/CT. Then Treg lines derived from CD4+CD25+FoxP3+ cells \ were/ retrovirally transduced with a construct encoding for the human Sodium Iodide Symporter (NIS) and the fluorescent protein mCherry. NIS expressing self-specific Tregs were specifically radiolabelled in vitro with Technetium-99m pertechnetate (9 mTcC)4~) and exposure of these cells to radioactivity was shown not to affect cell viability, phenotype and Treg function. In addition adoptively transferred Treg-NIS cells were imaged in vivo in C57BL/6 (BL/6) mice by SPECT/CT using 99mTcO4". After 24 hours NIS expressing Tregs were observed in the spleen and their localisation was further confirmed by organ biodistribution studies and flow cytometry analysis. Later, Treg lines with direct or indirect alloantigen specificity were imaged in skin transplant models using the same technique. It was observed that adoptively transferred Tregs migrate to the site of transplant at earlytime points and then migrated to various lymph nodes. The data presented here suggests that SPECT/CT imaging can be utilised in preclinical imaging studies of adoptively transferred Tregs without affecting Treg function and viability thereby allowing longitudinal studies within disease models. Moreover, new insight into pattern of migration of Tregs was identified.
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Ferreira, Monteiro Marta. "Characterization of CD8+ T-cell populations of the human peripheral blood." Paris 5, 2006. http://www.theses.fr/2006PA05N22S.
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Après stimulation antigénique, les lymphocytes T CD8+ naïves subissent plusieurs modifications, comme l’expression des molécules de surface. Chez l’homme, l’association du CCR7, CD45RA, CD27 et CD28 est fréquemment utilisée pour discriminer de façon reproductible des sous-populations de cellules T CD8+ fonctionnellement différentes. Néanmoins, la description de cespopulations reste incomplète, puisque plusieurs études ont utilisé des associations différentes et limitées de molécules de surface. En conséquence, certaines sous-populations de cellules T CD8+ n’ont pas encore été établies, en particulier dans les compartiments CCR7–CD45RA+ et CCR7– CD45R0+. .Following antigenic challenge, naïve CD8+ T lymphocytes undergo several changes, including the expression of cell-surface molecules. In humans, the association of CCR7, CD45RA, CD27 and CD28 is widely used to discriminate a reproducible set of functionally different subpopulations of CD8+ T cells. However, the prevailing data concerning the description of these subsets remains fragmentary, since a multitude of studies used a different and limited set of surface markers. Hence, some CD8+ T-cell subsets are still not clearly established, especially within the CCR7–CD45RA+ and CCR7–CD45R0+ compartments, and the correspondent differential roles and lineage relationships remain undisclosed. Following
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Honey, Karen J. "Mechanisms of transplantation tolerance." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301519.
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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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Li, Kun-Po M. S. "The Role of Bim in Determining Thymic and Peripheral T Cell Fate." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491560488232425.
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Burtles, S. S. "An in vitro analysis of T helper cell tolerance in mice." Thesis, University of Bristol, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233577.
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Erhardt, Annette. "Tolerance induction in the liver after T and NKT cell activation." kostenfrei, 2008. http://www.opus.ub.uni-erlangen.de/opus/volltexte/2008/1032/.
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Chung, Chen-Yen. "CD4+ T cell responses to myelin autoantigens : activation, memory and tolerance." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4013.
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Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell mediated autoimmune disease of the central nervous system and shares many characteristics with multiple sclerosis (MS). Induction of EAE is mediated by myelin reactive CD4+ T helper (Th) cells, particularly Th1 and Th17 cells, which can be provoked by the immunization with myelin derived protein (or peptide) and Toll-like receptor (TLR) stimulus (eg, complete Freund¡s adjuvant, CFA). If given an injection of soluble peptide before immunization, mice do not develop EAE (they are tolerant). This approach has been widely applied, evoking tolerance in primary responses (i.e., in naive T cells). Therefore the first hypothesis of this thesis is that peptide induced protection from EAE is a result from T cell deletion or / and anergy. As MS patients have ongoing disease and over 85% of MS patients develop a relapsing-remitting course, memory T cells are key targets when considering peptide-induced tolerance as a therapeutic strategy. Thus, a model for ¡memory EAE¡ was established to test a second hypothesis that the myelin reactive memory T cells can be controlled by the administration of soluble peptide. Here, adoptive transfer of T cells from T cell receptor transgenic mice (2D2) recognizing myelin oligodendrocyte glycoprotein 35-55 (pMOG) was used to investigate the pMOG-reactive memory responses. Soluble pMOG administration could induce a transient expansion of 2D2 T cells followed by their loss through apoptosis. A model using double immunization was established by immunizing mice first with pMOG together with unmethylated CpG oligonucleotide (CpG) as an adjuvant, and subsequently immunizing with pMOG in CFA. This produced EAE with early onset and high incidence compared to mice which received pMOG/CFA only. Cells from mice that received the double immunization protocol produced high levels of IFN-γ, suggesting that memory T cell responses have been triggered in the mice. Administration of soluble peptide before secondary immunization could ameliorate EAE, indicating that memory T cells are susceptible to tolerance induction. pMOG-reactive memory T cells were further assessed by isolating CD4+ CD25- CD44high CD62Llow cells from pMOG-experienced 2D2 mice. These cells showed early and high production of IFN-γ, and early but transient production of IL-2, compared with naive population. These data provide basic information relevant to translating peptide-induced T cell tolerance from mice to humans.
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Barra, Melanie Marianne [Verfasser], and Markus [Akademischer Betreuer] Feuerer. "Transcription factor 7 limits regulatory T cell generation and influences peripheral T cell subsets / Melanie Marianne Barra ; Betreuer: Markus Feuerer." Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1180735056/34.
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Wang, Dapeng. "The mechanism of glucocorticoid induced murine thymocyte and peripheral T cell apoptosis." Doctoral thesis, [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=979813506.
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Kenny, Emma. "Peripheral CD4'+ T cell subsets involved in primary and secondary immune responses." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343045.
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Wheeler, Paul Richard. "Characterisation of T cell anergy in allo-antigen specific CD4⺠cells." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288516.
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Morton, Angela Mary Young. "Investigation of T cell signalling events regulating immunity and tolerance in vivo." Thesis, Connect to e-thesis, 2008. http://theses.gla.ac.uk/59/.
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Thesis (Ph.D.) - University of Glasgow, 2007.Ph.D. thesis submitted to the Division of Immunology, Infection and Inflammation, Faculty of Medicine, University of Glasgow, 2007. Includes bibliographical references.
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Leung, Janson. "CD4 T cell tolerance and autoimmunity towards rare and sequestered self-antigens." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437182.
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Chan, Susan M. H. "Homing characteristics of peanut specific T cell responses in allergy and tolerance." Thesis, King's College London (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.566681.
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Chapman, C. J. "The study of T cell tolerance induction in thymus grafted nude mice." Thesis, University of Newcastle Upon Tyne, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383979.
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Perchellet, Antoine Luc. "Maintenance and disruption of CD8+ T cell tolerance to myelin basic protein /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8360.
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Jaigirdar, Shafqat Ahrar. "Investigating the molecular mechanisms of CD4 T cell persistence at inflamed peripheral tissues." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8952/.
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CD4 T cells play an important role in the initiation and maintenance of inflammation in numerous inflammatory diseases. Rheumatoid arthritis (RA) is one such autoimmune inflammatory condition where inflammation of the joint occurs. CD4 T cells are one of the key cells in RA pathogenesis due to their ability to activate or influence other cells in the joint including B cells, macrophages and osteoclasts, which collectively lead to joint destruction. The recruitment and function of CD4 T cells at inflamed tissues has been studied extensively. However, the signals that regulate CD4 T cell accumulation and persistence at peripheral inflamed sites are poorly understood. In this study, a novel in vivo model of inflammation was designed in the murine ear pinnae to study the signals which regulate CD4 T helper 1 (Th1) cell persistence at inflamed tissues. Congenically marked, in vitro polarised CD4 Th1 cells were adoptively transferred directly into inflamed or non-inflamed ear pinnae and their persistence and survival were studied using flow cytometry. Higher numbers of CD4 Th1 cells were found at the inflamed as compared to the non-inflamed site. Intravital microscopy was used to further study the behaviour of these cells. Th1 cells were found to be more mobile in inflamed compared to non-inflamed ear pinna. To investigate the molecular mechanism of this, either the ear pinnae or the T cells themselves were manipulated. Introducing cognate antigen at the inflamed site did not alter the number of recovered T cells, nor did the T cells proliferate at the site. Next, the survival of persistent CD4 Th1 cells was examined by investigating their expression of active caspases. Lower proportion of Th1 cells recovered from inflamed tissues were found to express active caspases compared to those from a non-inflamed site. Together these data suggest that local T cell activation is not required for persistence but rather, the increase in T cells at inflamed sites may be due to a combination of persistence and survival signals. The sphingolipid sphingosine-1-phosphate (S1P) has been implicated in driving both egress of T cells out of secondary lymphoid organs and their survival. To investigate whether S1P affects Th1 cell persistence and/or survival at inflamed tissues, Th1 cells were treated with S1PR agonists or antagonists, prior to transfer. Fewer Th1 cells were recovered from the inflammatory site of mice injected with antagonist treated cells. Additionally, S1PR agonism was sufficient to induce Th1 cell persistence at non-inflamed tissues. A trend towards increased expression of active caspases was also found in S1PR antagonist treated T cells recovered from inflamed ear pinnae compared to untreated controls. Finally, elevated levels of the S1P metabolising enzyme, SPHK1, was found in human RA joints compared to OA joints. In sum, I propose a novel function for S1P and its receptors in regulating the persistence of activated CD4 Th1 cells at inflamed tissue sites. Moreover, targeting S1P and its receptors at peripheral inflamed tissues could provide a novel target for the development of more effective anti-inflammatory therapeutics.
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Zheng, Ying. "A complementary activation of peripheral NK cell immunity in EBV related nasopharyngeal carcinoma." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B34605162.
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Strainic, Michael George Jr. "THE ABSENCE OF C3AR AND C5AR SIGNAL TRANSDUCTION PROMOTES T REGULATORY CELL DIFFERENTIATION AND REGULATES IMMUNOLOGIC TOLERANCE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1363707372.
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Cowan, Jennifer. "The role of the thymic medulla in T cell development and tolerance induction." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5066/.
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The thymus is organised into functionally distinct microenvironments that facilitates development of a diverse and self-tolerant T cell repertoire. Following positive selection, thymocytes undergo chemotactic migration from the cortex to the medulla, a site that mediates negative selection of potentially autoreactive CD4+ and CD8+ single positive (SP) thymocytes. Importantly, current models suggest that the medulla also fosters the continued maturation of SP thymocytes, post-selection. However, the mechanisms of thymic medulla function remain unclear. Using a novel approach based on chemokine receptor expression, we have mapped stages in the positive selection process, and developed a model to study αβT cell development in the absence of medullary thymic epithelial cells (mTEC), but in the presence of an otherwise intact immune system. We show that mTEC are dispensible for the continued development of newly selected CD4+CD69+ SP thymocytes, yet are essential for the generation of FoxP3+ regulatory T cells and their FoxP3-CD25+ progenitors. In addition, although CCR4 represents a marker of early stage CD4+ SP positive selection, it is dispensable for SP medullary accumulation and intrathymic development. Collectively these findings highlight differences in the developmental requirements of conventional and regulatory CD4+ T cells, and rule out a role for CCR4 in cortex to medulla migration.
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Liebenberg, Lenine Julie. "Phenotypic and functional characterisation of cervical and peripheral HIV-1 specific T cell responses." Master's thesis, University of Cape Town, 2007. http://hdl.handle.net/11427/2712.
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Includes bibliographical references (leaves 92-109).Distinct HIV variants occur at the genital mucosa compared to in blood, which may similarly result in differences in HIV T cell responses. There have been no studies of the maturational status of HIV-specific T cells present at the female genital mucosa. This study aimed to characterise HIV-specific cervical immune responses and to determine if compartmentalized immune responses occur in chronic HIV infection by comparing the characteristics of T cells at the cervical mucosa to those in blood.
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Tan, Lam Chin. "Peripheral blood T cell gene expression profiles in the early post renal transplant period." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/22681.
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Sequential monitoring of peripheral T lymphocyte gene expression was performed in renal transplant recipients in the first 6 weeks following transplantation. The level of gene expression was correlated with clinical events, with emphasis on changes occurring during acute rejection. Forty-three renal transplant patients were monitored. Twenty-eight did not reject while 15 did. The most significant finding was that peripheral T cell IL-4, IL-5 and IL-13 gene expression increased at the time of acute rejection and decreased following successful anti-rejection therapy. While clear differences in the gene expression profiles between non-rejectors and rejectors were seen for IL-5 and IL-13, there were more similarities in the profiles between the two groups for IL-4. The increase in IL-5 and IL-13 expression in the rejectors prior to, and during acute rejection, and the subsequent return of both cytokines to their respective patterns for the non-rejectors, suggest that these 2 cytokines may be important markers of acute rejection. The similar decrease in IL-4 gene expression below its pre-transplant baseline in the first week following transplantation in both non-rejectors and rejectors before returning to the baseline, and a similar reduction in expression below the baseline following anti-rejection therapy before returning again to the pre-transplant levels suggest that IL-4 was more likely a sensitive marker of the changing level of immunosuppression rather than of the changes in alloreactivity. IL-4, IL-5 and IL-13 also had different gene expression profiles in the non-rejectors. Both IL-5 and IL-13 had a flat post-transplant gene expression profile, with IL-5 consistently below its pre-transplant baseline at all post-transplant time points while IL-13 remained at its baseline level throughout, IL-4 on the other hand had a variable profile, being below its baseline during the first week post-transplant before returning to its baseline subsequently. In contrast, IL-10 gene expression profile was totally opposite to that for IL-4, IL-5 and IL-13 in both non-rejectors and rejectors. In the non-rejectors, IL-10 gene expression was consistently above its pre-transplant baseline at all post-transplant time points.
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Pletinckx, Katrien [Verfasser], and Manfred [Akademischer Betreuer] Lutz. "Dendritic cell maturation and instruction of CD4+ T cell tolerance in vitro / Katrien Pletinckx. Betreuer: Manfred Lutz." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/1032131373/34.
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Zheng, Ying, and 鄭盈. "A complementary activation of peripheral NK cell immunity in EBV related nasopharyngeal carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B34605162.
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Berglund, David. "Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-220873.
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Solid organ transplantation has evolved from being an experimental procedure to a life-saving treatment for patients with end-stage organ failure. The risk of losing a transplant due to acute rejection is very low with the use of modern immunosuppressive protocols and the short-term results are impressive. However, long-term outcomes are suboptimal and transplant recipients are at increased risks for severe complications such as cancers, opportunistic infections and cardiovascular events. The previous struggle to achieve short-term survival has turned into a search for new strategies to improve patient and transplant longevity. Regulatory T cells (TRegs), a subset of T cells, occur naturally in the immune system and have the capacity to down regulate immune responses. Under normal conditions they maintain self-tolerance and prevent excessive immune activation. Functional TReg defects lead to a massive autoimmune response and are not compatible with life. Preclinical data support that TRegs can be used as a cell therapy to prevent transplant rejection, with the potential to minimize the need for traditional immunosuppression and improve the long-term outcome. This thesis aims to enhance the translation of TReg cell therapy to clinical organ transplantation. In particular, strategies for isolation and expansion of TRegs from uremic patients awaiting kidney transplantation have been assessed. A non-invasive imaging technique to study T cell products after intravenous administration was developed, for use in future clinical trials. The performance of a novel cell purification technique was investigated to potentially improve the clinical production of TRegs. The thesis demonstrates that TRegs can be isolated and expanded from uremic patients to display potent suppressive properties in vitro. The mode of isolation and expansion affect the functional characteristics, where cells purified with cytometry based techniques and expanded with mature dendritic cells were the most advantageous. T cells can be labeled using the radioactive tracer [111In]oxine with preserved viability and subsequently followed in vivo with SPECT/CT for more than 1 week after intravenous administration. The use of microfluidic switch technology offers a novel way of purifying TRegs at high speed, purity and viability, under conditions compatible with clinical use.
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Seamons, Audrey. "Implications of myelin basic protein processing and presentation on T cell activation and tolerance /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/10851.
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Phan, Tri Giang. "The SWHEL model for studying B cell responses in tolerance and immunity." University of Sydney. Medicine, 2005. http://hdl.handle.net/2123/626.
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Classical immunoglobulin transgenic (Ig-Tg) mouse models such as the MD4 anti-hen egg lysozyme (-HEL) Ig-Tg line have been used extensively to study B cell responses in tolerance and immunity. This thesis describes a new generation of gene-targeted mice (designated SWHEL mice) whereby the VH10 Ig variable gene encoding the HyHEL-10 specificity of the original anti-HEL Ig-Tg mouse was targeted to the Ig heavy chain locus. B cells in the SWHEL mouse are therefore capable of undergoing class switch recombination (CSR) and somatic hypermutation (SHM), representing a major advance on the original MD4 mouse model. SWHEL mice were found to not only contain a large population of HEL-specific (HEL+) B cells but also a significant population of non-HEL-binding (HEL-) B cells generated by VH gene replacement. HEL+ SWHEL B cells were found to belong to the B2 lineage and displayed high levels of surface IgM. Nevertheless, they matured normally and colonised the primary B cell follicle and marginal zone (MZ) of the spleen. The SWHEL model thus provided an opportunity to re-examine some of the original observations made in the MD4 system and also to extend these observations, particularly with regard to the regulation of CSR by self-reactive B cells. As expected, analysis of SWHEL B cells exposed to high avidity membrane-bound HEL revealed that they underwent clonal deletion in the bone marrow (BM). More interestingly, analysis of HEL+ B cells exposed to low avidity soluble HEL revealed that they were able to emigrate from the BM to the spleen as anergic B cells. However, unlike anergic MD4 B cells, anergic SWHEL B cells were reduced in frequency, displayed an immature B cell phenotype, were excluded from the follicle and had a reduced lifespan. Direct measurement of B cell antigen receptor (BCR) occupancy by HEL and the frequency of HEL- competitor B cells was combined with mixed BM irradiation chimeras to demonstrate unequivocally that the difference in phenotype and fate of HEL+ B cells in the two systems was due solely to competition from HEL- B cells. In addition, the SWHEL model of B cell self-tolerance was used to show that while self-reactive B cells were hypo-responsive to BCR stimulation, BCR-independent signals delivered via anti-CD40 plus IL-4 or lipopolysaccharide could trigger them to undergo CSR and secretion of potentially pathogenic isotype-switched autoantibodies. Finally, the SWHEL model was used to study the responses of adoptively transferred follicular (Fo) and MZ B cells to in vivo activation with HEL conjugated to sheep red blood cells (HEL-SRBC). These studies revealed that both HEL+ MZ and Fo B cells were capable of mounting a robust T cell-dependent IgG1 antibody response to HEL-SRBC. However, HEL+ MZ B cells did not efficiently localise to the T cell-B cell border following antigen engagement and preferentially migrated to the bridging channels and red pulp. In contrast, HEL+ Fo B cells rapidly localised to the T cell-B cell border and subsequently colonised numerous germinal centres. As a result, the rate and pattern of SHM by HEL+ Fo and MZ B cells was shown to be distinct, with preferential targeting of mutations to the second complementarity-determining region in the former and to the second framework region in the latter. Together these data indicate illustrate the value of the SWHEL model and its potential to greatly advance the current understanding of B cell responses in tolerance and immunity.
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Brede, Christian [Verfasser], and Andreas [Akademischer Betreuer] Beilhack. "Peripheral alloantigen expression directs the organ specific T cell infiltration after hematopoietic cell transplantation / Christian Brede. Betreuer: Andreas Beilhack." Würzburg : Universität Würzburg, 2013. http://d-nb.info/1111886768/34.
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Cabbage, Sarah E. "Reversible regulatory T cell-mediated suppression of myelin basic protein-specific T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5034.
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