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1
Soper, David Michael. "Interleukin-2 receptor and T cell receptor signaling in regulatory T cells /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8344.
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2
Carson, Bryan David. "Impaired T cell receptor signaling in regulatory T cells /". Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8337.
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3
Ebert, Lisa Michelle. "The regulation of chemokine receptor expression upon T lymphocyte activation". Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phe165.pdf.
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4
Parra, Eduardo. "Molecular basis for costimulation of human T lymphocytes". Lund : Lund University, 1998. http://books.google.com/books?id=SgFrAAAAMAAJ.
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5
Carlsson, Fredrik. "Antibody Feedback Regulation and T Cells". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7631.
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6
Tanaka, Yujiro. "Selection of T cells in the thymus". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294749.
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7
Chan, Ping-lung, e 陳秉隆. "Roles of TLR5 and ICOS on the human allogenic CD40-activated B cell-induced CD4hiCD25+ regulatory T cells". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47149735.
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8
Neeraj. "Studies on equine helper T cells and Fcγ receptors". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627077.
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9
Crocker, Glenn. "A study of surface receptors on rat T lymphocytes". Thesis, University of Oxford, 1991. http://ora.ox.ac.uk/objects/uuid:5c74a70b-1f5e-4c78-904f-7c4ff1b543a8.
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A double immunolabelling technique was developed to study microscopically the interactions between CD4, CD45 and the T cell receptor on the surface of rat T cells induced by the phenomenon of co-capping. It was found that both CD4 and CD45 passively co-cap with the actively capped T cell receptor, that the T cell receptor and CD45 passively co-cap with CD4, but that neither CD4 nor the T cell receptor co-cap with CD45. Co-crosslinking and active capping of CD45 with either the T cell receptor or CD4 prevented CD4 or the T cell receptor respectively, from passively co-capping. These experiments were extended to study the effects of particular antibody crosslinking conditions on T cell proliferation and tyrosine phosphorylation. A correlation was found to exist between receptor distribution and the effects of particular antibody combinations on proliferation and tyrosine phosphorylation. The significance of this with respect to T cell activation is discussed. Finally, an observation is reported concerning the failure of some cell lines to cap antibody-crosslinked surface molecules. Preliminary investgations into the nature and extent of the phenomenon are described.
10
Jiang, Ning. "Kinetic analysis of Fcγ receptor and T cell receptor interacting with respective ligands". Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/26716.
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Low affinity Fcg receptor III (FcgRIII, CD16) triggers a variety of cellular events upon binding to the Fc portion of IgG. A real-time flow cytometry method was developed to measure the affinity and kinetics of such low affinity receptor/ligand interactions, which was shown as an easily operated yet powerful tool. Results revealed an unusual temperature dependence of reverse rate of CD16aTM dissociating from IgG. Except for a few studies using mammalian cell CD16s, most kinetics analyses use purified aglycosylated extracellular portion of the molecules, making it impossible to assess the importance of the receptor anchor and glycosylation on ligand binding. We used a micropipette adhesion frequency assay to demonstrate that the anchor length affects the forward rate and affinity of CD16s for IgG in a species specific manner, most likely through conformational changes. Receptor glycosylation dramatically reduced ligand binding by 100 folds. T cell receptor (TCR) is arguably the most important receptor in the adaptive human immune system. Together with coreceptor CD4 or CD8, TCR can discriminate different antigen peptides complexed with major histocompatibility complex (MHC) molecule (pMHC), which differ by as few as only one amino acid, and trigger different T cell responses. When T cell signaling was suppressed, TCR had similar affinity and kinetics for agonist and antagonist pMHC whose binding to CD8 was undetectable. TCR on activated T cell had a higher affinity for pMHCs, suggesting that TCRs organize themselves differently on activated T cells than on naïve T cells. In the absence of inhibitors for signaling, TCR binds agonist pMHC with several orders of magnitude higher affinity than antagonist pMHC. In addition, engagement of TCR by pMHC signals an upregulation of CD8 binding to pMHC, which is much stronger than the TCR-pMHC binding. The transition from weak TCR binding to the strong CD8 binding takes place around 0.75 second after TCR in contact with pMHC and can be reduced by several inhibitors of tyrosine and lipid phosphorylation, membrane rafts, and actin cytoskeleton. These results provide new insights to understanding T cell discrimination.
11
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.
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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.
12
Wang, Aibo. "Phosphorylation of Nur77 by MEK-ERK-RSK cascade induces mitochondrial translocation and apoptosis in T cells". Amherst, Mass. : University of Massachusetts Amherst, 2009. http://scholarworks.umass.edu/dissertations/AAI3372283/.
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13
Cowan, Teresa. "The TCRBJ and TCRBV repertoire in naive and memory human T-cells". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ34173.pdf.
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14
Sandalova, Elena. "Regulation of the pro-apoptotic protein bim by T cell receptor triggering in human T cells /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-041-1/.
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15
Morrison, Vicky L. "Innate and cognate roles of B cells in T cell differentiation and memory". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/4873.
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B cells recognise antigens on micro-organisms through their B cell receptor (BCR) and via Toll-like receptors (TLRs), and thus respond in both innate and adaptive manners during the subsequent immune response. Innate recognition through TLRs has the potential to alter the behaviour of whole B cell populations. I show, here, that MyD88-dependent activation of B cells via TLR2 or TLR9 causes the rapid loss of expression of CD62L, by metalloproteinasedependent shedding, resulting in the exclusion of these cells from lymph nodes and Peyer’s patches, but not the spleen. Moreover, systemic infection with Salmonella typhimurium causes shedding of CD62L and the subsequent focussing of B cell migration to the spleen. I reveal that splenic B cells undergo further changes during S. typhimurium infection, including TLR-dependent differentiation of marginal zone B cells into IgM-secreting plasma cells. Together, these TLR-mediated alterations to B cells are likely to influence the development of immunity to pathogens carrying the appropriate ligands. In addition to these innate responses of B cells, endocytosis of cognate antigen through their BCR allows antigen presentation. This, together with their ability to secrete cytokines, means they have the potential to drive T helper cell responses. I investigate the role of B cells in such CD4+ T cell responses by following antigen-specific T cells in vivo, using both a peptide immunisation strategy and the S. typhimurium infection model. I use anti-CD20 B cell depletion antibodies to deplete B cells at various stages of the immune response, and analyse the effects on T follicular helper and memory cell populations. I show that both the generation and maintenance of T follicular helper cells is dependent on the presence of B cells. Furthermore, I demonstrate that B cells are necessary very early in immune responses, during the first 10 days, for efficient generation of memory T cells.
16
Vessey, S. J. R. "A molecular analysis of the T-cell receptor". Thesis, University of Oxford, 1997. http://ora.ox.ac.uk/objects/uuid:87b560f9-b1d6-4b12-9c94-fd1b4de397f6.
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The recognition of MHC-peptide ligands by the T cell receptor (TCR) is central to the induction of the adaptive immune response. This thesis describes the development of a bioassay for TCR recognition which was then used to undertake a molecular analysis of the TCR/MHC-peptide interaction. 1. A TCR-CD3ϛ chimeric receptor was stably expressed in the cell line RBL-2H3 to give the transfectant RBL-008. RBL-008 was shown to exhibit MHC-restricted peptide-specific responses to both cellular and multimerised recombinant HLA-A2-pol peptide targets (Chapter 3). 2. By competitively inhibiting the response of RBL-008 to HLAA2 pol complexes with monovalent soluble recombinant MHCpeptide complexes it was confirmed that the TCR makes significant contact with both the MHC and peptide parts of its ligand. Furthermore it was found that only a few peptides in a random mixture can prevent contact between the TCR and HLA-A2. This has implications for positive selection since it supports evidence suggesting that some TCRs can be selected on a wide range of unrelated peptides (Chapter 4). 2. The bioassay was used to examine the flexibility of TCRpeptide interactions using a panel of variant peptides designed on the basis of the previously published HLA-A2-pol peptide structure (Chapter 5). Several variant peptides were recognised by the TCR and interestingly one of these altered peptide ligands was actually recognised better than the index peptide, raising the prospect of designing 'improved epitopes'. 3. By mutating the β chain of TCR-CD3ϛ chimeric receptor it was shown that allelic variation in the TCR genes can have a significant effect on antigen recognition and may therefore be disease susceptibility candidates genes (Chapter 6). 4. The structural relationship between the V and C domains of the TCR was examined and found to be of considerable functional significance since disruption of this relationship resulted in loss of expression of the TCR-CD3ϛ receptor.
17
Gray, Daniel Herbert Donald. "Thymic stromal cells : population dynamics and their role in thymopoiesis". Monash University, Dept. of Pathology and Immunity, 2003. http://arrow.monash.edu.au/hdl/1959.1/9409.
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18
Wallace, Zoë R. "Application of engineered T cell receptors to investigate the failure of cytotoxic T lymphocytes to eliminate the HIV reservoir". Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:a7b1d93d-2637-4197-b18a-726d96352043.
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HIV establishes a reservoir comprising long lived, latently infected CD4+ T cells and monocytic cells early during primary infection. This population represents a major barrier to an HIV cure. This thesis aimed to investigate the role of the immunological synapse in the failure of cytotoxic T lymphocytes (CTLs) to eliminate the HIV reservoir and the potential for engineered bispecific Immune-mobilising monoclonal T cell receptors Against Viruses (ImmTAV) to overcome this by redirecting fully functional CD8+ T cells against viral targets. A primary cell model of latency was used to investigate the expression of HIV Gag on latently infected cells and their susceptibility to ImmTAV-mediated elimination. A subset of cells expressed low levels of Gag without spreading infection and ImmTAV-redirected healthy donor CD8+ T cells were able to eliminate up to 40% of infected cells without latency reversal. CD8+ T cells from chronic HIV infected (CHI) donors showed impaired antiviral activity even with ImmTAV redirection. To investigate this further, confocal microscopy was used to study immunological synapse formation using primary CD8+ T cells from HIV-negative and CHI donors. CD8+ T cells from CHI donors were able to form conjugates with virus-infected cells but exhibited impaired synapse maturation, indicated by reduced Zap70 localisation, delayed microtubule-organising centre polarisation and impaired perforin recruitment to the synapse. ImmTAV redirection partially overcame these defects. Finally, the impact of antiretroviral agents on T cell mitochondrial function was explored. Exposure to zidovudine increased mitochondrial reactive oxygen species production and susceptibility to apoptosis. However, there was no evidence of impaired mitophagy. These data show that defects in CD4+/CD8+ T cell synapse maturation contribute to HIV persistence but nevertheless suggest that a subset of HIV reservoir cells may be susceptible to ImmTAV-mediated elimination. The therapeutic potential of ImmTAVs may depend in part on correction of CD8+ T cell exhaustion.
19
Kwong, Pearl Chu. "Characterization of an antigen-specific T helper cell clone and its products". Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27366.
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A T helper cell clone, referred to as clone 9, was derived from an allogeneic mixed lymphocyte culture. Clone 9, as well as supernatant factor(s) derived from it, could help the cytotoxic T lymphocyte (CTL) responses of H-2 Db (Db) responder cells to alloantigens, or they could help the CTL responses of non- Db responder cells to Db alloantigens. Clone 9 cells or their factor(s) were active only when added during the first 24 hours of a five-day culture period. Clone 9 or its factor(s) could also synergize with interleukin-2 (IL-2)-containing medium in mounting cytotoxic responses to alloantigens. The helper activity in clone 9 supernatant was not due to IL-2 and it was specifically absorbed out by Db -spleen cells. The characterization of the Db -specific helper factor(ASHF) was facilitated by the isolation of a T hybridoma clone (clone 25), obtained from fusion of clone 9 cells with the T cell lymphoma, BW5147, and a B cell hybridoma that produced an IgM monoclonal antibody (clone 30 IgM) which bound ASHF. An additional monoclonal antibody (F23.1), which recognizes a
determinant of the Vβ8 family of the T cell receptor, was also particularly useful for the
characterization of ASHF. Analysis with these reagents showed that both clone 30 IgM and F23.1 immunoadsorbents could retain ASHF activity. Preabsorption of the ASHF with Db spleen cells prior to affinity purification over a clone 30 IgM column resulted in the absorption of Db-specific helper activity as well as the loss of a 50,000 molecular weight (MW) band on SDS-PAGE under reducing conditions. Furthermore, affinity purification of ASHF over the F23.1 immunoadsorbent, but not an irrelevant monoclonal antibody (mAb) column, also yielded a 50,000 MW molecule. Taken together, these findings suggest that the 50,000 MW molecule is a component of the ASHF and it is intimately related to the B chain of the T-cell receptor.
The mode of action of clone 9 and its products in the induction bfCTL responses was also investigated. It was found that clone 9 and ASHF could help CTL responses by inducing IL-2 production in B6-stimulated cultures. In addition to ASHF, clone 9 cells also produced an additional factor(s) which participated in the induction of CTL responses. This additional factor(s) was referred to as IL-X. IL-X synergized with excess human recombinant IL-2 in the activation of CTL precursors (CTL-P) in the absence of antigenic stimulation. A model which involves the participation of ASHF, T helper cells, IL-2 and IL-X in the induction of CTL responses is proposed.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
20
Galperin, Moran. "Molecular and functional characterization of high avidity T cell receptors preferentially expressed by HIV-specific CD4 + T cells from HIV controllers". Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC251.
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Les « HIV controllers » (HICS) sont de rares patients qui contrôlent spontanément la réplication du VIH en absence de thérapie antirétrovirale. Ces patients sont caractérisés par un taux normal de Cellules T CD4+ et le maintien d'une charge virale indétectable (< 50 copies d'ARN viral / ml de plasma), et montrent un très faible risque de progression vers le sida, de nombreux travaux suggèrent que le contrôle de la réplication virale chez ces patients est dû à une réponse cellulaire antivirale. Particulièrement efficace, notre équipe a montré que ces hics maintiennent des réponses T CD4+ très sensibles, associées à l'expression de TCRS ayant une forte avidité pour certains peptides gag du VIH. Il a été montré en particulier que les cellules T CD4+ de hics répondent à de très faibles concentrations de l'épitope immunodominant GAG293. Dans une première étude, nous avons montré que les cellules T CD4+ des hics maintiennent une population de cellules effectrices de type THI, caractérisées par une production importante d'IFN gamma et du marqueur de dégranulation CD107a en réponse à une stimulation par GAG293, notamment, ces réponses TH1 effectrices persistent malgré la faible quantité d'antigènes viraux présents dans l'organisme des hics. Par contre, les patients traités voient leurs réponses T CD4+ effectrices décroître avec le temps suite à une inhibition par l'IL-10, ce qui suggère la persistance d'une immunosuppression. Malgré la thérapie antirétrovirale prolongée (> 10 ans), la persistance de réponses effectrices T CD4+efficaces malgré une faible virémie pourrait s'expliquer par la présence de cellules T CD4+ de haute avidité chez les hics. Ces résultats nous ont conduit à explorer les niveaux d'expression de T-BET dans les cellules de hics ex vivo, car ce facteur de transcription est critique pour la différenciation des T CD4+ naïves en cellules de type THI. Les niveaux d'expression de T-BET se sont révélés supérieurs chez les cellules TCD4+ des hics par rapport aux cellules issues de donneurs sains. Néanmoins, nous n'avons pas détecté une augmentation de l'expression de T-BET dans les cellules T CD4+ des hics par rapport à celles des patients traités. La possibilité que l'expression de T-BET diffère dans les cellules T CD4+ spécifiques du VIH chez les HICS et chez les patients traités reste à être explorée. La réponse de haute avidité observée pour les cellules T CD4+ des HICS semble s'expliquer par une propriété intrinsèque de leur TCR, en effet, les tétramères de molécules CMH II chargés en peptide GAG293 lient plus efficacement les TCR présents à la surface des cellules T CD4+ + des HICS que celles des patients traités, indiquant une différence dans l'avidité intrinsèque des TCRS, pour identifier les déterminants moléculaires qui sous-tendent cette réponse de haute avidité, nous avons caractérisé le répertoire TCR des cellules T CD4+ spécifiques de l'épitope immunodominant GAG293, les HICS ont montré un répertoire TCR hautement biaisé, caractérisé par une expression préférentielle des chaînes TCR TRAV24 et TRBV2, la présence de motifs conservés au sein des régions CDR3 de ces deux chaînes, et une prévalence élevée de clonotypes publics (n"18 pour chaque chaine de TCR). Les clonotypes publics les plus représentés ont été capables de générer des TCR fonctionnels ayant de affinité de l'ordre du micromolaire pour le complexe PCMH II, ce qui est remarquablement élevé pour les TCRS restreints par le CMH II. Nous avons montré que les TCR de haute affinité spécifiques pour GAG293 sont capables de reconnaitre jusqu'à 5 allèles différents de HLA-DR, de plus, après transduction à l'aide de lentivecteurs, ces TCR ont conféré une réponse spécifique à GAG293 très sensible et polyfonctionnelle aux cellules T CD4+ primaires. Par ailleurs, l'expression de ces TCR dans des cellules T CDS+ leur a permis de répondre à GAG293, malgré l'absence du corécepteur CD4, ces résultats suggèrent que des clonotypes publics ayant une fonctionnalité plus efficace sont impliqués dans le contrôle de l'infection par le VIH. Le transfert de ces TCR dans des cellules hétérologues pourraient contribuer au développement de nouvelles approches immunothérapeutiques contre le VIHHIV controllers are rare individuals who spontaneously control HIV replication without the need for therapeutic intervention, these patients are characterized by normal CD4+ T cell counts and viral loads, which remain below the limit of detection (<50 RNA copies per milliliter plasma) for extended periods of time, importantly, HIV controllers very rarely progress to aids, accumulating evidence suggests that control of viral replication in these patients is mediated by a particularly efficient cellular immune response. Indeed, our team previously reported that HIV controllers maintain a population of specific CD4+ T cells of high functional avidity, these cells were shown to produce IFN gamma in response to minimal amounts of the immunodominant GAG293 peptide. In a first study, we have shown that HIV controller CD4+ T cells maintain a population of highly efficient effector cells, which are characterized by increased production of IFN gamma and the degranulation marker CD107A in response to stimulation with GAG293, notably, these THI responses persisted in HIV controllers despite the minimal amount of viral antigens available to induce such responses, in contrast, CD4+ T cells from treated patients showed increased expression of IL-10, indicating negative immunoregulation after long-term antiretroviral therapy, the persistence of efficient CD4+ T effector responses in spite of low antigenemia may be explained by the presence of high avidity CD4+ T cells in HIV controllers. These findings prompted us to explore the ex vivo expression patterns of T-BET, which is a key transcription factor driving the differentiation towards THI lineage, T-BET expression levels were higher in HIV controllers compared with healthy blood donors, However, we did not detect Increased T-BET expression in controller CD4+ T cells compared to patients receiving highly active antiretroviral therapy (haart), the possibility that T-BET expression differs in the HIV -specific CD4+ T cells of controllers and treated patients remains to be tested. The high functional avidity observed in controller CD4+ T cells could be explained by an intrinsic property of their t cell receptors (TCRS), which efficiently round GAG293-loaded MHC class-II tetramers, to identify the molecular determinants underlying this hight avidity response, we characterized the TCR repertoire directed at the immunodominant capsid epitope, GAG293. HIV controllers showed a highly skewed repertoire characterized by a predominance of the TRAV24 and TRBV2 variable gene families, the presence of conserved motifs in both CDR3 regions, and a high prevalence of public clonotypes (N=18 for each TCR chain), the most prevalent public clonotypes generated TCR with affinities in the micro-molar range, at the high end of values reported for naturally occurring TCRS, the high-affinity GAG293-specific TCRS conferred broad HLA 11 cross-restriction, with up to 5 HLA-DR alleles recognized, high antigen sensitivity, and polyfunctionalityTo primary CD4+ T cells, in addition, CD8+ T cells could be redirected to target the conserved capsid major homology region by expressing a high-affinity GAG293-specific TCR, these findings indicate that TCR clonotypes with superior functions are associated with HIV control, amplifying or transferring such clonotypes may contribute to immunotherapeutic approaches that aim at a functional HIV cure
21
Wong, Yin-ling. "The effects of respiratory syncytial virus on alveolar epithelial cells toll-like receptors expressions and T cell apoptosis". Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B4218230X.
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Sáez, Borderias Andrea. "Regulation of natural killer and cd4+T cell function by NKG2 C-type lectin-like receptors". Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/7133.
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This work is centered on the study of the NKG2 C-type lectin-like receptors on NK and CD4+T cells. We provide evidence supporting that CD4+T cells specific for Human Cytomegalovirus (HCMV) may express different NK cell receptors, and demonstrate that the C-type lectin-like receptor NKG2D is expressed on cytotoxic CD4+T cells with an effector/memory phenotype, enhancing their TCR-dependent proliferation and cytokine production. A second part of the work is centered on the study of the CD94/NKG2 receptors on NK cells. We show that NKG2A can be induced on NKG2C+ NK cells upon activation with rIL-12 or when cocultured with HCMV-infected dendritic cells, and that NKG2A expression inhibits the response of NKG2C+NK clones against HLA-E-expressing targets, providing a potential regulatory feedback mechanism to control cell activation. Altogether, our results support that expression of NKG2 C-type lectin like receptors may be shaped during the course of viral infections, providing mechanisms to finely regulate both NK and CD4+T cell functions.Aquesta tesi es centra en l'estudi dels receptors lectina de tipus C NKG2 en cèl·lules Natural Killer i T CD4+. Demostrem que les cèl·lules T CD4+ específiques pel Cytomegalovirus Humà poden expressar diferents receptors NK, i que el receptor lectina tipus C NKG2D s'expressa en cèl·lules citotòxiques i de memòria, potenciant la proliferació i secreció de citocines depenent del TCR. La segona part d'aquesta tesi es centra en l'estudi de l'expressió dels receptors CD94/NKG2 en cèl·lules NK. Mostrem com l'expressió de CD94/NKG2A s'indueix en cèl·lules CD94/NKG2C+ estimulades amb IL-12 o cultivades amb cèl·lules dendrítiques infectades pel Cytomegalovirus Humà, i que l'expressió de CD94/NKG2A inhibeix la resposta de clons NK CD94/NKG2C+ envers dianes HLA-E+, constituint un possible mecanisme de feedback negatiu per controlar l'activació cel·lular. En resum, els nostres resultats demostren que l'expressió dels receptors lectina tipus C NKG2 pot ser modificada durant les infeccions víriques consitutint un possible mecanisme per regular la resposta tant de cèl·lules NK com T CD4+.
23
Goldrath, Ananda W. "T cell homeostasis : a role for specific peptide/MHC ligands in homeostasis driven proliferation of naive CD8⁺ T cells /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/8332.
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Khan, Nouman Ullah. "The effect of chemokines on T regulatory cells following heart transplantation". Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/the-effect-of-chemokines-on-t-regulatory-cellsfollowing-heart-transplantation(6b5b194d-f2fd-4869-9b22-95ce099ac3ed).html.
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Heart transplantation (HTx) is now an established therapy for end-stage cardiac failure not responding to medical treatment. Recent decades have seen improved outcome following HTx due to more effective and targeted immunosuppressive therapy. However, acute and chronic rejection remains a major cause of morbidity and mortality. At the same time, immunosuppressive strategies are associated with significant side effects, including development of tumours. Hence, the induction of immunologic tolerance to alloantigen is considered the “holy grail” of transplant research. T regulatory cells (Tregs) are a subset of T cells that appear to suppresscytotoxic cell and initiate tolerance to foreign tissues. The Tregs suppresscytotoxic cells through specific cytokine pathways and cell-cell contact. In-vivo T reg migration has been a matter of debate in recent years. Treg trafficking is governed by chemokines, which are small secreted proteins, acting via their distinct trans-membrane serpentine receptors. Experimental work has demonstrated an involvement of distinct chemokine pathways in Tregs migration and localization following cardiac transplantation; however, there is paucity of data in humans. I investigated the effects of chemokines on Tregs in heart transplant recipients through a series of observational studies. My study demonstrated that acute rejection following heart transplantation is associated with a significant elevation of peripheral blood Th1 chemokine levels. I hereby further show that peripheral blood Treg counts in stable heart transplant recipients are not affected by immunosuppression but are significantly lower in patients taking statins. I have demonstrated via in-vitro chemotaxis assays a specific pattern of chemotactic response for Tregs and the effector T cells. Using double immunofluorescence staining and immunostaining, I show for the first time that Tregs may migrate to the allograft under the influence of CCL17.
25
Bento, Rui Pedro Garcia de Oliveira. "CAR-modified T cells targeted to CD19 antigen for lymphocytic leukemia". Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13445.
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Mestrado em Biomedicina FarmacêuticaCellular immunotherapies, or Advanced Therapy Medicinal Products (ATMPs), are emerging as novel and specific therapeutic approaches to treat diseases, such as certain types of leukemias, which are difficult or impossible to treat with today’s biopharmaceutical products. Breakthroughs in basic, preclinical, and clinical science spanning cellular immunology, and cellprocessing technologies has allowed clinical applications of chimeric antigen receptor–based therapies. A recent example is CTL019, a lentivirus-based gene therapy for autologous T cells, acquired by Novartis in 2012 through a global alliance with the University of Pennsylvania. Although this technology is still in its infancy, clinical trials have already shown clinically significant antitumor activity in chronic lymphocytic leukemia and acute lymphocytic leukemia. Trials targeting a variety of other adult and pediatric malignancies are under way. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer. The regulatory environment for these Advanced Therapies Medicinal Products is complex and in constant evolution. Many challenges lie ahead in terms of manufacturing process, non-conventional supply chain logistics, business models, intellectual property, funding and patient access.
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Wong, Yin-ling, e 王燕玲. "The effects of respiratory syncytial virus on alveolar epithelial cells toll-like receptors expressions and T cell apoptosis". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B4218230X.
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Lee, James C. "Inventing New CARs: Analysis of Chimeric Antigen Receptor Gene-Targeted T cells Modified to Overcome Regulatory T cell Suppression in the Tumor Microenvironment". Yale University, 2009. http://ymtdl.med.yale.edu/theses/available/etd-03052009-202819/.
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Human T cells may be genetically modified to express targeted chimeric antigen receptors (CARs). We have previously demonstrated that T cells modified to express a CAR specific to the B cell tumor antigen CD19, termed 19-28z, successfully eradicate systemic human CD19+ tumors in SCID-Beige mice. While these results are encouraging, this xenogeneic tumor model fails to address potential limitations of this therapeutic approach in the clinical setting wherein these modified T cells encounter a hostile tumor microenvironment. Specifically, these models fail to address potential effector T cell inhibition mediated by endogenous regulatory T cells (Tregs). To investigate the role of inhibitory Tregs, we initially assessed the in vitro function of CAR-modified T cells in the context of Tregs. We found that CD19-targeted T cell proliferation and cytotoxicity were inhibited by purified natural Tregs. To further assess the role of these Tregs in vivo, we isolated and genetically modified Tregs to express the CD19-targeted 19z1 CAR. We verified specific trafficking of targeted Tregs to CD19+ tumors in vivo, and demonstrate that 19z1 Tregs wholly inhibit anti-tumor function of subsequently injected 19-28z effector T cells even at low Treg to effector T cell ratios (1:8). In order to overcome this limitation, we assessed whether the addition of a pro-inflammatory cytokine in vitro could overcome Treg inhibition. Indeed, the addition of exogenous IL-12 mediated resistance of 19-28z T cells to Treg inhibition. In light of this data we generated a bicistronic retroviral vector containing both the 19-28z CAR as well as the murine IL-12 fusion gene (19-28z IRES IL-12). Significantly, we found that 19-28z/IL-12+ T cells when compared to 19-28z+ T cells exhibited enhanced proliferation in vitro as well as resistance to Treg mediated inhibition. Finally, we demonstrate that 19-28z/IL-12+ T cells overcome Treg inhibition in vivo in our SCID-Beige Treg tumor model. In conclusion, tumor targeted T cells modified to express IL-12 demonstrate significantly enhanced in vivo anti-tumor efficacy in the presence of Tregs that are similarly targeted to the site of tumor. These results validate utilization of IL-12 secreting tumor targeted T cells in future clinical trials.
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Edmunds, Catherine. "A study of PI3K regulation by costimulatory and inhibitory receptors in T and B lymphocytes". Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341105.
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Asad, Suzanne. "Expression of Trafficking Receptors by Regulatory T Cells in Human Health and Autoimmune Disease". Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16442.
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Abnormalities in CD4+CD25+CD127loFoxP3+ regulatory T cells (Tregs) have been implicated in susceptibility to autoimmune disease. To define migratory Treg subsets that may be implicated in the pathogenesis of diseases manifested in different tissues, we designed 11 and 13 colour flow-cytometry panels to measure the expression of a range of chemokine receptors and integrins on Tregs in the peripheral blood (PB) of healthy individuals (n=44) and patients with rheumatoid arthritis (RA) (n=34) or psoriasis (n=44). We showed that CLA, CCR4, CCR5, CCR6, CCR10 and CD62L were expressed on a higher proportion of CD4+CD25+CD127lo Tregs than conventional CD4+ T cells (Tconvs) in healthy adults. A significantly lower proportion of Tregs expressed the gut homing α4 (CD49d) and β7 when compared to Tregs that expressed the skin homing CLA, CCR4 and CCR10. Furthermore, the skin homing receptors, CLA, CCR4 and CCR10, were expressed on a much higher proportion of Tregs than Tconvs. We used flow cytometry to analyse the levels of CXCR3+, CCR4+, CCR5+ and CCR6+ Tregs in the PB of RA patients. RA patients had significantly reduced levels of effector/memory Tregs in their PB. We also found a significantly reduced frequency of effector/memory Tregs expressing each of the chemokine receptors examined in the PB of RA patients. This could indicate a trafficking deficiency, resulting in less Tregs entering the joints and a consequent disruption of immune homeostasis at the site. We examined the levels of β7+, CD49d+, CLA+, CCR4+, CCR10+, CCR5+, CD62L+, CXCR3+ and CCR6+ Tregs in the PB of psoriasis patients. We found Treg frequency to be increased in the PB of untreated psoriasis patients. However, the frequency of effector/memory Tregs expressing CXCR3 and CCR6 was significantly reduced in the PB of these patients. CXCR3+ and CCR6+ Tregs are known to be crucial to regulating Th1 and Th17 type immune responses, which are both involved in the pathogenesis of psoriasis. Therefore a reduction in iv CXCR3 and CCR6 expression on Tregs could indicate a trafficking deficiency resulting in less Treg entry into psoriatic lesions. We used bioinformatic tools to analyse all flow cytometry data obtained from patients and controls. We hope these methods of analysis will facilitate the uptake of flow cytometry in detecting preclinical disease or selecting patients for optimal treatment.
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Iaboni, Andrea. "An evolutionary and functional analysis of the extended B7 family of costimulatory molecules". Thesis, University of Oxford, 2002. http://ora.ox.ac.uk/objects/uuid:e769d4ab-81c9-4f92-918f-8ddfb718b596.
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Teixeira, de Matos Cristina. "Modulation of natural killer cell and T-cell functions by CD94/NKG2A receptors /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-846-0/.
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DeVault, Victoria. "Regulation Of Natural Killer T Cell Subset Development And Function By Slam Family Receptors". ScholarWorks @ UVM, 2019. https://scholarworks.uvm.edu/graddis/990.
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Semi-invariant natural killer T (iNKT) cells are critical components of the host immune response in peripheral tissues such as the lung, liver, and gut, and they play important roles in cancer, bacterial infections, autoimmunity, wound repair, and atherosclerosis. Tissue-resident iNKT cells exert their effects early in the developing immune response by rapidly producing a wide variety of cytokines and chemokines, and it was recently discovered that different tissues possess iNKT cell subsets that preferentially produce IFN-γ (NKT1), IL-4 (NKT2), or IL-17 (NKT17). Despite their critical role in the immune response, the mechanisms that regulate iNKT cell function in the periphery remain unclear. Signaling lymphocyte activation marker (SLAM) proteins are cell surface-expressed molecular switches that are expressed on all hematopoietic cells. The nine SLAM family receptors serve a variety of functions including promotion of cell-cell adhesion, regulation of cytokine production, co-stimulation, and inhibition. Importantly, SLAM family receptors are critical for the development of iNKT cells. Yet, numerous efforts to ascribe discrete roles of SLAM family receptors in iNKT cell function has proven difficult.
We conducted a comprehensive analysis of SLAM family receptor co-expression on iNKT cell subsets in the lung, spleen, liver, and thymus and identified co-expression profiles that varied in a tissue and strain-dependent manner. Interestingly, we found that SLAM family receptor expression profiles varied among different iNKT cell subsets. In particular, we noted a close association of SLAMf6 expression with the NKT2 and NKT17 subsets in both the periphery and in the thymus. Further investigation using SLAMf6-deficient mice revealed a critical role for SLAMf6 in NKT2 and NKT17 subset development, and in iNKT IL-4 and IL-17 cytokine production in the periphery. This investigation also revealed that the SLAMf6high NKT2 and NKT17 subsets exhibited significantly higher proliferative capacity than the NKT1 subset and the NKT2 and NKT17 proliferation was dependent, in part, on SLAMf6 expression.
Since Slam family genes are highly polymorphic, we next investigated whether these polymorphisms regulated iNKT function. We employed a B6.129 congenic mouse exhibiting impaired NKT cell function, in which a 6.6 Mbp 129/SvJ locus encompassing Slam genes was introgressed onto the C57BL/6 background. To test the hypothesis that Slam gene polymorphisms regulate iNKT cell function, we refined this genetic interval by generating B6.129 subcongenic lines and assessing iNKT cell function. Unexpectedly, we found that while Slam gene polymorphisms in this model do regulate iNKT cell function, the dominant regulator was in a 0.14 Mbp interval centromeric to the Slam genes. Further experimentation revealed that impaired iNKT cell development and function was associated with changes in the expression of Fcgr3 (Fc gamma receptor III) on iNKT cells, suggesting it as a novel candidate gene regulating iNKT cell function.
Taken together, these data reveal for the first time a specific role for SLAMf6 on NKT2 and NKT17 subset development and function. In addition, these data identify Fcgr3 as a novel candidate gene that regulates iNKT cell subset development and cytokine production. Cumulatively, these data reveal the presence of discrete regulatory mechanisms at work in different iNKT subsets, a finding that has broad implications for our understanding of iNKT-cell mediated immunity.
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Karlsson, Hannah. "CD19-targeting CAR T Cells for Treatment of B Cell Malignancies : From Bench to Bedside". Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-232638.
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Immunotherapy for cancer is a young research field progressing at high speed. The first chimera of an antibody and a signaling chain was designed by Zelig Eshhar and was later further developed to enhance existing T cell therapy by combining a single-chain fragment of an antibody with the CD3 zeta chain of the TCR complex. T cells expressing these chimeric antigen receptors (CARs) could recognize and specifically kill tumor cells. However the T cells, lacked in persistence and tumor rejection did not occur. Thus, the CAR constructs have been improved by providing the T cell with costimulatory signals promoting activation. The focus of this thesis has been to evaluate second and third generation αCD19-CAR T cells for the treatment of B cell leukemia and lymphoma. B cell tumors commonly upregulate anti-apoptotic proteins such as Bcl-2, which generates therapy resistance. In the first paper a second generation (2G) αCD19-CD28-CAR T cell was combined with the Bcl-2 family inhibitor ABT-737. ABT-737 sensitized tumor cells to CAR T cell therapy and may be an interesting clinical combination treatment. In paper II, the phenotype and function of a third generation (3G) αCD19-CD28-4-1BB-CAR T cell were evaluated. B cell-stimulated CAR T cells showed increased proliferation and an antigen-driven accumulation of CAR+ T cells. 3G CAR T cells had equal cytotoxic capacity, similar lineage, memory and exhaustion profile phenotype compared to 2G CARs. However, 3G CAR T cells proliferated better and had increased activation of intracellular signaling pathways compared to 2G CAR T cells. In paper III, αCD19-CD28-4-1BB-CAR T cells were used to stimulate immature dendritic cells leading to an upregulation of maturation markers on co-cultured dendritic cells. Hence, CAR T cells may not only directly kill the tumor cells, but may induce bystander immunity that indirectly aids tumor control. This thesis also include supplementary information about the development and implementation of protocols for GMP production of CAR T cell batches for a phase I/IIa clinical trial currently ongoing for patients with refractory B cell leukemia and lymphoma. So far, two patients have safely been treated on the lowest dose.
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Hossain, Md Kamal. "Targeting Fc Receptors for More Effective Cancer Vaccines". University of Toledo Health Science Campus / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=mco1544800037742347.
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Simmons, Daimon P. "Effects of Toll-Like Receptors and Type I Interferon on Dendritic Cell Maturation and Activation of T Cells". Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1311278278.
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Dossett, Michelle Leigh. "Generation and expression of high affinity, tumor antigen-specific mouse and human T cell receptors to genetically modify CD8⁺ T cells for adoptive immunotherapy of cancer /". Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8316.
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Nikitin, Artemii. "Role of nuclear receptor RORα in regulatory T cells". Thesis, Université de Lille (2018-2021), 2019. http://www.theses.fr/2019LILUS073.
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Les facteurs de transcription de la superfamille des récepteurs nucléaires jouent de multiples rôles dans le développement et la fonction des lymphocytes T régulateurs (TREG). Les TREG sont des cellules régulatrices/suppressives qui contrôlent les réponses d’autres types cellulaires et l’homéostasie locale des tissus.Comme les TREG sont actives au sein de divers organes, tant à l’homéostasie qu’en conditions inflammatoires,ils doivent répondre à la fois aux contexte local au sein du tissus et à un environnement immunologiquement agressif tout en préservant leurs propriétés tolérogéniques au cours du temps. Ces caractéristiques apparemment antinomiques sont contrôlées par un réseau transcriptionnel complexe au sein duquel le facteur de transcription FOXP3 joue un rôle prédominant. Au cours des dernières années, de nombreuses études se sont intéressées aux TREG présent dans les tissus non lymphoïdes (NLT). Ces populations ont été étudiées aussi bien à l’homéostasie qu’en conditions inflammatoires dans diverses pathologies. Des facteurs de transcriptions spécifiques d’un tissus ou d’une fonction déterminées ont été mis en évidence et leur rôle régulateur dans le développement, l’activation, la migration et l’immunosuppression a été caractérisé. RORa est un récepteur nucléaire qui contrôle le développement cérebellaire et hépatique, le métabolisme systémique, la différenciation des lymphocytes auxiliaires TH17, des cellules lymphoïdes innées (ILC) de type 2 et 3. RORa est fortement exprimé dans les TREG des NLT, y compris dans le tissus adipeux viscéral (VAT), l’intestin et la peau. . . .Ces populations de TREG exprimant RORa ont été associées à diverses pathologies. Cependant seule une étude récente a été consacrée à leur rôle précis. L’implication de RORa dans de nombreuses fonction, sa forte expression au sein des TREG des NLT nous a poussé a étudier le rôle de ces TREG exprimant RORa dans diverses pathologies. Dans ce butit, nous avons généré des souris spécifiquement déficientes pour RORa au sein des TREG (RORaFoxp3/Foxp3 ). Nous avons émis l’hypothèse que RORa contrôle le développement ou la fonction des TREG en conditions homéostatiques et dans des pathologies inflammatoires des NLT. Aussi nous avons caractérisé le phénotype des animaux RORaFoxp3/Foxp3 et en particulier les TREG du VAT à l’homéostasie, où la réponse de type 2 est protectrice et dans un modèle d’obésité (et d’insulino-résistance) induit par l’obésité (DIO) dans laquelle nous avons mis en évidence un rôle protecteur important des TREG exprimant RORa dans ces deux conditions expérimentales. Nous également étudié la contribution de ces cellules dans un modèle d’inflammation allergique (AAI) induite par un acarien (HDM) caractérisé par une forte réponse de type 2 et montré une aggravation de la pathologie. Pour étudier le mécanisme moléculaire de l’action de RORa au sein des TREG, nous avons procédé à une analyse transcriptomique des cellules isolées dans diverses conditions expérimentales in vivo et in vitro et avons étudié le rôle de RORa dans les modifications épigénétiques au sein des TREG en caractérisation l’acétylation des histones dans le génome entier. Cette étude nous a permis de mieux appréhender comment les TREG étaient régulées par un facteur nucléaire à l’homéostasie et en conditions inflammatoires. Les récepteurs nucléaires représentent des cibles thérapeutiques intéressantes compte tenu de leur action pléiotropique et de leurs ligands de petite taille. Compte tenu de l’importance des TREG dans l’homéostasie tissulaire et dans de nombreuses pathologies, cibler de tels facteurs au sein d epopulations cellulaires spécifiques représente une stratégie prometteuse dans le case de RORa et des TREGTranscription factors of the nuclear receptor superfamily have a vast influence on development and function ofregulatory T cell (TREG) cells. TREG cells are suppressive immune cells of adaptive immune system. Their mainfunctions are control of inflammatory response mounted by other immune cells and maintenance of localtissue homeostasis. As TREG act at various sites of the body and both in homeostatic and inflammatory state,they need to adequately respond to local tissue-specific cues as well as adapt to aggressive immuneenvironments while preserving their long-lasting tolerogenic properties. This is achieved by weaving complextranscriptional networks, converging at transcription factors with various coordination functions, the mainbeing forkhead box P3 (FOXP3). During last few years, many studies focused on TREG cells found innon-lymphoid tissue (NLT). These populations of TREG are examined in the contexts of homeostasis and manyinflammatory diseases, and tissue- or function-specific transcription factor (TF) were assigned to some ofthem as regulators of development, activation, proliferation, stability, migration and suppressive functions.Retinoic acid receptor-related orphan receptor alpha (RORa) is a nuclear receptor, which controls cerebellumdevelopment, liver and whole-body metabolism and differentiation of T-helper (TH)17, type 2 innate lymphoidcells (ILC2) and type 3 innate lymphoid cells (ILC3). RORa is highly expressed in NLT TREG, includingpopulations in visceral adipose tissue (VAT), intestine and skin, and gets more and more mentions in thearticles dedicated to TREG in NLT. These RORa-expressing populations of TREG were all shown to be involvedin various pathologies. However, RORa role in TREG was directly addressed only once in a recent study. It’sactive involvement in various processes, high expression in NLT TREG and lack of knowledge make RORa anattractive target for investigation, to deepen current view of homeostasis control by TREG and thus betterunderstand mechanisms of development of associated diseases. To attain these objectives, a mouse strain withTREG-specific RORa deficiency was generated. Our central hypothesis is that RORa controls development orfunction of TREG cells in homeostasis of NLT and potentially in inflammatory diseases. For studying a role ofRORa in NLT TREG during control of tissue homeostasis, in particular, VAT TREG, we have charachterizedphenotype of untreated RORaFoxp3/Foxp3 mice and challenged mice with a model of diet-induced obesity(DIO). In both cases we have found an important role of TREG-expressed RORa. To further investigate a roleof RORa in TREG during pathologies and it’s contribution to various types of immune response we have testedan involvement of RORa in TREG in the model of allergic pathology, namely house dust mite (HDM)-inducedallergic airway inflammation (AAI) model.To elucidate molecular mechanisms of RORa action in TREG cells, we have performed gene expression profilingof TREG cells from examined tissues and conditions in vivo, as well as in vitro. We also have studied a role ofRORa in epigenetic landscape of TREG cells in vitro by probing histone acetylation marks genome wide. As aresult of this study, we have gained a broader understanding of TREG control by nuclear receptors and TF ingeneral in homeostatic conditions and during inflammation. Nuclear receptors proved to be useful targets fortherapeutic agents thanks to their versatile functions inside the cell and to ligand-dependency. Given thecrucial importance of TREG cells in organismal homeostasis and their involvement in numerous pathologies,targeting particular cues inside these cells may be a powerful tool in new treatment strategies. Results of ourstudy might serve as a basis for development of novel pharmaceutical agents targeting RORa
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Vas, Jaya. "REGULATORY ROLES FOR NATURAL KILLER T CELLS AND TOLL-LIKE RECEPTORS IN MERCURY-INDUCED AUTOIMMUNITY". Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/20283.
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Microbiology and ImmunologyPh.D.
The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar antibody production and immune system activation. Regulatory components of the innate immune system such as NKT cells and TLRs can also modulate the autoimmune process. We examined the interplay among environmental chemicals and NKT cells in the regulation of autoimmunity. Additionally, we studied NKT and TLR ligands in a tolerance model where pre-administration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. We also studied the effect of Sphingomonas capsulata, a bacterial strain that carries both NKT cell and TLR ligands, on metal-induced autoimmunity. Overall, NKT cell activation by synthetic ligands enhanced the manifestations of metal-induced autoimmunity. Exposure to S. capsulata exacerbated autoimmunity elicited by mercury. Although the synthetic NKT cell ligands that we used are reportedly similar in their ability to activate NKT cells, they displayed pronounced differences when co-injected with environmental agents or TLR ligands. Individual NKT ligands differed in their ability to prevent or break tolerance induced by low-dose mercury treatment. Likewise, different NKT ligands either dramatically potentiated or inhibited the ability of TLR9 agonistic oligonucleotides to disrupt tolerance to mercury. Our data suggest that these differences could be mediated by the modification of cytokine profiles and regulatory T cell numbers. The mechanisms by which a heavy metal with an elementary chemical structure induces autoimmunity are unknown. Herein we show that mercury administration results in release of endogenous ligands that activate TLR7, an innate immune receptor implicated in the development of systemic autoimmunity. Moreover, our results suggest that fine specificity of autoantibodies recognizing RNA-containing snoRNPs could be a consequence of TLR7 activation.
Temple University--Theses
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Skarsvik, Susanne. "Aberrancies associated with dendritic cells and T lymphocytes in type 1 diabetes /". Linköping : Linköpings universitet, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med920s.pdf.
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Souza, Luciana Bento de. "Avaliação da expressão de receptores e ligantes Notch nas populações de linfócitos T em desenvolvimento, linfócitos T reguladores naturais e células dendríticas no timo humano". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-27112012-102148/.
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O timo é o órgão linfóide primário responsável pela maturação dos linfócitos T onde se observam estruturas e células especializadas. A sinalização intra-tímica durante a maturação de linfócitos T não é bem esclarecida. Entre outras, a via de sinalização Notch, composta por receptores (Notch 1 a 4) e ligantes (DLL1, 3 e 4, Jagged 1 e 2), pode regular este processo. Neste trabalho temos como objetivo avaliar a expressão gênica e proteica de receptores e ligantes Notch nas diferentes fases de maturação de linfócitos T, linfócitos T reguladores naturais (nTreg) e células dendriticas tímicas (tDC). Para tanto, timos de 10 crianças submetidas à cirurgia cardíaca corretiva foram manipulados e as populações CD4-CD8-, CD4+CD8+, CD4+CD8-, CD4-CD8+, nTreg e tDC foram purificadas por citometria de fluxo. O RNA total foi isolado e os genes NOTCH1, 2 e 3, DLL1 e 4, JAG1 e 2, FOXP3 foram amplificados por RT-PCR. Alguns fragmentos de tecido foram avaliados por imunohistoquímica, quanto a expressão dos receptres Notch 1, 2, 3 e 4 e dos ligantes, DLL1 e 4, Jagged 1 e 2 em timócitos totais, células FOXP3+ e células S100+ em cada região tímica. Todos os genes de receptores e ligantes Notch foram expressos nas populações estudadas. Na população CD4-CD8- o gene NOTCH1 é mais expresso em comparação as outras populações de timócitos imaturos. Na população CD4+CD8+ o gene NOTCH2 é menos expresso, e o gene JAG2 mais expresso quando comparados à população CD4+CD8-. Os demais genes de receptores ligantes Notch são expressos de maneira similar entre as populações de timócitos. A avaliação relativa dos genes Notch nas populações de timócitos mostrou uma maior expressão do gene DLL1 na população CD4+CD8- e JAG1 na população CD4-CD8+ em comparação à CD4-CD8-. A expressão dos receptores e ligantes Notch no tecido mostrou ser homogênea entre as regiões. As nTreg expressam o gene do ligante JAG1 em maior nível entre os avaliados. A expressão gênica relativa das nTreg mostrou uma maior expressão de NOTCH1, NOTCH2, DLL4 e JAG1 e menor expressão de NOTCH3, DLL1 e JAG2 em relação as CD4-CD8-. Quando a relação utilizou a população CD4+CD8- observamos que as nTreg expressam mais os genes NOCTH1, NOCTH2, NOTCH3, DLL4 e JAG1, e em níveis similares DLL1 e JAG2. A avaliação histológica mostrou uma maior expressão de DLL4 em nTreg em comparação às demais proteínas avaliadas, e uma distribuição homogênea entre as regiões com exceção de Notch3 e Jagged2. As tDC mostraram uma maior expressão do gene JAG1 em comparação aos demais, e uma maior expressão da proteína DLL4. A expressão do receptor Notch2 em tDC difere entre as regiões tímicas. Em conjunto, nossos resultados mostraram que os receptores e ligantes Notch são expressos de forma gênica e proteica em todos os estágios de maturação de linfócitos T, nTreg e tDC do timo humano, com algumas variações quanto ao nível de expressão e distribuição no timo. Dados que se assemelham às avaliações murinas, porém com pontos a serem discutidos. Nossa inédita avaliação em nTreg propõem uma nova abordagem ao envolvimento da via Notch em sua maturação e a avaliação das tDCs sugere sua participação direta via Notch na maturação dos timócitos humanosThe thymus is a primary lymphoid organ responsible of maturing T lymphocytes, where specialized structures and cells are observed. The intrathymic signaling during lymphocytes maturation is unclear. Among them, Notch signaling pathway, which comprises in receptors (Notch1-4) and ligands (DLL1, 2 and 3, Jaaged1 and 2), may regulate this process. In this work our aim is to evaluate the expression of Notch receptors and ligands in different phases of T lymphocytes maturation, natural T regulatory cells (nTreg), and thymic dendritic cells (tDC). For this purpose, thymuses from 10 children who underwent corrective cardiac surgery were manipulated and populations CD4-CD8-, CD4+CD8+, CD4+CD8-, CD4- CD8+, nTreg and tDC were sorted by flow cytometry. Total RNA was purified and genes NOTCH1, 2 and 3, DLL1 and 4, JAG1 and 2, FOXP3 were amplified by RT-PCR. Some thymic fragments were evaluated by immunohistochemistry and screened for expression of Notch 1, 2, 3 and 4 receptors, DLL1 and 4, Jagged and e 2 ligands in total thymocytes, FOXP3+ cells and S100+ cells in each thymic region. All Notch receptors and ligands genes were expressed in studied populations. In CD4-CD8- subset NOTCH1 gene is more expressed in comparison to others immature thymocytes. In CD4+CD8+ subset NOTCH2 gene is less expressed, and JAG2 gene is more expressed when compared to CD4+CD8- population. The other receptors and ligands genes were expressed in a similar level among developing lymphocytes subsets. The relative Notch genes evaluation in developing lymphocytes populations showed a higher expression of DLL1 gene in CD4+CD8- population and JAG1 gene in CD4-CD8+ subset in comparison to CD4-CD8- thymocytes. The Notch receptors and ligands expression in thymic tissue showed to be homogeneous between thymic regions. The nTreg cells express JAG1 ligand gene in highest level among evaluated genes. The relative gene expression in nTreg presented higher expression of NOCTH1, NOTCH2, DLL4 and JAG1 genes, and low levels of NOTCH3, DLL1 and JAG2 related to CD4-CD8- subset. When relative gene expression were performed using CD4+CD8- subset, we observed that nTreg cells expressed more NOCTH1, NOCTH2, NOTCH3, DLL4 and JAG1, and in a similar level of expression DLL1 and JAG2 genes. The histological analysis showed that DLL4 was more expressed in nTreg cells in comparison to others proteins evaluated in this work, and a homogeneous distribution in thymic regions, in exception Notch3 and Jagged2. tDC cells presented higher expression of JAG1 gene among the others, and a higher expression of DLL4 protein. Notch2 expression in tDC was different between thymic regions. All together, our results showed that both genes and proteins of Notch receptors and ligands are expressed in distinct developmental stages of the maturation of T lymphocytes and nTreg cells and in the tDC cells in human thymus, with some variations in levels of expression and distribution in the thymus. These data are similar to the murine evaluations, but with some issues to be discussed. Our unpublished assessment in nTreg propose a new approach about the involvement of Notch pathway in its maturation and the evaluation of tDC suggests its direct participation of Notch signaling in the process of human thymocytes maturation
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Barton, Gregory Methven. "Positive selection of CD4 T cells by specific peptide-MHC class II complexes /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/4994.
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Chau, Suk-yi, e 周淑怡. "A study of the expression of Sonic hedgehog and its receptors in T cells and the identification of Sonic hedgehog dowm-stream targets inactivated CD4+T cells". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31386234.
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Berger, DeAnna L. "Investigation of the role of CD137 (4-1BB) costimulation in human CD8⁺ T cell responses". Free to MU Campus, others may purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p1421114.
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Weigand, Luise [Verfasser], Heinrich H. D. [Akademischer Betreuer] Meyer e Angela [Akademischer Betreuer] Krackhardt. "Characterization of human MHC II-restricted T cell receptors with reactivity against B cells and tumor cells for therapeutic application in the context of adoptive T cell transfer of transgenic CD4 T cells / Luise Weigand. Gutachter: Angela Krackhardt ; Heinrich H. D. Meyer. Betreuer: Heinrich H. D. Meyer". München : Universitätsbibliothek der TU München, 2011. http://d-nb.info/1016727798/34.
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Chau, Suk-yi. "A study of the expression of Sonic hedgehog and its receptors in T cells and the identification of Sonic hedgehog dowm-stream targets in activated CD4+T cells". Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31386234.
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Öberg, Linda. "Influence of Ly49 inhibitory receptors and MHC class I on T cell and NK cell function /". Stockholm : Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-217-9/.
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Hjelm, Fredrik. "Early Immunostimulatory Effects of IgE- and IgG Antibodies". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7209.
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Halford, Emily Elisabeth. "The role of group 3 innate lymphoid cells and tumour necrosis factor receptors in the survival and function of regulatory T cells". Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6679/.
Texto completo da fonteResumo:
The ability to therapeutically manipulate regulatory T (Treg) cell survival/function would have far reaching implications; with the potential to limit immune pathology in autoimmune disease, allergy and transplantation; and to reduce regulation of anti-tumour responses in cancer. This study has established a method to study the survival and function of antigen specific Treg cells in vivo, adapting an existing approach in which an endogenous naïve T cell population is expanded and tracked. Multiple immunisation of antigen, and an agonistic anti-DR3 antibody were used to ensure a sufficient number and proportion of Treg cells could be expanded. Further to this, an assay for investigating Treg cell function in vivo was applied to this system. This approach revealed that the tumour necrosis factor receptors OX40 and CD30 may play a role in Treg function, as well as expansion. Unexpectedly, these data also revealed that in the absence of OX40 there is a gross defect in the function of CD4 T cells. A regulatory role of group 3 Innate Lymphoid cells is emerging in the literature, and in accordance with this, this study demonstrates that Treg cell expansion is grossly impaired in mice which lack RORγt, their lineage defining transcription factor.
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Shen, Zu T. "Molecular Studies of T Cell Recognition and Cross-Reactivity: A Dissertation". eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/630.
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Intracellular pathogens are recognized by a specialized subset of lymphocytes known as CD8+ T cells. Pathogen recognition by CD8+ T cells occurs through binding of T cell receptors (TCR) to processed antigens in complex with major histocompatibility complex (MHC) class I proteins. TCR engagement of antigens in complex with MHC class I typically lead to cytotoxic CD8+ T cell responses, which result in pathogen clearance. Due to the large number of foreign antigens that might be encountered by any given host a diverse repertoire of TCRs must be available for immune recognition. The main source of TCR diversity is generated by somatic recombination of the TCR genes. However, it has been suggested that selection eliminates so many recombined TCR sequences, that a high degree of TCR cross-reactivity must occur for the immune system to be able to recognize a large set of foreign pathogens. The work presented in this thesis was directed towards the understanding of the molecular mechanisms of CD8+ T cell recognition and cross-reactivity.
Chapter I of this thesis gives an overview of the immune system, with a focus on CD8+ T cells.
Chapter II of this thesis describes the development of novel bi-specific MHC heterodimers that are specific towards cross-reactive CD8+ T cells. Classically, MHC tetramers have been used for phenotypic characterization of antigen-specific T cells. However, identification of cross-reactive T cells requires the simultaneous use of two MHC tetramers, which was found to result in MHC tetramer cross-competition. For this reason, we generated bi-specific MHC heterodimers, which would not be affected by the affinity between the component peptide-MHC complexes for TCR. We generated T cell lines, which cross-react with antigens from lymphocytic choriomeningitis virus (LCMV) and vaccinia virus (VV), to test our bi-specific MHC heterodimers. We show that the heterobifunctional cross-linking utilized to generate bi-specific MHC heterodimers does not affect specific binding onto cross-reactive CD8+ T cells.
Chapter III describes a mechanism for a cross-reactive CD8+ T cell response between the disparate antigens, lymphocytic choriomeningitis virus (LCMV)-GP34 (AVYNFATM) and vaccinia virus (VV)-A11R (AIVNYANL), which share the three underlined residues. The recognition determinants for LCMV-GP34 and VV-A11R were compared by an alanine/lysine scanning approach for both epitopes. Functional analysis of the mutated peptides clearly indicates that the shared P4N residue between LCMV-GP34 and VV-A11R is an important TCR contact for the recognition of both epitopes. In addition, we determined the crystal structures of both Kb-VV-A11R and Kb-LCMV-GP34. Structural analysis revealed that the two complexes are nearly identical structural mimics, which was unexpected due to the primary sequence disparity. Together with the functional studies, our results highlight that structural similarities between different peptide-MHC complexes can mediate cross-reactive T cell responses.
Chapter IV of this thesis includes additional discussion, overall conclusions and future directions.
Chapter V includes the protocols and the gene constructs that were used in this work. Also included in Chapter V are results from two unrelated incomplete projects which have yielded significant findings.
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Gozalo, Sara. "The Role of γс Cytokines in T Cell Development, T Cell Homeostasis and CD8+ T Cell Function: A Dissertation". eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/140.
Texto completo da fonteResumo:
T lymphocytes are essential components of the immune system and as such are continually regulated by a variety of factors. Every step of their development, survival and function is tightly monitored to ensure their ability to recognize most foreign agents and mount adaptive immune responses during pathogenic infections, while remaining tolerant to self-antigens. Among the many factors that participate in the regulation of T cell development and function are the cytokines. Cytokines that signal through the common gamma (γс) chain and the Janus kinase 3 (Jak3) include IL-2, -4, -7, -9, -15, and -21 and have been implicated in the regulation of every stage in the life of a T cell. Therefore, it is not surprising that mutations in the γс chain or Jak3 lead to a SCID condition in humans and mice. Specifically, Jak3-deficient mice are characterized by a reduction in thymic cellularity and dysregulated T cell homeostasis. They have an expansion of memory-like CD4+ mature T cells and an almost complete absence of mature CD8+ T cells. By investigating the TCR repertoire of CD4+ T cells in the thymus and spleen of Jak3-/- mice, I deduced that the CD4+ T cell activation and expansion is TCR-specific and takes place in the periphery of the mice. After crossing Jak3-deficient mice to Bcl-2 transgenic mice I showed that the developmental block observed in Jak3-/- mice could not be rescued by the anti-apoptotic factor, despite the fact that its expression did increase, slightly, the total numbers of developing thymocytes. The enforced expression of Bcl-2 was also not sufficient to revert the dysregulation of T cell homeostasis in Jak3-/- mice. Finally, in order to further understand the role played by γс cytokines during T cell function, I investigated the ability of mature Jak3-/- CD8+ T cells to become activated and differentiate into effector cells in response to a viral infection. My results indicate that CD8+ T cells are activated and proliferate in response to a viral infection, but their survival, as well as their ability to proliferate and differentiate into effector cells are greatly impaired, resulting in the inability of Jak3-deficient mice to mount a protective response.