To see the other types of publications on this topic, follow the link: T cells responses.
Dissertations / Theses on the topic 'T cells responses'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'T cells responses.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Crawford, A. "How B cells influence T cell responses." Thesis, University of Edinburgh, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.645118.
Full textAbstract:
Although studies using B cell deficient mice have been useful in understanding the importance of B cells under different conditions, it is difficult to then dissect exactly how B cells could be regulating T cell responses. By transferring OT-II transgenic T cells into either B cell deficient (μMT) or C57BL/6 mice, expansion and contraction of T cells can be tracked ex vivo. Expansion of OT-II cells is reduced in μMT mice compared to C57BL/6 mice. Thus, B cells can provide costimulatory signals, secrete cytokines and influence the lymphoid microarchitecture. To dissect which B cell factor(s) are involved in enhancing OT-II T cell expansion, a model system was used where one molecule on the B cells is depleted at one time. This was achieved by creating bone-marrow chimeras using a combination of μMT bone-marrow and wildtype or deficient bone-marrow. Thus, all the B cells are either wildtype or deficient for a particular molecule. The molecules examined were MHC-II, which is required for antigen presentation, CD40, due to its costimulatory role, and lymphotoxin-alpha, for its role in maintenance of splenic architecture. Using the OT-II adoptive transfer system, we have shown a requirement for MHC-II but not CD40 on B cells for efficient T cell expansion. In light of these observations, the role of B cell-derived MHC-II for T cell memory generation was examined. To do this, I used MHC-II tetramers to track a polyclonal population of T cells in the host. Using this technique, I have shown that T cell memory is also diminished when the B cells do not express MHC-II. Thus, a cognate interaction with B cells is required for both efficient expansion and memory generation of CD4+ T cells.
2
Crawford, Alison. "Role of B cells in influencing T cell responses." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/13483.
Full text
3
Smith, Trevor Robert Frank. "Modulation of CD4+ T cell responses by CD4+CD25+ regulatory T cells and modified T cell epitopes." Thesis, Imperial College London, 2004. http://hdl.handle.net/10044/1/11317.
Full text
4
Preciado-Llanes, Lorena. "Inhibition of T-cell responses by microbes and immune cells." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/4717/.
Full textAbstract:
Some antigens can induce B-cell activation and antibody production without 'T cell help' and hence are called T-independent (TI) antigens. Similarly to bacterial capsular polysaccharides, anti- IgDconjugated dextran (α-δ-DEX) is a TI type 2 mimic which stimulates B lymphocytes by crosslinking of numerous B-cell receptor molecules. This thesis demonstrates that α-δ-DEX-activated B-cells directly inhibit TCR-induced CD4+ T-cell proliferation and activation in vitro. Experiments performed with purified cell populations excluded the possibility of α-δ-DEX acting directly on CD4+ T lymphocytes and confirmed that B lymphocytes exposed to α-δ-DEX for a period of 24 hours become activated and acquire a suppressive phenotype. Interestingly, these suppressor Bcells appear to be effective even when they are present at numbers below the physiological T:B ratio. Although the exact mechanism of action remains obscure, this is the first evidence of TI type 2 antigen activated B-cells mediating inhibition of activation and proliferation of helper T lymphocytes. Neisseria meningitidis is a bacterium which rarely causes invasive disease and sepsis, but perpetuates colonisation in the nasopharynx by avoiding immune recognition and killing. Because several N. meningitidis constituents are TI type 2 antigens and/or provide second signals to B-cells via TLRs, it was hypothesized that paraformaldehyde fixed meningococcus could exert immunomodulatory properties. A deep suppression of CD4+ T-cell responses occurred when aCD3-stimulated PBMCs where incubated with small meningococci counts (ratios between 0.1 to 10:1 bacteria per cell). A clear TH1 cytokine profile and IL-10 secretion was observed in supernatants from these cultures. Interestingly, outer membrane vesicles (OMVs) from N. meningitidis and N. lactamica replicated the suppression phenomenon induced by the whole organism. Bacterial capsule, lipooligosaccharides and Opa are not responsible for the suppressive effect. Depletion of B-cells, monocytes or NK cells does not reverse the meningococcus-mediated inhibition in PBMC cultures. Several bacterial components stimulate nitric oxide (NO) production, however N. meningitidis can counteract the bactericidal effect of reactive nitrogen intermediates by a partial denitrification pathway. Since NO is also produced as a result of TCR engagement, it was investigated whether NO donation or inhibition could influence CD4+ T-cell responses. A novel specific eNOS inhibitor (Cavtratin) derived from the caveolin-1 structure was tested for the first time in PBMC cultures. Cavtratin concentrations of 10 and 15 μM increases proliferation of CD4+ T lymphocytes and reduce the percentage of cell death in the PBMC culture after anti-CD3 stimulation.
5
Barroso, Herrera Osquel Miguel. "Manipulation of antigen-specific T cell responses by modified dendritic cells." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405941.
Full text
6
Li, Xiaoying. "T cell receptor repertoires of immunodominant CD8 T cell responses to Theileria parva." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/19552.
Full textAbstract:
Previous research has provided evidence that CD8 T cells mediate immunity against infection with Theileria parva. However, the immunity induced by one parasite strain doesn‟t give complete protection against other strains and this is associated with parasite strain specificity of the CD8 T cell responses. There is evidence that such strain specificity is a consequence of the CD8 T cell responses of individual animals being focused on a limited number of immunodominant polymorphic peptide-MHC determinants. Dominant responses to the Tp2 antigen have been demonstrated in animals homozygous for the A10 MHC haplotype. Three Tp2 epitopes recognised by A10+ animals (Tp249-59, Tp250-59 and Tp298-106) have been defined. This project set out to investigate the dominance of these epitopes and to examine the T cell receptor (TCR) repertoires of the responding T cells. The specific objectives were to: (i) Determine the dominance hierarchies of the three defined Tp2 epitopes in both A10-homozygous and -heterozygous cattle. (ii) Examine the clonal repertoires of epitope-specific responses by analysis of TCR gene expression. (iii) Isolate full-length cDNAs encoding TCR α and β chain pairs from T cell clones of defined epitope specificity and use them to generate cells expressing the functional TCRs. Using MHC class I tetramers the relative dominance of CD8 T cell responses were found to differ between A10-homozygous and heterozygous cattle. All A10-homozygous cattle examined had detectable responses to all 3 Tp2 epitopes, the Tp249-59 epitope consistently being the most dominant. By contrast, only some A10-heterozygous cattle had detectable responses to Tp2 and when present the response was specific only for the Tp298-106 epitope. Analyses of the sequences of expressed TCR β chains showed that the responses in individual animals were clonotypically diverse, but often contained a few large expanded clonotypes. The TCRs of Tp298-106–specific T cells showed preferential usage of the Vβ13.5 gene and the frequent presence of a “LGG” motif within the CDR3 of the B chain. A conserved (public) TCRβ clonotype shared by the Tp250-59-specific CD8 T cells from all A10-homozygous cattle was identified. The TCRα chains co-expressed with this public TCRβ clonotype were identified for a number of T cell clones. Lentivirus transduction of Jurkat cells with three full-length TCR α and β chain pairs resulted in successful expression of one of the α/β chain pairs as a functional TCR, thus providing the basis for future work to generate bovine T cells expressing defined TCRs in vitro.
7
Wangteeraprasert, Apirath. "CD8+ T-cells responses in Dengue virus infection." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39398.
Full textAbstract:
Dengue virus, which has four serotypes, has several clinical manifestations including asymptomatic infection, a self-limiting febrile illness termed dengue fever (DF) and a severe form characterized by plasma leakage termed dengue hemorrhagic fever (DHF). The pathogenesis of DHF is not fully understood and many studies have shown that it is more prevalent during secondary infection. In addition to a mechanism termed antibody dependent enhancement (ADE), the role of T-cells in the pathogenesis of dengue also has been investigated. It has been hypothesized that upon secondary infection dengue-specific memory T-cells generated during a previous infection, which are cross-reactive and have low avidity for the current serotype dominate the T-cell response. This phenomenon is called 'Original antigenic sin' and the consequence of this low avidity T-cell response may be ineffective viral elimination leading to increased production of inflammatory cytokines which could cause plasma leakage. To study CD8+ T-cell responses to dengue-peptide variants, HLA-A11-restricted NS3 133-142-specific T-cell clones were generated and their cytotoxicity, proliferation and cytokine production in response to variant epitopes was tested. The results support that the magnitude of T-cell responses is related to the strength of the TCR-peptide-MHC interaction. AG129 mice, which lack both IFN (symbol missing) and IFN (symbol missing) receptors, show susceptibility to dengue virus infection and develop symptoms seen during human infection such as vascular leakage. This allows for investigation of the role of T-cell responses generated towards sequential infections with well defined serotypes. Experiments that would be very difficult to carry out in human dengue patients. Splenocytes from sequentially infected AG129 mice were assayed for their response to whole dengue proteins from serotype 1 and 2 virus. New epitopes were identified and CD8+ T-cell lines and clones were generated and their functions studied using peptide variants. The results showed that dengue-specific cross-reactive memory CTLs displayed better recognition of epitopes encountered during primary immunisa tion as compare to those recognised during secondary immunisation, which supports the idea of original antigenic sin in dengue-specific CD8+ T -cells. In conclusion, this study focuses on cross-reactive dengue-specific CD8+ T-cells and their functions when recognizing heterologous dengue peptides to clarify their role in pathogenesis.
8
Deng, Jun, and 鄧軍. "Leptin modulates T cells responses in autoimmune arthritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208601.
Full textAbstract:
Leptin, a protein hormone encoded by obese (ob) gene, is mainly produced by adipocytes. Leptin plays an important role in regulating neuroendocrine function and energy metabolism. As a cytokine, leptin is involved in modulating the hematopoiesis and lymphopoiesis. Although leptin has been found to promote T cells activation, it is largely unclear whether and how leptin regulates T cell differentiation and function.
Leptin has been associated with disease severity in rheumatoid arthritis (RA). Elevated leptin levels have been detected in the sera and synovial fluid of active RA patients. Th17 cells play key roles in synovitis and joint damage during arthritis development. However, the role of leptin on Th17 cells has not been investigated so far. In culture, leptin promoted Th17 cells differentiationfrom naïve 〖CD4〗^+ T cells via upregulating ROR-γt expression. Moreover, Th17 cells and IL-17 levels were significantly increased in leptin-treated naïve CD4+ T cells. Moreover, this study found that synoviocytes and chondrocytes produced large amounts of leptin especially during acute and chronic stages of mice with collagen-induced arthritis (CIA). Furthermore, leptin levels, Th17 cells in the joint and IL-17 levels in the synovial fluid were closely related to disease activity. Leptin intraarticular injection led to earlier onset of disease, higher clinical score, and more severe joint destruction compared with PBS-treated control mice. Importantly, leptin-injected mice had higher percentages of Th17 cells and cell numbers, elevated IL-17 levels in the synovial fluid, and increased infiltration of Th17 cells in the inflamed joint tissues compared with PBS-treated mice.
T follicular helper (Tfh) cells are indispensible for pathogenic autoantibodies production. However, whether leptin receptor (ObR) signaling has a role on Tfh cells and its implication in CIA remain elusive. Upon a T cell-dependent antigen TNP-KLH immunization, germinal center (GC) response, plasma cells (PCs) and memory B cells formation were impaired in db/db mice compared with wild-type (WT) controls. In coculture of Tfh cells from db/db and WT mice with WT GC B cells, anti-TNP IgGs titers in supernatants of db/db Tfh cells were significantly reduced. Intravenously transfer of naïve CD4+ T cells from db/db and WT mice to BoyJ recipient mice, donor CD4+ T cells from db/db mice showed impaired Tfh cells generation in spleens of BoyJ recipient mice compared with mice received with WT CD4+ T cells. These data indicated that ObR-mediated signaling intrinsically modulate Tfh cells generation. In culture, leptin promoted Tfh cells differentiation via inducing Bcl6 expression, and increased IL-21 production in Tfh cells in a dose-dependent manner. Leptin significantly enhanced the phosphorylation of STAT3, upregulated Bcl6 expression, and increased p-STAT3 binding to the Il21 promoter in CD4+ T cells with leptin receptor b (Ob-Rb) overexpression. Upon CIA induction, db/db mice exhibited ameliorated disease severity with impaired Tfh cells response. However, WT Tfh cells transfer to db/db mice restored GC responses, PCs formation, antibody production, and exacerbated synovium inflammation and joint damage in db/db recipient mice.
Together, these findings demonstrate that leptin modulates arthritis development via enhancement of Th17 and Tfh cells responses.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
9
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.
Full textAbstract:
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.
10
Easterfield, Alistair John. "Foetal modulation of maternal T lymphocyte responses." Thesis, St George's, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325057.
Full text
11
Ritchie, Adam John Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Modulation of T cell responses by N-(3-oxododecanoyl)-L-homoserine lactone." Awarded by:University of New South Wales. Biotechnology and Biomolecular Sciences, 2005. http://handle.unsw.edu.au/1959.4/22005.
Full textAbstract:
In Pseudomonas aeruginosa, which causes severe secondary infections in immunocompromised patients, virulence factor expression is regulated by quorum sensing signal molecules known as acyl homoserine lactones (AHLs). One of the major AHLs produced by P. aeruginosa, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), has also been shown to alter the function of a range of mammalian cells. The goals of experiments reported in this thesis were to use murine models to investigate the effects of in vivo exposure to OdDHL on TH responses, define the direct effects of OdDHL on TH cells and to explore the mechanism by which OdDHL alters the function of TH cells. It was found that in vivo exposure to OdDHL led to changes in cytokine and antibody subclass production indicative of a shift towards the underlying TH bias of the mouse strain studied. Such shifts may play a role in infections with P. aeruginosa, as strong TH1 or TH2 responses have been associated with worsening prognosis for the host, while more balanced responses have been associated with decreases in both infection and pathology. These results suggest that treatments targeting the immunomodulatory activities of OdDHL may be of benefit in the clinical setting in the future. Direct analysis of TH cells in defined in vitro systems revealed that exposure to OdDHL led to uniform decreases in cytokine production and proliferation. These decreases in cytokine production were found to be the result of OdDHL acting on both TH cells and the antigen presenting cells (APCs) that activate them, and only occurred when cells were exposed to OdDHL within 4 hours of stimulation. These findings suggest that OdDHL is acting on a molecular target common to several cells types, and that in TH cells and APCs, this target is involved in the early stages of TH cell activation. Experiments in which T cells were activated with mitogens that bypass the cell membrane revealed that OdDHL is not acting on the cell membrane or membrane-associated activation factors, suggesting that OdDHL is instead inhibiting TH cell function through interactions with one or more intracellular signalling molecules.
12
Mathieson, Peter William. "Role of T lymphocytes in autoimmune responses." Thesis, University of Cambridge, 1992. https://www.repository.cam.ac.uk/handle/1810/251527.
Full text
13
Wikstrom, Matthew E. "The regulation of peripheral T cell responses in TCR transgenic mice." Thesis, The University of Sydney, 1997. https://hdl.handle.net/2123/27641.
Full textAbstract:
Transgenic mice expressing a T cell receptor specific for cytochrome C in association
with I-Ek were employed to study the mechanisms regulating the decision between
tolerance and immunity. Tolerance and immunity to the same peptide antigen were
. induced by using different routes of administration. Thus tolerance was induced by the
intravenous route and immunity by the subcutaneous route. The results presented in
this thesis provide a detailed map of the cellular events that occur during these two
distinct responses.
Intravenous immunisation induced activation of CD4+ cells expressing the transgenic
TCR (CD4+Tg0L+ cells), resulting in CD69 expression within two hours, priming of T
cell proliferation and Th1 cytokine production by 24 hours. Clonal expansion peaked 3-
4 days after immunisation. The number of CD4+Tg0t+ cells decreased rapidly after day
four, such that only 50% of initial cell numbers remained 7—10 days after immunisation.
Intravenous peptide also upregulated CD44 expression, increasing the proportion and
number of CD4+Tg0t+CD44hi cells at the peak of the response, but having no net effect
at the resolution of the response. When labelled CD4+Tg0t+ cells were adoptively
transferred to syngeneic non-transgenic hosts, deletional tolerance to intravenous
peptide was still seen, demonstrating that it was not an artefact of the high precursor
frequency in TCR transgenic mice. Antigen re-challenge experiments demonstrated that
CD4+Tg0t+ cells remaining at the resolution of the primary response to intravenous
peptide could not respond as vigorously as naive cells either in vitro and in vivo.
Interestingly, intravenous administration of intact cytochrome C also stimulated T cell
activation, but failed to induce peripheral deletion, and resulted instead in a minor
increase in the final proportion of CD4+Tg0t+CD44hi cells.
14
MacArthur, Georgina. "Characterisation of CD4+ T cell responses towards Epstein-Barr virus-infected B cells." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420895.
Full text
15
Tso, Hoi-wan. "Effects of phagocytosis of apoptotic cells by mesenchymal stem cells on osteogenesis and T cells responses /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39585475.
Full text
16
曹凱韻 and Hoi-wan Tso. "Effects of phagocytosis of apoptotic cells by mesenchymal stem cells on osteogenesis and T cells responses." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39707520.
Full text
17
Ahem, David John. "Characterisation of CD4+CD25+ T cells regulatory responses to allergens." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499049.
Full text
18
Dianda, Lee. "Immune responses in mice deficient in #alpha##beta# T cells." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244769.
Full text
19
De, Campos Pereira Lemos Sara Sofia. "CD8 T cell differentiation during immune responses." Phd thesis, Université René Descartes - Paris V, 2014. http://tel.archives-ouvertes.fr/tel-01059806.
Full textAbstract:
CD8 T cells are essential for the elimination of intracellular pathogens and tumor cells. Understanding how naïve CD8 T cells differentiate into effector cells capable of eliminating pathogens and to generate adequate memory cells during immune responses is fundamental for optimal T cell vaccine design. In this PhD thesis work we addressed two central questions: 1) What are the mechanisms by which early effector T cells could act as pro-inflammatory effectors? And what is their role in the immune response? 2) How heterogeneous are CD8 responses? Could different pathogens modulate CD8 T cell differentiation programs and be responsible for CD8 cell-to-cell heterogeneity? Could they also generate memory cells with different protection capacities? To address these questions related to the diversity of CD8 T cell differentiation during immune responses, we used the single cell RT-PCR technique to detect ex vivo expression of mRNA in each individual cell, and Brefeldin A injected mice to detect ex vivo intracellular proteins. As experimental system to evaluate in vivo cell activation we used T cell receptor transgenic (TCR-Tg) CD8 T cells. Since the use of TCR-Tg cells to study immune responses has been subjected to criticism (due to high frequency of naïve-precursor transfers), in a first Ms. we compared the behavior of TCR-Tg and endogenous (non-transgenic and present at low frequency) cells in the same mouse. We found fully overlapping behavior between these two cell populations, which reinforced the advantage of using TCR-Tg cells to study CD8 immune responses. In addition, we concluded that the frequency of naïve-precursors do not induce diversity on CD8 T cell differentiation patterns. In a second Ms. we evaluated the impact of different pathogens in the diversity of CD8 T cell properties during two different immune responses: OT1 TCR-Tg cells (specific for OVA antigen) in the response to LM-OVA (Listeria Monocytogenes expressing OVA) infection; and P14 TCR-Tg cells (specific for GP33 epitope) in the response to Lymphocytic choriomeningitis vírus (LCMV) infection. We found that OT1 and P14 cells had different properties. As this difference could also be attributed to the different TCR avidity between OT1 and P14 cells, we then compared the behavior of P14 and OT-1 cells in the same mouse, co-injected with LM-OVA and LM-GP33. Since no differences were then detected, these results demonstrated that priming with different pathogens generates CD8 T cells with different characteristics that are not determined by TCR usage, but rather by the infection context. In addition, when looking for the protection capacity of endogenous CD8 memory cells generated in bacterial or viral context, we found that memory cells generated after LCMV priming were more efficient in responding to a second challenge, than memory cells generated after LM-GP33 priming. We also found that this better protection is associated with a T cell effector memory (TEM) phenotype associated with the LCMV infection, in contrast with a T cell central memory (TCM) phenotype generated after LM-OVA infection. These results demonstrate that different pathogens are responsible for diversity of CD8 T cell differentiation patterns and that even when distinct pathogens are efficiently eliminated during the primary immune response the quality of the memory generated may differ. In a third Ms. we studied the mechanisms by which effector CD8 T cells attracted other cell types in the early days of an immune response. We used two experimental systems: the response of OT1 TCR-Tg cells to LM-OVA infection; and the response of anti-HY TCR-Tg cells to male cells ("sterile"-non infectious context). In both cases we found that immediately after activation, CD8 T cells expressed high levels of pro-inflammatory cytokines and chemokines (such as TNFα, XCL1, CCL3 and CCL4). (...)
20
Saunders, Margaret. "Analysis of immune responses to transformed cells in vitro." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481435.
Full text
21
Gurung, Prajwal. "Regulation of immune responses by apoptotic cells." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/974.
Full textAbstract:
Billions of cells die everyday as a result of normal tissue turnover, infection, trauma or injury. These dead cells are taken up, processed and presented to T cells by antigen presenting cells resulting in tolerance or immunity. Apoptotic cells induce tolerance; however, the precise mechanisms are still unknown. Previous studies have shown that direct infusion of apoptotic cells induce tolerance mediated by TRAIL-expressing CD8+ T cells. We hypothesized that immunologic tolerance induced by apoptotic cells is dependent on the activation status of apoptotic cells and mediated by direct killing of target cells by TRAIL-expressing CD8+ T cells. Three different experimental systems were used to elucidate the mechanisms by which apoptotic cells regulate immune responses.
Using a classical system of tolerance induction, we examined the immunological consequence of intravenous (i.v.) delivery of ex vivo-generated naïve or activated apoptotic cells. Naïve apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154 in the tolerogenic or immunogenic nature of the naïve or activated apoptotic cells, respectively, as tolerance resulted after i.v. injection of either naïve or activated apoptotic CD154-/- cells, while co-injection of an agonistic anti-CD40 mAb with naïve apoptotic T cells induced robust immunity.
The infusion of large numbers of apoptotic cells has limited physiological relevance, so the investigation of the influence of apoptotic cells on the immune system turned to another experimental tolerance model where soluble peptide antigen is injected systemically to induce the peripheral deletion of a population of antigen-specific T cells. Using this system, we investigated how apoptotic cells generated in vivo leads to T cell tolerance. Following adoptive transfer of OT-II cells, wild-type mice injected with soluble OVA323-339 became unresponsive to subsequent CFA/OVA immunization. Interestingly, Trail-/- or Dr5-/- mice developed robust immunity; even though all strains displayed peripheral deletion of OVA-specific T cells. Subsequent investigation found the mechanism of action of the CD8+ T cells was TRAIL-mediated deletion of the OVA-responsive T cells in a TCR-specific manner.
The experimental systems used above have some clinical relevance but are still not physiologic. To study the impact of apoptotic cells in a physiologic setting, we took advantage of the medical condition sepsis, which is accompanied by massive apoptosis of multiple immune cell populations. Thus, the final set of experiments in this thesis examined the tolerance induced during sepsis using a clinically-relevant cecal-ligation and puncture (CLP) model that included a secondary bacterial infection. CLP-treated WT mice had a reduced ability to control the secondary bacterial infection, which was paralleled by suppressed T cell responses, compared to sham-treated WT mice. In contrast, CLP- and sham-treated Trail-/- and Dr5-/- mice were able to similarly control the bacterial infection and generated bacterial antigen-specific T cell responses. The ability of CLP-treated wild-type mice to control the secondary infection and generate T cell immunity could be restored by the administration of a blocking anti-TRAIL mAb. These results suggest the importance of TRAIL in the induction of sepsis-induced immune suppression, such that TRAIL neutralization may be a potential therapeutic target to restore cellular immunity in septic patients.
22
Cobb, Dustin. "T-bet-dependent regulation of T cell responses during Trypanosoma cruzi infection." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/372.
Full textAbstract:
The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection.
23
Tomkins, Paul Thomas. "Interferon modulation of T-cell responses to Semliki Forest virus infected murine brain cells." Thesis, University of Warwick, 1989. http://wrap.warwick.ac.uk/101165/.
Full textAbstract:
Cultures of astrocytes prepared from the brains of newborn mice, G26-24 oligodendroglioma cells and C1300 neuroblastoma cells were treated with Interferon (IFN) and the effect on major histocompatibility complex (MHC) antigen expression assessed by indirect immunofluorescence. IFN-αβ increased class I, but not class II, MHC antigen expression on astrocytes, G26-24 cells and C1300 cells. IFN-β1, increased class I, but not class II, MHC antigen expression on astrocytes. IFN-γ increased both class I and class II MHC antigen expression on astrocytes and G26-24 cells. IFN-γ increased class I, but not class II, MHC antigen expression on C1300 cells. IFN-αβ and IFN-β were additive with IFN-γ in the induction of class I MHC antigen expression on astrocytes, but inhibited the ability of IFN-γ to induce class II MHC antigen expression. IFN-αβ and IFN-γ increased the susceptibility of astrocytes, C26-24 cells and C1300 cells to lysis by alloreactive cytotoxic T-lymphocytes (CTL) indicating that IFNs increased the ability of the cells to participate in class I MHC restricted T-cell immune reactions. Astrocytes treated with IFN-αβ or IFN-γ, and G26-24 cells and C1300 cells treated with IFN-γ, prior to infection with Semliki Forest virus (SFV), showed a similar or increased susceptibility to SFV-specific CTL lysis, despite a reduction of SFV antigen display on the cells, as assessed by indirect immunofluorescence and susceptibility to lysis by anti-SFV antibody plus complement. It is concluded that even when SFV antigen expression is reduced by IFN treatment, in the context of enhanced class I MHC antigen expression cells remain susceptible to SFV-specific CTL lysis. IFN-αβ and IFN-γ treatment of astrocytes, and IFN-γ treatment of G26-24 cells, prior to treatment with a β-propiolactone inactivated preparation of SFV, increased the ability of the cells to stimulate SFV-specific T-cell release of IFN-γ. This increased ability correlated with an increase in MHC antigen expression on the cells. IFN-γ released by SFV-specific T-cells increased class I and class II MHC antigen expression on astrocytes and G26-24 cells indicating that a positive feedback mechanism could operate. SFV-infected newborn and adult mice possessed high levels of IFN-αβ in the brain. Brain extracts prepared from SFV-infected newborn and adult mice increased class I, but not class II, MHC antigen expression on astrocytes in vitro. Class I and class II MHC antigen expression was slightly elevated in the brains of SFV-infected newborn mice. To study the role of endogenous IFN-γ, R4-6A2 anti-IFN-γ monoclonal antibody was administered to adult mice, prior to infection with SFV, and the effect on the clinical course of SFV-disease monitored. R4- 6A2 antibody had no effect and preliminary experiments indicated that the antibody may not neutralise all IFN-γ activity in vivo under the conditions used.
24
Stelekati, Erietta [Verfasser]. "The role of mast cells in CD8+ T cell-mediated immune responses / Erietta Stelekati." Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1019951877/34.
Full text
25
Lidehäll, Anna Karin. "Cellular Immune Responses to Cytomegalovirus." Doctoral thesis, Uppsala University, Department of Oncology, Radiology and Clinical Immunology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8578.
Full textAbstract:
Cytomegalovirus (CMV) is a widespread infection affecting 50-90% of the human population. A typical silent primary infection is followed by life-long persistence in the host under control by virus-specific CD8 (“killer”) and CD4 (“helper”) T cells. Although harmless in most people, CMV may cause disease and sequelae in patients with deficient cellular immunity, such as AIDS patients, recipients of organ transplants and children who have acquired the virus before birth. In this thesis we have characterized the cellular immunity to CMV in immunocompetent subjects, in patients receiving transplants and in infants.
In healthy individuals with latent CMV, the frequencies of CMV-specific CD8 T cells varied considerably between the donors. Within the same individual, the changes over time were usually small. In patients with primary, symptomatic CMV infection, the frequencies of CMV-specific CD8 T cells peaked within the first month after the appearance of symptoms. The frequencies then declined to levels similar to those in latently infected CMV carriers. The CD4 T-cell function followed the same pattern, but with lower peak values.
Immunosuppressed renal transplant patients with latent CMV had CMV-specific CD4 cell function similar to healthy controls. The frequencies of CMV-specific CD8 T cells were also comparable, but their function was impaired. When renal transplant recipients were investigated longitudinally, we found that their CMV-specific T cells decreased rapidly after transplantation. Whereas the frequencies and function of CD8 T cells rebounded within 3 months, CD4 T-cell recovery was impaired during the entire first year after transplantation.
Finally, the frequencies and function of CMV-specific T-cells were investigated in children with congenital and postnatal CMV. CMV-specific CD8 T cells could be detected in even the youngest children, suggesting that these cells can develop early in life. In contrast, CMV specific CD4 T cells were low or absent in the youngest children but increased slowly with age.
26
Omodho, Becky. "Early growth response gene (Egr) 2 and 3 control inflammatory responses of tolerant T cells." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/13516.
Full textAbstract:
This study investigated the role of tolerance induction in an inflammatory setting in regard to the early growth response genes Egr2 and Egr3. T cells robustly respond to pathogenic antigens during infection, but are tolerant to stimulation by self-antigens. The intrinsic mechanisms for self-tolerance in the periphery are still not clear. Egr2 and 3 are induced in tolerant T cells in response to antigen stimulation by NFAT-medicated tolerant signalling; however, their function in tolerant T cells is still unknown. The study demonstrated that Egr2 and 3, induced in tolerant T cells, are not directly involved in defective proliferation and IL-2 production, the hallmarks of T cell tolerance. However, they are essential for preventing inflammatory response of tolerant T cells. In the absence of Egr2 and 3, tolerant T cells show impaired proliferation and production of IL-2, but produce high levels of IFN-γ, a key inflammatory cytokine. This phenotype resembles CD4 T cells from autoimmune diseases such as lupus which show poor proliferative response, but hyper-inflammation. Our study demonstrated, for the first time, a distinctive mechanism to control inflammation from proliferative tolerance regulated by Egr2 and 3, which may be an important mechanism for the control of autoimmune diseases.
27
Marshall, Heather D. "Sensitization of CD8 T Cells During Acute Viral Infections Impacts Bystander and Latecomer CD8 T Cell Responses : A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/440.
Full textAbstract:
Many virus infections induce a transient state of immune suppression in the infected host. Virus-induced T cell suppression can be caused by T cell activation-induced cell death (AICD), dendritic cell (DC) apoptosis, DC dysfunction, and/or the enhanced expression of immune-suppressive cytokines. It has been previously demonstrated that naïve bystander CD8 T cells derived from hosts experiencing an acute virus-specific T cell response underwent AICD when polyclonally activated by anti-CD3 in vitro (Zarozinski et al., 2000). Susceptibility of naïve bystander T cells to AICD could prevent the development of a new T cell response during an ongoing immune response, and thus render infected hosts immune suppressed. Although immune suppression could result in an enhanced susceptibility to superinfections, virus-infected individuals are more commonly resistant to superinfecting pathogens. Because of these seemingly contradictory conditions, we sought to investigate how acute viral infections impact naïve bystander CD8 T cells in vivo. More specifically, we asked whether bystander CD8 T cells are susceptible to immune suppression or whether they can contribute to the resistance to superinfections. In order to address this, we examined the responses of bystander CD8 T cells activated with cognate antigen during acute viral infections in vivo. We generated several in vivomodels using P14 (LCMV glycoprotein-specific), HY (male antigen-specific), and OT-I (ovalbumin-specific) transgenic CD8 T cells, which we defined as bystander during acute infections with lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), vaccinia virus (VV), and murine cytomegalovirus (MCMV).
Consistent with the enhanced susceptibility to cell death noted in vitro, we found that bystander CD8 T cells activated with cognate antigen in vivo during acute viral infections underwent markedly reduced proliferation. Virus-induced transient T cell suppression in vivo was not exclusively mediated by Fas-FasL- or TNF-induced AICD or due to an enhanced susceptibility to apoptosis. Instead, immune suppression in vivowas associated with a delayed onset of division, which we found not to be due to a defect in antigen presentation, but rather due to a T cell intrinsic defect.
Despite the suppressed proliferation of TCR-stimulated bystander CD8 T cells in vivo, we found an enhancement of the effector functions exerted by bystander CD8 T cells activated during acute viral infections. During acute viral infections or after stimulation with type 1 IFN (IFN-αβ) inducers, some bystander CD8 T cells were sensitized to immediately exert effector functions such as IFN-γ production and degranulation upon stimulation with high affinity cognate antigen. Sensitization of naïve CD8 T cells required self-MHC I and indirect effects of IFN-αβ, while IL-12, IL-18, and IFN-γ were not individually required. IL-15 was not required for the rapid expression of IFN-γ, but was required for up-regulation of granzyme B (GrzB). P14 and OT-I CD8 T cells, which are capable of homeostatic proliferation, could be sensitized by poly(I:C), but HY CD8 T cells, which are poor at homeostatic proliferation, could not, suggesting that the requirement for MHC I may be to present low affinity cryptically cross-reactive self antigens. Sensitized naive CD8 T cells up-regulated the t-box transcription factor Eomesodermin (Eomes), which can regulate these rapid effector functions.
In conclusion, we demonstrate in this thesis that acute viral infections impact naïve bystander CD8 T cells such that their response to cognate antigen is altered. Prior to cognate antigen engagement, bystander CD8 T cells up-regulated Eomes, CD122, and GrzB. Following cognate antigen engagement, bystander CD8 T cells rapidly degranulated and expressed the effector cytokine IFN-γ. The ability of bystander CD8 T cells to rapidly exert effector functions may contribute to the resistance of virus-infected individuals to superinfections. Despite these rapid effector functions, the proliferation of TCR-stimulated bystander CD8 T cells was markedly inhibited. This reduced proliferation was found not to be a defect in antigen presentation, but was a T cell intrinsic defect in initiating division. Thus, bystander CD8 T cells were also susceptible to virus-induced immune suppression.
It is also likely that virus-specific CD8 T cells that are not activated until later in the response, so-called latecomer CD8 T cells, may also be susceptible to immune enhancement and suppression. Thus, latecomer CD8 T cells would be able to rapidly exert effector functions at the expense of proliferation. Taken together, we propose that during an immune response, due to spatial and temporal gradients of antigen and inflammation, it is likely that a combination of heterogeneous T cells with different signal strengths and sequences of exposure from cytokines and peptide-MHC constitute the total T cell response to pathogens.
28
Sanchez-Silva, Martin Antonio. "Analysis of local T cell responses in experimental visceral leishmaniasis." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326241.
Full text
29
Worthington, Joy. "T cell responses in the pathogenesis of cholestatic liver disease." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.564278.
Full textAbstract:
The cholestatic liver diseases include Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC). The aetiologies of PBC and PSC are not yet known but it is thought that there are both inherited and environmental factors associated with pathogenesis. In this thesis, I set out to explore the immunologic and virologic basis of cholestatic liver diseases. In recent years a novel human betaretrovirus has been proposed as an antigenic target in PBC. Using separate T cell assays, I analysed responses to both autoantigens and foreign antigens in parallel, backed up with a molecular approach. I have shown that although there is definite evidence of prior encounter with HBRV peptides at the immunologic level the virus is not closely associated with the pathogenesis of PBC. I have shown that there are links between the composition of the cellular infiltrate and the histologic scores as well as the clinical status. In PBC, the accumulation of CD8+ cells in particular correlates with liver fibrosis stage and Foxp3 cells may have an influence on portal and lobular inflammation. In PSC, the frequency of T helper cells and B cells correlate with alkaline phosphatase and liver stage. This may indicate a closer relationship between tissue histochemistry results and fibrosis and clinical markers in PSC than in PBC and may not simply be a result of portal tract inflammation but be associated with disease pathogenesis. The quality of life tool PBC-40 showed similar results to the original Newcastle cohort. Fatigue is the symptom with the greatest apparent impact and there was no association found between symptoms and biological parameters of disease activity and severity. In PSC, there was a negative correlation between the average CD8 count per infiltrate and the emotional and social domain suggesting alterations in CD8 liver cell counts may have an influence on human behaviour or vice versa. Overall these data provide new insight into the pathogenesis of both PBC and PSC, and provide new avenues for immunologic analysis of these diseases in future.
30
Ahern, David John. "Characterisation of CD4+CD25+ T cells in regulatory responses to allergens." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/11507.
Full text
31
Martin, Matthew David. "Naive and memory CD8 T cell responses after antigen stimulation in vivo." Thesis, University of Iowa, 2011. https://ir.uiowa.edu/etd/1246.
Full textAbstract:
The extent to which the progeny of one primary memory CD8 T cell differs from the progeny of one naïve CD8 T cell of the same specificity remains an important question. In order to explore cell autonomous functional differences between naïve and memory CD8 T cells that are not influenced by differences in the priming environment, an experimental model has been developed in which physiological numbers of both populations of cells were co-transferred into naïve host before antigen-stimulation. Interestingly, naïve CD8 T cells expand in numbers more than primary memory CD8 T cells after various infections or immunizations. The intrinsic ability of one naïve CD8 T cell to give rise to more effector CD8 T cells than one memory CD8 T cell is independent of the number of primary memory CD8 T cells present in vivo. The sustained proliferation of primary, but not the increased death of secondary effectors was shown to contribute to the differences in the observed magnitudes of expansion. In addition, longitudinal analysis of primary and secondary CD8 T cell responses revealed that the ability of naïve CD8 T cells to generate long-lived progeny (`memory generation potential') is better than for primary memory CD8 T cells despite the differences in overall kinetics of both responses after infection. Taken together, the data presented here revealed previously unappreciated differences between naïve and memory CD8 T cells and will help further define the functional potential for both cell types.
The goal of immunization is to generate memory CD8 T cells of sufficient quality and quantity, and it has been shown that the naïve to primary memory CD8 T cell differentiation in vivo is controlled, at least in part, by the amount and duration of inflammation present early after the initiation of the response. In experiments where naïve CD8 T cells were co-transferred with increasing numbers of primary memory CD8 T cells, we observed a negative correlation between the number of primary memory present and the magnitude of primary CD8 T cell responses. Interestingly, the conversion of newly recruited (either TCR-Tg or endogenous) primary CD8 T cells into CD8 T cells with the phenotype (CD62Lhi, CD27hi) and function (tissue distribution, Ag-driven proliferation, cytokine production) of long-term memory was facilitated when they were primed in the presence of memory CD8 T cells of the same or unrelated specificity. Therefore, these data suggest that the presence of anti-vectorial immunity will not necessarily decrease the efficacy of CD8 T cell vaccination since newly recruited CD8 T cells, despite their decreased magnitude of expansion, might differentiate into functional memory cells faster.
32
Goddard, Ruth Victoria. "Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells." Thesis, University of Plymouth, 2002. http://hdl.handle.net/10026.1/2695.
Full textAbstract:
Immunotherapy using dendritic cells has shown encouraging results in both haematological and non-haematological malignancies. In this study, monocyte-derived dendritic cells from patients with B-cell Chronic Lymphocytic Leukaemia were generated by culture in Interleukin-4 and Granulocyte Macrophage-Colony Stimulating Factor. Lysate-pulsed autologous dendritic cells were used as antigen presenting cells in co-culture with autologous B-cell Chronic Lymphocytic Leukaemia T-cells. B-cell Chronic Lymphocytic Leukaemia T-cells stimulated with B-cell Chronic Lymphocytic Leukaemia lysate-pulsed autologous dendritic cells showed a significant increase in cell surface expression of Interleukin-2 Receptor (CD25), Interferongamma secretion and cytotoxicity against autologous B-cell Chronic Lymphocytic Leukaemia B-cell targets hut not against targets from healthy volunteers. Responses were only stimulated by the B-cell Chronic Lymphocytic Leukaemia B cell lysate. Cytotoxicity was Major Histocompatibility Complex Class II restricted. The addition of maturation agents such as Lipopolysaccharide, Tumour Necrosis Factor-alpha and Polyriboinosinic Polyribocytidylic Acid to monocyte derived dendritic cells was unsuccessful at increasing anti-tumour responses. Pre-treatment of T cells with Interleukin-15 before stimulation by lysate pulsed autologous dendritic cells increased numbers of activated cells, cytokine secretion and specific cytotoxicity to B-cell Chronic Lymphocytic Leukaemia 8-cells. Fusion of monocyte derived dendritic cells and B-cell Chronic Lymphocytic Leukaemia B-cells generated both Major Histocompatibility Complex Class I and Class II restricted cytotoxicity to B-cell Chronic Lymphocytic Leukaemia B-cell targets. When B-cell lysates were analysed using reducing sodium dodecyl sulphate-polyacrylamide gel electrophoresis, a B-cell Chronic Lymphocytic Leukaemia specific hand at 42,000 Dalton and other patient specific bands were observed. Only the 65,000 Dalton and 42,000 Dalton hands were capable of stimulating comparable T cell responses as the whole lysate. The 65,000 Dalton band from normal healthy volunteers showed a dominant peptide that closely matched Human Serum Albumin. The 42,000 Dalton band from B-cell Chronic Lymphocytic Leukaemia patients showed a possible match with Human Actin.
33
Lemos, Sara Sofia de Campos Pereira. "CD8 T cell differentiation during immune responses." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T009/document.
Full textAbstract:
Les lymphocytes T CD8 ont un rôle essentiel dans la protection contre les agents pathogènes intracellulaires et la progression tumorale. Ainsi, la compréhension de la diversité des mécanismes de différenciation des lymphocytes T CD8 naïfs en cellules effectrices, ainsi qu’en cellules mémoires compétentes, est fondamentale pour le développement efficace de vaccins à cellules T. Dans ce travail de thèse, nous avons abordé deux questions centrales : (1)Très tôt après l’activation des cellules T CD8, quels sont les mécanismes par lesquels les cellules T effectrices agissent comme effecteurs pro-inflammatoires en recrutant d’autres cellules? Et quel est leur rôle dans la réponse immunitaire? (2) Quel est le rôle du contexte infectieux dans le programme de différenciation des lymphocytes T CD8 ? Est-il responsable de l’hétérogénéité des cellules répondeuses et a-t-il un rôle dans les différents effets protecteurs des cellules mémoires? Afin de répondre à ces questions, nous avons choisit d’utiliser des cellules T CD8 exprimant un récepteur pour l’antigène transgéniques (TCR-Tg) pour suivre la différentiation in vivo des lymphocytes T CD8. De plus, la méthode de RT-PCR sur des séries de cellules uniques, nous a permis d’analyser la co-expression des ARNm dans ces cellules. Comme l’utilisation à haute fréquence de cellules TCR-Tg a été fortement critiquée, nous avons comparé la différenciation de ces cellules avec celle des cellules endogènes (non transgéniques et rares). Dans ce premier manuscrit nous avons observé un comportement similaire, ce qui a renforcé l'avantage d'utiliser des cellules TCR Tg pour étudier les réponses immunitaires des lymphocytes T CD8. De plus, nous avons conclu que la diversité des réponses immunitaires des lymphocytes T CD8 n’est pas conditionnée par la fréquence de cellules naïves. Dans un deuxième manuscrit, nous avons comparé la réponse des cellules OT1 TCR-Tg (spécifiques de l’antigène OVA) à l'infection bactérienne LM-OVA (Listeria Monocytogènes exprimant OVA) avec la réponse des cellules P14 TCR-Tg (spécifiques de l’épitope GP33) à l’infection par le virus LCMV. Nous avons montré que les cellules OT1, stimulées par l’OVA dans un contexte bactérien (LM-OVA), présentent un profil d’expression génique distinct de celui des cellules P14 stimulées par le GP33 dans un contexte viral (LCMV). Nous avons également co-stimulé les cellules P14 et OT1 dans une même souris suivant le même contexte bactérien avec LM-GP33 et LM-OVA. Dans ce cas, nous n’avons pas observé de différence dans le profil d’expression génique. L’ensemble des résultats démontrent que les stimulations spécifiques des cellules T CD8 par différents agents pathogènes génèrent des cellules T CD8 présentant des caractéristiques différentes qui ne sont pas déterminées par la spécificité du TCR mais plutôt par le contexte infectieux. De plus, nous avons montré que les cellules mémoires endogènes résultant de la stimulation des CD8 en présence de LCMV ont été plus efficaces après une deuxième réponse immunitaire que des cellules mémoires générées après stimulation avec LM-GP33 (bactérie). Nous avons également observé que la protection plus efficace dans le contexte viral est associée à des cellules T CD8 qui présentent un phénotype de cellules T mémoires effectrices (TEM) tandis que les cellules T CD8 générées dans un contexte bactérien ont plutôt un phénotype associé aux cellules T mémoires centrales (TCM). Ces résultats démontrent que différents pathogènes induisent différents profils de différentiation des cellules T CD8 et que malgré l’élimination efficace des différents pathogènes dans une réponse primaire, la qualité des cellules mémoires générées au cours de cette réponse peut être différente. Dans un troisième manuscrit, nous avons étudié les mécanismes de recrutement d’autres cellules par les lymphocytes T CD8 activés à un temps précoce de la réponse immunitaire. (...)CD8 T cells are essential for the elimination of intracellular pathogens and tumor cells. Understanding how naïve CD8 T cells differentiate into effector cells capable of eliminating pathogens and to generate adequate memory cells during immune responses is fundamental for optimal T cell vaccine design. In this PhD thesis work we addressed two central questions: 1) What are the mechanisms by which early effector T cells could act as pro-inflammatory effectors? And what is their role in the immune response? 2) How heterogeneous are CD8 responses? Could different pathogens modulate CD8 T cell differentiation programs and be responsible for CD8 cell-to-cell heterogeneity? Could they also generate memory cells with different protection capacities? To address these questions related to the diversity of CD8 T cell differentiation during immune responses, we used the single cell RT-PCR technique to detect ex vivo expression of mRNA in each individual cell, and Brefeldin A injected mice to detect ex vivo intracellular proteins. As experimental system to evaluate in vivo cell activation we used T cell receptor transgenic (TCR-Tg) CD8 T cells. Since the use of TCR-Tg cells to study immune responses has been subjected to criticism (due to high frequency of naïve-precursor transfers), in a first Ms. we compared the behavior of TCR-Tg and endogenous (non-transgenic and present at low frequency) cells in the same mouse. We found fully overlapping behavior between these two cell populations, which reinforced the advantage of using TCR-Tg cells to study CD8 immune responses. In addition, we concluded that the frequency of naïve-precursors do not induce diversity on CD8 T cell differentiation patterns. In a second Ms. we evaluated the impact of different pathogens in the diversity of CD8 T cell properties during two different immune responses: OT1 TCR-Tg cells (specific for OVA antigen) in the response to LM-OVA (Listeria Monocytogenes expressing OVA) infection; and P14 TCR-Tg cells (specific for GP33 epitope) in the response to Lymphocytic choriomeningitis vírus (LCMV) infection. We found that OT1 and P14 cells had different properties. As this difference could also be attributed to the different TCR avidity between OT1 and P14 cells, we then compared the behavior of P14 and OT-1 cells in the same mouse, co-injected with LM-OVA and LM-GP33. Since no differences were then detected, these results demonstrated that priming with different pathogens generates CD8 T cells with different characteristics that are not determined by TCR usage, but rather by the infection context. In addition, when looking for the protection capacity of endogenous CD8 memory cells generated in bacterial or viral context, we found that memory cells generated after LCMV priming were more efficient in responding to a second challenge, than memory cells generated after LM-GP33 priming. We also found that this better protection is associated with a T cell effector memory (TEM) phenotype associated with the LCMV infection, in contrast with a T cell central memory (TCM) phenotype generated after LM-OVA infection. These results demonstrate that different pathogens are responsible for diversity of CD8 T cell differentiation patterns and that even when distinct pathogens are efficiently eliminated during the primary immune response the quality of the memory generated may differ. In a third Ms. we studied the mechanisms by which effector CD8 T cells attracted other cell types in the early days of an immune response. We used two experimental systems: the response of OT1 TCR-Tg cells to LM-OVA infection; and the response of anti-HY TCR-Tg cells to male cells (“sterile”-non infectious context). In both cases we found that immediately after activation, CD8 T cells expressed high levels of pro-inflammatory cytokines and chemokines (such as TNFα, XCL1, CCL3 and CCL4). (...)
34
Omilusik, Kyla Dione. "The requirement for competent antigen presenting dendritic cells and poised T cells for immune responses." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36789.
Full textAbstract:
Immune responses are initiated by dendritic cells (DCs) that cross present exogenous antigen to naïve T cells. DC cross presentation is essential for generating primary immune responses, yet the mechanistic details remain undefined. Using a CD74⁻/⁻ mouse model, a CD74-MHC I association was shown to mediate trafficking of MHC I from the endoplasmic reticulum to endolysosomal compartments for antigenic loading. These studies describe a novel CD74-mediated cross presentation pathway in DCs that plays a major role in the generation of cytolytic T lymphocyte (CTL) responses against viral and cell-associated antigens. Viruses such as Human Immunodeficiency Virus (HIV) have evolved mechanisms to interfere with immune activation allowing persistence in the host. HIV can infect DCs so the HIV virulence factor, Nef, which interacts with MHC I, has the potential to interfere with MHC I trafficking in the cross presentation pathway. Using a Nef-expressing DC line, Nef was shown to downregulate surface MHC I by inhibiting Golgi-to-surface transport of newly synthesized MHC I and by increasing the recycling of surface MHC I. Coordinately, Nef was shown to inhibit both direct and cross presentation of viral and soluble antigen. Similarly, in a Nef transgenic mouse, Nef was shown to inhibit CTL responses to bacterial and viral infections. This unique immunosubversion mechanism likely contributes to immunodeficiency associated with Acquired Immunodeficiency Syndrome. Peripheral pools of naïve T cells capable of responding to DC stimulus are maintained through homeostatic cues including TCR signalling. Key to this is the second messenger calcium (Ca²⁺); however, the identity of the components regulating intracellular Ca²⁺ concentrations is unclear. Through examination of a knock-out mouse model, the Ca²⁺ channel, CaV1.4, was shown to play a cell-intrinsic role in naïve T cell development and survival. CaV1.4 is critical for regulation of intracellular Ca²⁺ stores and for TCR-induced increases in cytosolic Ca²⁺, which impacts Ras/ERK and NFAT activation. The CaV1.4 deficiency causes a loss of naïve T cells and results in immunodeficiency. These studies reveal a critical function for CaV1.4 in naïve T cell homeostasis. Collectively, this thesis demonstrates the importance of cross presenting DCs and maintenance of T cells for functional immunity.
35
Sampangi, Sandeep. "Autologous human kidney proximal tubule epithelial cells (PTEC) modulate dendritic cell (DC), T cell and B cell responses." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/82033/1/Sandeep_Sampangi_Thesis.pdf.
Full textAbstract:
This is a comprehensive study of human kidney proximal tubular epithelial cells (PTEC) which are known to respond to and mediate the pathological process of a range of kidney diseases. It identifies various molecules expressed by PTEC and how these molecules participate in down-regulating the inflammatory process, thereby highlighting the clinical potential of these molecules to treat various kidney diseases. In the disease state, PTEC gain the ability to regulate the immune cell responses present within the interstitium. This down-regulation is a complex interaction of contact dependent/independent mechanisms involving various immuno-regulatory molecules including PD-L1, sHLA-G and IDO. The overall outcome of this down-regulation is suppressed DC maturation, decreased number of antibody producing B cells and low T cell responses. These manifestations within a clinical setting are expected to dampen the ongoing inflammation, preventing the damage caused to the kidney tissue.
36
Sivaganesh, Sivasuriya. "Recipient DCs presenting intact and processed MHC alloantigen mediate CD8⁸ T-cell responses." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609327.
Full text
37
Narendran, Partheepan. "Immune responses to proinsulin in type 1 diabetes mellitus." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325704.
Full text
38
Son, Aoi. "Dendritic cells derived from TBP-2 deficient mice are defective to induce T cell responses." Kyoto University, 2008. http://hdl.handle.net/2433/124222.
Full text
39
Haileselassie, Yeneneh. "Lactobacilli- and Staphylococcus aureus mediated modulation of immune responses in vitro." Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-127399.
Full textAbstract:
The human gut harbors a vast number of microbes. These microbes are not passive bystanders. They are important in modulating the immune system. We have previously shown that early colonization with lactobacilli and Staphylococcus (S.) aureus differentially associates with allergy development and/or immune profile at early ages. Here we focus on understanding how these microbes modulate the response of intestinal epithelial cells and immune cells in vitro. In paper I, we investigated the impact of UV-killed and/or cell free supernatant (CFS) of different Lactobacillus (L.) species and S. aureus strains on cytokine production from intestinal epithelial cells (IEC) and immune cells. Enterotoxin-expressng S. aureus 161:2-CFS triggered CXCL-1/GRO-α and CXCL-8/IL-8 production by IEC. S. aureus-induced CXCL-8/IL-8 production was hampered by MyD88 gene silencing of IEC, indicating the importance of TLR signaling. Further, lactobacilli-CFS and S. aureus-CFS were able to induce the production of a number of cytokines by peripheral blood mononuclear cells (PBMC) from healthy donors, but only S. aureus triggered T-cell associated cytokines: IL-2, IL-17, IFN-γ and TNF-α; which were dampened by the co-treatment with S. aureus and any of the different Lactobacillus strains. Flow cytometry of the stimulated PBMC further verified IFN-γ and IL-17 production by T cells upon treatment with S. aureus-CFS, which also induced CTLA-4 expression and IL-10 production by Treg cells. In paper II, we investigated the influence of CFS of L. reuteri and S. aureus on the differentiation of monocyte to DC and subsequently how the generated DC influence T cell response. DC generated in the presence of L. reuteri exhibited an increase in expression of surface markers (HL-DR, CD86, CD83, CCR7) and cytokine production (IL-6, IL-10 and IL-23), but had a decreased phagocytic capacity compared with conventional Mo-DC, showing a more mature phenotype. However, upon LPS stimulation, DC generated in the presence of L. reuteri-CFS displayed a more regulatory phenotype, with a reduced cytokine response both at mRNA and protein levels. On the contrary, DC generated in the presence of S. aureus-CFS resembled the control Mo-DC both at mRNA and protein expression, but SA-DC was more efficient in inducing cytokine production in autologous T cells. In paper III, we studied the influence of L. reuteri-CFS on the retinoic acid (RA)-driven mucosal-like DCs’ phenotype and function to modulate T regulatory cells (Treg) in vitro. DC generated in the presence of RA showed a mucosal-like regulatory-DC phenotype with its CD103 expression, high IL10 production and decreased expression of genes associated with inflammation (NFκB1, RELB and TNF). Further, treatment with L. reuteri-CFS enhanced the regulatory phenotype of RA-DC by increasing the production of several chemokines, such as CXCL1, CXCL5, CCL3, CCL15 and CCL20, which are involved in gut homeostasis, while dampening the expression of most chemokine receptor genes. L. reuteri-CFS also increased CCR7 expression on RA-DC. RA-DC co-cultured with T cell increased IL10 and FOXP3 expression in Treg. However L. reuteri-CFS pre-conditioning of the RA-DC did not improve the Treg phenotype. In conclusion, bacteria-CFS can have an impact on the response of IEC, differentiation and function of DC and, subsequently the T cell response, when taken together in the context of gut; these can have an impact on the health and disease of the host.At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Submitted.
40
Sivakuru, Thamayanthi. "Lung mucosal Th2 responses are regulated by CD4+CD25+ suppressor T cells." Thesis, University of Southampton, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404470.
Full text
41
Provine, Nicholas Mcdermott. "CD4 T Cells Regulate Adenovirus Vector-Elicited Cellular and Humoral Immune Responses." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718733.
Full textAbstract:
The processes that regulate viral vector vaccine-elicited cellular and humoral immune responses remain poorly defined. Thus, in this thesis, the role of CD4+ T cells – master regulators of adaptive immunity – in modulating adenovirus (Ad) vector-elicited cytotoxic CD8+ T cell responses and transgene-specific antibody responses was investigated. CD4+ T cell help is critical for the induction of CD8+ T cell and antibody responses, but the mechanisms and timing of help to each of these two arms of the immune system are distinct. CD4+ T cell help is required immediately and continuously for one week to drive functional CD8+ T cell effector differentiation and prevent dysfunction. Elevated signaling via PD-1, decreased IL-2 signaling, and increased non-canonical NFAT signaling all appear important for driving this CD8+ T cell dysfunction and impairing effector functionality. Absence of CD4+ T cells at the time of Ad vector immunization prevents the development of antigen-specific antibody responses. However, if the CD4+ T cell population is allowed to recover then fully functional antigen-specific antibody responses develop without the re-administration of antigen. Thus, CD4+ T cell help is absolutely required for the development of antibody responses following Ad vector immunization, but, intriguingly, help can be provided at a time separate from initial antigen exposure. Collectively, CD4+ T cell help and the appropriate timing of this help are critical for the generation of optimal CD8+ T cell and antibody responses following Ad vector immunization. These data advance our understanding of how CD4+ T cells regulate Ad vector-elicited cellular and humoral immune responses, and may improve rational vaccine design.Medical Sciences
42
Malavige, Gathsaurie Neelika. "Investigation of varicella zoster virus glycoprotein-specific T cell responses." Thesis, University of Oxford, 2007. http://ora.ox.ac.uk/objects/uuid:52445512-fce7-4083-a4b1-f8adf3d3b315.
Full textAbstract:
T cells are believed to be important in the control of varicella zoster virus (VZV) replication but little is known of T cell epitopes and the relationships between T cell responses, viral load and clinical disease during primary infection. I initially set to investigate the immune responses to two of the main VZV glycoproteins (gE and gI) using ex vivo and cultured IFNγ ELISpot assays. I identified several novel CD4+ T cell epitopes within gE and gI and characterized the phenotype of gE DRB1*1501 tetramer specific responses in healthy immune donors. I then set out to investigate the function and phenotype of VZV specific T cells in primary infection and their relationship to viral loads and clinical disease severity by using glycoprotein E/DRB1*1501 specific MHC class II tetramers, ex vivo IFNγ ELISpot assays and quantitative real time PCR assays. I compared the frequency and phenotype of specific T cells with virological and clinical outcomes in 32 adult individuals with primary VZV infection. In healthy immune donors, the gE specific T cells showed a early intermediate stage of differentiation with evidence of recent activation. Patients with acute primary infection had higher VZV/DRB1*1501 tetramer specific T cell responses and expressed markers of activation and effector differentiation. Viral loads were found to be significantly higher in patients with moderate to severe infection compared to those with mild infection (p<0.001). A significant inverse correlation was seen between the viral loads and the ex vivo IFNγ ELISpot responses of the patients (p<0.05, r=-0.64). These data would be compatible with a role for gE and gl-specific T cells in the control of viral replication during both primary infection and re-activation.
43
Lu, Yu-Jung. "The Role of CD4 T Cell Help in Effective CD8 T Cell Responses during Mycobacterium Tuberculosis Infection." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1139.
Full textAbstract:
Tuberculosis (TB), a transmissible disease caused by Mycobacterium tuberculosis (Mtb), is a global health threat. To design an effective vaccine, we need to better understand how different elements of our immune system collaborate to fight against Mtb. CD4 T cells are crucial in protective immunity to Mtb because they produce cytokines including interferon-γ. In contrast, CD8 T cells are thought to play a modest role. Whether CD4 T cells act as “helper” cells to promote optimal CD8 T cell responses during TB is unknown. We argue CD8 T cells’ role are likely underestimated because CD8 T cell functions are compromised without CD4 T cells. Here, using two independent models, I show that CD4 T cell help promotes CD8 T cell effector functions and prevents CD8 T cell exhaustion. I demonstrate CD4 and CD8 T cells synergistically enhance the survival of infected mice. Purified helped, but not helpless, CD8 T cells effectively restrict intracellular Mtb growth. Thus, CD4 T cell help is indispensable for generating protective CD8 T cell responses. In addition, I investigate the mechanisms of CD4 T cell help. Signals from CD4 T cells, and signals relayed by antigen presenting cells collectively shape CD8 T cell responses. We infer that vaccines aimed for eliciting both CD4 and CD8 T cells, in which CD8 T cells are properly helped by CD4 T cells, are more likely to be successful.
44
Hall, Håkan. "T cell responses and NK cell function in experimental autoimmune diabetes /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-152-0/.
Full text
45
Benlahrech, Adel Ridha. "Activation of natural killer and cytotoxic T cell responses by dendritic cells in HIV-1 infection." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440445.
Full text
46
Wasser, Beatrice [Verfasser]. "Myeloid cells in the CNS counteract neuroinflammation via cellular responses to T cell infiltration / Beatrice Wasser." Mainz : Universitätsbibliothek Mainz, 2020. http://d-nb.info/1208881582/34.
Full text
47
Sircar, Piya. "Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses." Thesis, Harvard University, 2011. http://dissertations.umi.com/gsas.harvard:10035.
Full textAbstract:
CD8+ T cells responses are critical in the immune defense against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. A major challenge for vaccine development is that HIV/SIV can rapidly mutate to escape containment by the CD8+ T cell response. Therefore, optimal virus control by a vaccine will likely require clonally diverse CD8+ T cells capable of recognizing mutant viruses. Mucosal tissues play a fundamental role in early HIV/SIV pathogenesis by serving as the site for viral entry, CD4+ T cell depletion, and a reservoir for viral replication. Vaccine strategies that induce effective mucosal immunity will likely be critical for protection against HIV/SIV. We examined the SIV Gag p11C-specific CD8+ T cell responses in peripheral blood, gastrointestinal (GI) mucosal and lung mucosal tissues of rhesus monkeys expressing the MHC class I molecule Mamu-A*01. We first investigated the clonal composition of this cell population during the acute and chronic phases of SIVmac infection. We showed that there is a narrowing of the clonal repertoire from acute to chronic infection and the same clonal populations of virus-specific CD8+ T cells are present in the systemic and mucosal compartments of chronically SIV-infected animals. These data indicated that virus-specific CD8+ T cells establish broadly distributed immune responses. Next, we examined the clonal diversity of systemic and mucosal p11C-specific CD8+ T cells induced by prime-boost vaccination. We found that systemic prime-boost vaccination induced clonally diverse p11C-specific populations in mucosal tissues. There were high levels of clonal sharing between systemic and mucosal compartments soon after vaccination. However, later following vaccination there was decreased clonal sharing between the GI mucosa and the systemic circulation. We showed that this was due to limited trafficking of p11C-specific CD8+ T cells to the GI mucosa following vaccination. Overall, these studies indicate that following SIV infection and systemic vaccination the same p11C-specific clones are present in mucosal and systemic compartments. Moreover, the apparent immune compartmentalization is a consequence of differences in cell trafficking between systemic and mucosal CD8+ T cells. These observations have important implications for the design of HIV vaccines that generate effective mucosal immunity.
48
Fankhauser, Sarah Carmela. "Characterization of impaired CD8+ T cell responses to Chlamydia trachomatis." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11158.
Full textAbstract:
Chlamydia trachomatis infection is the most common bacterial sexually transmitted disease in the United States. Irregular screening to identify infected individuals and a lack of sterilizing immunity to C. trachomatis has led to a dramatic increase in the number of reported C. trachomatis infections over the last twenty years. Repeated infections with C. trachomatis lead to serious sequelae such as pelvic inflammatory disease and ectopic pregnancy, which can result in infertility.
49
Raymond, Meera V. "Early growth response gene-2 controls inflammatory responses of CD4+ T cells by negatively regulating Th17 differentiation." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8953.
Full textAbstract:
CD4+ T cells play a central role in controlling the adaptive immune response by secreting cytokines to control the responses of different lymphocytes. Naïve CD4+ T cells differentiate into at least four subsets, Th1, Th2, Th17, and inducible regulatory T cells under antigen and corresponding cytokine microenvironment during an immune response. Therefore, each subset has unique functions for pathogen elimination. The differentiation of these subsets is induced in response to conditioned cytokine stimulation, which induces specific master regulator transcription factors. Multiple other transcription factors, both subset specific and shared, are also involved in promoting subset differentiation. Previously, our group has discovered that early growth response gene-2 (Egr-2) is important for the maintenance of T cell homeostasis and controls the development of autoimmune disease. However, the underlying mechanisms are unknown. In this study, using Egr-2 conditional knockout mice, a novel mechanism of Egr-2 in the control of Th17 differentiation has been discovered. Egr-2 is induced by TGFβ and IL-6 in naïve CD4+ T cells. The induced Egr-2 negatively regulates the expression of IL-17, the signature cytokine for Th17. In contrast, Egr-2 has less effect on the expression of IL-2 or IFN-γ in effector T cells. In the absence of Egr-2, CD4+ T cells produce high levels of Th17 cytokines. Deletion of Egr-2 in T cells renders mice susceptible to EAE induction; a model for Th17 mediated autoimmune diseases. T cells lacking Egr-2 show increased propensity for Th17, but not Th1 or Th2, differentiation in vitro. The key mechanism of Egr-2 in regulation of Th17 differentiation is to inhibit the function of Batf for transactivation of IL-17 expression and promotion of Th17 differentiation. Egr-2 interacts with Batf in CD4+ T cells and suppresses its interaction with DNA sequences derived from the IL-17 promoter, while the activation of STAT3 and expression of RORγt is unchanged in Th17 cells in the absence of Egr-2. Thus, Egr- 14 2 plays an important role to intrinsically control Th17 differentiation. We also found that CD4+ T cells from multiple sclerosis (MS) patients have reduced expression of Egr-2 and increased expression of IL-17 following stimulation with anti-CD3 in vitro. Collectively, our results demonstrate that Egr-2 is an intrinsic regulator that controls Th17 differentiation by inhibiting Batf activation which may be important for the control of inflammatory autoimmune diseases.
50
Arima, Hiroshi. "B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T cell responses via IL-33." Kyoto University, 2019. http://hdl.handle.net/2433/236612.
Full text