• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 40
  • 21
  • 14
  • 4
  • 4
  • 3
  • 2
  • 2
  • 1
  • Tagged with
  • 103
  • 32
  • 30
  • 28
  • 24
  • 17
  • 14
  • 14
  • 13
  • 9
  • 9
  • 8
  • 8
  • 8
  • 8
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Therapeutic effects of TGT-β induced regulatory T cells on the established autoimmune and inflammatory diseases / Effets thérapeutiques des cellules T regulatrices induitent par TGF-β sur l’autoimmunité et l’inflammation préétablies

Zheng, Song Guo 05 December 2011 (has links)
Des études récentes ont montré que les cellules nTregs ont moins d'effets thérapeutiques lors de traitements de maladies auto-immunes. L'étude actuelle cherche à déterminer si les iTregs pourraient, être plus efficaces. Dans l'asthme allergique, nous avons observé que le transfert adoptif de iTreg supprime de façon significative l’inflammation des voies respiratoires et péri-vasculaires, réduit la résistance et le remodelage de ces voies aériennes, le recrutement des éosinophiles, l’hyperproduction de mucus, et les niveaux d'IgE. Cet effet thérapeutique a pu être associé à une augmentation du nombre de Tregs (CD4 + Foxp3 +) dans les ganglions lymphatiques drainant, et à la réduction des réponses Th1, Th2, Th17. Dans l'arthrite induite par le collagène (CIA), les iTregs antigène-spécifiques comme les nTregs proliférant, préviennent le développement de la pathologie. Toutefois, seul le transfert d’iTregs permet de supprimer la CIA lorsque celle-ci est déjà établie. Dans cette situation, les nTregs contrairement aux iTregs, étaient converties en Th17, et perdaient l’expression de Foxp3, cela dans des expériences aussi bien in vitro qu’in vivo. Les iTregs suppriment la différenciation Th17, ce qui corrèle avec l'amélioration des scores cliniques et des symptômes. Dans le modèle GVHD chronique, la perfusion d’iTregs diminue les symptômes du lupus. Le blocage de la liaison TGF-"/TGF-"R ou des voies de signalisation de l'IL-10 abolit de façon significative les effets thérapeutiques des iTregs. Celles-ci rendent les DC tolérogéniques, par l’intermédiaire du TGF-" mais pas de l’IL-10. Les DC isolées de souris atteintes de lupus et recevant des iTregs peuvent supprimer la progression de la maladie grâce au TGF-" mais pas à l'IL-10. Ainsi, iTregs ciblent les DC dans le milieu inflammatoire et ces DC devenues tolérogéniques empêchent la progression de maladies auto-immunes grâce à des effets directs ou indirects (induisant par exemple de nouvelles iTregs. Par ailleurs, nous démontrons que l’acide rétinoïque « all-trans » (atRA) promeut et soutient les cellules Tregs Foxp3+. atRA augmente la méthylation des histones et l'acétylation, dans les locus du gène Foxp3, tandis que la méthylation de l'ADN du gène Foxp3 n'est pas significativement modifiée. Ces résultats peuvent fournir de nouvelles connaissances sur la thérapie cellulaire clinique pour les patients atteints de maladies auto-immunes et pour ceux qui ont besoin de greffes d'organes. / Recent studies revealed that nTregs has less therapeutic effects on established autoimmune diseases. Current study asks if iTregs induced ex-vivo with TGF- can treat the established autoimmune diseases. In allergic asthma we observed that adoptive transfer of iTreg significantly suppressed airway and peri-vascular inflammation, reduced airway résistance, eosinophil recruitment, mucus hyper-production, airway remodeling and IgE levels. This therapeutic effect was associated with increase of Tregs (CD4+Foxp3+) in the draining LNs, and with reduction of Th1, Th2, and Th17 responses. In collagen-induced arthritis (CIA) both antigen-specific iTregs and expanded nTregs prevented CIA. However, only iTregs transfer suppressed established CIA. nTregs but not iTregs were converted into Th17 and lost Foxp3 in vitro and in vivo in established CIA. iTregs suppressed Th17 cell differentiation that paralleled with improved clinical scores and symptoms. In the chronic GVHD model mimicking lupus the iTregs infusion significantly decreased lupus symptoms. Blocking of TGF- !"#$- %&'(&)*-10 signaling pathways significantly abolished the therapeutic effects. iTregs induced the formation of tolerogenic DCs through TGF- but not IL-10 signaling on DC. DC isolated from lupus mice receiving iTregs can suppress lupus development through TGF- & but not IL-10 signaling. Thus, iTregs target DC in the inflammatory milieu and newly formed tolerogenic DC suppress disease progression through its direct or indirect effect (inducing new iTregs) in autoimmune disease settings. Moreover, we demonstrated that all-trans retinoic acid (atRA) promotes and sustains the Foxp3+ regulatory T cells. atRA increased histone methylation and acetylation within Foxp3 gene locus, while DNA methylation in Foxp3 gene was not significantly altered. These results may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.
2

Lymphocytes T régulateurs et Transplantation hépatique : modulation de l'activité des lymphocytes T régulateurs CD4+CD25+ par les drogues immunosuppressives

Miroux, Céline 11 February 2011 (has links) (PDF)
Lorsque l'hépatite chronique C a occasionné une cirrhose et que, du fait de ses complications, le pronostic vital est en jeu au terme de quelques mois, la transplantation hépatique (TH) représente l'unique traitement efficace,. Malheureusement, la récidive quasi-systématique de la cirrhose C, après la transplantation hépatique, est la principale barrière à la survie du greffon. De nombreux facteurs ont été associés à la sévérité des récidives, et une implication des lymphocytes T régulateurs CD4+CD25+ (Treg) et de certains immunosuppresseurs a été suggérée. Par ailleurs, le patient transplanté peut également être confronté au problème du rejet aigu d'allogreffe, qui est partiellement contrôlé par les Treg et par une thérapie immunosuppressive rigoureuse. Paradoxalement, plusieurs études ont suggéré que certains immunosuppresseurs sont moins efficaces que d'autres dans la prophylaxie du rejet d'allogreffe et peuvent même être associés à des épisodes de rejet plus fréquents. Il existait donc un besoin urgent d'évaluer le rôle joué par les immunosuppresseurs sur les Treg dans la récidive de la fibrose C et dans le rejet du greffon. Dans un premier temps, nous avons confirmé l'implication des Treg dans la progression de la récidive de l'hépatite C. En effet, les marqueurs associés à cette population sont surexprimés dans le foie et dans le sérum de patients, 1 an et 5 ans après la TH, et ce proportionnellement à la sévérité de la récidive. Dans un deuxième temps, nous avons évalué l'effet d'immunosuppresseurs utilisés après la TH (cyclosporine A (CsA), tacrolimus, rapamycine et mycophénolate mofétif) sur l'activité des Treg. Nous avons ainsi montré que seule la CsA a une action inhibitrice sur l'activité des Treg, et ce, uniquement aux doses thérapeutiques de 20 et 40 ng/mL (doses administrées au long terme, 5 ans après la TH). Cette inhibition de l'activité des Treg par la CsA ne modifie pas leur phénotype (expression protéique ou génique), mais conduit à la sécrétion d'IL-2 et d'IFN-γ par les Treg, cytokines de la voie Th1. Le mécanisme immunosuppresseur de la CsA étant d'inhiber la transcription de l'IL-2, via la voie calcineurine/N-FAT, nous avons tenté d'identifier si elle agissait sur les Treg par cette voie ou par une voie indépendante de la calcineurine. Deux observations ont renforcé l'hypothèse d'un mode d'action calcineurine/N-FAT - indépendant : (i) le fait que le tacrolimus, qui a le même mécanisme immunosuppresseur que la CsA, n'inhibe pas l'activité des Treg et (ii) le fait que NIM811, un analogue de la CsA n'agissant pas sur la voie de la calcineurine, inhibe l'activité des Treg aux mêmes doses que la CsA. Cette hypothèse a par ailleurs été directement confirmée par l'absence de modification du profil de déphosphorylation du facteur de transcription N-FAT, en présence de CsA. Enfin, bien que les corticoïdes soient connus pour préserver l'activité des Treg et induisent leur prolifération in vitro, ils sont incapables de reverser l'effet inhibiteur de la CsA sur les Treg. Nos résultats suggèrent donc qu'une dose thérapeutique de CsA inhiberait l'activité des Treg CD4+CD25+. Les cellules T régulatrices jouent un rôle important dans la tolérance du greffon et dans la sévérité des récidives après la TH, leur inhibition par la CsA pourrait alors favoriser le rejet du greffon et diminuer la sévérité des récidives. Ces résultats sont importants dans la mesure où la transplantation hépatique est à l'heure actuelle la seule alternative de survie au stade du carcinome hépatocellulaire, et qu'il n'existe aucun traitement efficace contre le rejet du greffon ou la récidive de l'hépatite C. Le traitement immunosuppresseur idéal n'existe pas, cependant il ne devrait pas augmenter l'activité suppressive des Treg, au risque de favoriser la récidive de l'hépatite C, ni inhiber cette activité, au risque de favoriser le rejet du greffon.
3

Dynamika tvorby T regulačních lymfocytů během těhotenství / The dynamics of T regulatory lymphocytes generation during pregnancy

Kopřivová, Helena January 2017 (has links)
Regulatory T cells (Tregs) are CD 4+ T lymphocytes with regulatory and reparative properties. Tregs are functionally and differentially controlled by Foxp3 transcription factor, and they are considered a key factor inducing feto-maternal tolerance. Disruption of this unique type of time-limited immune tolerance leads to pregnancy complications including miscarriages, intrauterine growth retardation of the fetus, and premature delivery. Tregs' production and functional properties are influenced by the cytokine environment, especially by TGF-β1, IL-2, and retinoic acid. These pleiotropic factors are involved in the differentiation of tolerogenic populations of decidual cells. In the present work, a detailed immunophenotyping of Tregs was performed, and a determination of serum concentrations of TGF-β1 during physiological pregnancy was realized. The examined subpopulations of Tregs have shown different signs or markers of their functional and maturity properties. In some subpopulations, apparent changes in Treg counts were observed during pregnancy. Moreover, typical development was observed for TGF-β1 serum levels. The main goal of the current work was an examination of differences in Treg subpopulation counts in women with premature deliveries compared to females with full term births....
4

Role of the transcription factor c-Maf in regulating inflammatory immune responses

Hussein, Hind 16 October 2020 (has links) (PDF)
Regulatory T cells (Treg) are a suppressive subset of helper T cells that controls immune responses using a variety of mechanisms. Despite initially being thought of as a homogenous population, Treg cells were recently found to adapt their function to their environment and acquire specialized phenotypes depending on their tissue of residence. The molecular mechanisms underlying this functional and tissular adaptation remain to be fully elucidated.In the course of this work, we studied the role of transcription factor c-Maf in the differentiation and the function of Treg cells. For this, we used a murine model invalidated for c-Maf specifically in Treg cells. Transcription factor c-Maf is preferentially expressed by intestinal Treg cells, particularly among the RORγt+ Treg subset, which controls immune responses directed towards the gut microbiota. We have shown that the differentiation of RORγt+ Treg cells results from the integration of multiple environmental signals, highlighting the plasticity of Treg specialization. Furthermore, we have shown that c-Maf is required for the differentiation of RORγt+ Treg cells as well as the expression of the anti-inflammatory cytokine IL-10 by intestinal Treg cells, thus endowing Treg cells with the ability to control homeostatic Th17 responses in the intestine. Mice deficient for c-Maf in Treg cells exhibit an exacerbated Th17 response and spontaneously develop colitis. However, c-Maf-deficient mice develop fewer polyps in a model of colitis-associated colon cancer. This suggests that c-Maf expression in Treg cells plays a beneficial role on intestinal homeostasis at steady state, but is detrimental in a tumoral context.Our results allow a better understanding of the mechanisms involved in the specialization of intestinal Treg cells. The knowledge of these mechanisms is crucial for the identification of new therapeutic targets in the context of inflammatory bowel disease and colon cancer. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished
5

Pharmacological targeting of acid sphingomyelinase increases CD4\(^+\) Foxp3\(^+\) regulatory T cell subsets in patients with major depression / Pharmakologische Hemmung der sauren Sphingomyelinase verstärkt CD4\(^+\) Foxp3\(^+\) regulatorische T-Zell-Subpopulationen bei Patienten mit Depression

Wiese, Teresa January 2022 (has links) (PDF)
Lack of acid sphingomyelinase (ASM) activity, either through genetic deficiency or through pharmacological inhibition, is linked with increased activity and frequency of Foxp3+ regulatory T cells (Treg) among cluster of differentiation (CD) 4+ T cells in mice in vivo and in vitro1. Thus, pharmacological blockade of ASM activity, which catalyzes the cleavage of sphingomyelin to ceramide and phosphocholine, might be used as a new therapeutic mechanism to correct numeric and/ or functional Treg de-ficiencies in diseases like multiple sclerosis or major depression. In the present study, the effect of pharmacological inhibition of ASM in humans, in vitro and in vivo, was analyzed. In the in vitro experiments, peripheral blood mono-nuclear cells (PBMC) of healthy human blood donors were treated with two widely prescribed antidepressants with high (sertraline, Ser) or low (citalopram, Cit) capaci-ty to inhibit ASM activity. Similar to the findings in mice an increase in the frequency of Treg among human CD4+ T cells upon inhibition of ASM activity was observed. For the analysis in vivo, a prospective study of the composition of the CD4+ T cell com-partment of patients treated for major depression was done. The data show that pharmacological inhibition of ASM activity was superior to antidepressants with little or no ASM-inhibitory activity in increasing CD45RA- CD25high effector Treg (efTreg) frequencies among CD4+ T cells to normal levels. Independently of ASM inhibition, correlating the data with the clinical response, i.e. improvement of the Hamilton rat-ing scale for depression (HAMD) by at least 50 per cent (%) after four weeks of treatment, it was found that an increase in efTreg frequencies among CD4+ cells dur-ing the first week of treatment identified patients with a clinical response. Regarding the underlying mechanism, it could be found that the positive effect of ASM inhibition on Treg required CD28 co-stimulation suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Treg among human CD4+ T cells. Inhibition of ASM activity was further associated with changes in the expression and shuttling of CTLA-4, a key inhibitory molecule ex-pressed by Treg, between cellular compartments but the suppressive activity of CTLA-4 through its transendocytosis activity was unaffected by the inhibition of ASM activity. In summary, the frequency of (effector) Treg among CD4+ T cells in mice and in hu-mans is increased after inhibition of ASM activity suggesting that ASM blockade might beneficially modulate autoimmune diseases and depression-promoting in-flammation. / Ein Mangel an Aktivität der sauren Sphingomyelinase (ASM), entweder durch ge-netisches Defizit oder durch pharmakologische Hemmung, ist mit einer erhöhten Aktivität und Häufigkeit von Foxp3+ regulatorischen T-Zellen (Treg) innerhalb der CD4+ (cluster of differentation 4) T-Zellen in Mäusen in vivo und in vitro verbun-den1. Daher könnte die pharmakologische Blockade der ASM-Aktivität, die die Spaltung von Sphingomyelin in Ceramid und Phosphocholin katalysiert, als neuer therapeutischer Mechanismus zur Korrektur von numerischen und/oder funktionel-len Treg-Defiziten bei Erkrankungen wie Multipler Sklerose oder schwerer Depres-sion eingesetzt werden. In der vorliegenden Studie wurde die Wirkung der pharmakologischen Hemmung von ASM beim Menschen, in vitro und in vivo analysiert. In den In-vitro-Experimenten wurden die peripheren mononukleären Blutzellen (PBMC) gesunder menschlicher Blutspender mit zwei weithin verschriebenen Antidepressiva mit ho-her (Sertralin, Ser) oder niedriger (Citalopram, Cit) Fähigkeit zur Hemmung der ASM-Aktivität untersucht. Ähnlich wie bei Mäusen wurde bei Hemmung der ASM-Aktivität ein Anstieg der Häufigkeit von Treg innerhalb der menschlichen CD4+ T-Zellen festgestellt. Für die Analyse in vivo wurde eine prospektive Studie über die Zusammensetzung des CD4+ T-Zellkomplexes bei Patienten, die wegen einer De-pression im Krankenhaus behandelt wurden, durchgeführt. Die Daten zeigen, dass die pharmakologische Hemmung der ASM-Aktivität Antidepressiva mit ge-ringer oder keiner ASM-hemmenden Aktivität überlegen war, was die Vermehrung der CD45RA- CD25hoch-Effektor-Treg (efTreg)-Frequenzen innerhalb der CD4+ T-Zellen betraf. Unabhängig von der Untersuchung zur ASM-Aktivität beobachteten wir, dass die klinische Reaktion (d.h. der Verbesserung der Hamilton-Bewertungsskala für Depressionen (HAMD) um mindestens 50 Prozent (%) nach vierwöchiger Behandlung) mit einem frühen Anstieg der efTreg-Frequenzen unter CD4+-Zellen während der ersten Behandlungswoche positiv korrelierte. Hinsichtlich des zugrunde liegenden Mechanismus konnte festgestellt werden, dass die positive Wirkung der ASM-Hemmung auf Treg eine CD28-Kostimulation erforderte, was darauf hindeutet, dass eine verstärkte CD28-Kostimulation die Ur-sache für den beobachteten Anstieg der Frequenz von Treg innerhalb menschli-cher CD4+ T-Zellen war. Die Hemmung der ASM-Aktivität war darüber hinaus mit Veränderungen in der Expression und im zellulären Umsatz von CTLA-4, einem von Treg exprimierten inhibitorischen Schlüsselmolekül, verbunden. Die suppressi-ve Aktivität von CTLA-4 durch seine Transendozytose-Aktivität wurde jedoch durch die Hemmung der ASM-Aktivität nicht beeinflusst. Zusammenfassend lässt sich sagen, dass die Häufigkeit von (Effektor-)Treg unter-halb der CD4+ T-Zellen in Mäusen und beim Menschen nach Hemmung der ASM-Aktivität erhöht ist, was darauf hindeutet, dass eine ASM-Blockade Autoimmuner-krankungen und depressionsfördernde Entzündungen vorteilhaft modulieren könn-te.
6

Role of ICOS in Foxp3+ Treg responses induced by parasitic helminths

Redpath, Stephen Alexander January 2012 (has links)
Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in immunosuppressed hosts harbouring chronic infections. This immune suppression forms a major barrier to the acquisition of protective Th2 immunity, both in regard to natural infections and potential vaccinations. At the same time, immune downregulation plays a beneficial role in protecting the host from pathology during chronic infection, and epidemiological links between helminth infections and the amelioration of allergy and autoimmunity diseases indicate that helminth-induced immune suppression can be therapeutically applied to the treatment of these conditions. Foxp3+ regulatory T cells (Treg) play central downregulatory roles in controlling reactivity to self-antigens and preventing autoimmune diseases, as well as in limiting inflammatory responses during infection. Helminths induce dominant Foxp3+ Treg responses that play key roles in inhibiting protective immunity and alleviating immunopathology, and that can protect against allergic inflammation. Thus, Foxp3+ Tregs are a fundamental mechanism of immune regulation during helminth infections, and an understanding of the mechanisms governing the induction of Foxp3+ Treg responses is of principal importance for the design of both prophylactic helminth treatments and therapies for allergies and autoimmunity. However, the nature of the T cell co-stimulatory signals driving Treg generation during helminth infection is largely unclear. Recent evidence suggests that the inducible costimulator (ICOS) contributes to Treg control of autoimmune inflammation. Further, ICOS expression is upregulated by Foxp3+ Treg during infection with the filarial nematode Litomosoides sigmodontis suggesting ICOS is important for Treg during helminth infection. Therefore, we investigated the role of ICOS in helminth-induced Treg responses. Similar to L. sigmodontis infection, Foxp3+ Treg increased ICOS expression in response to infection with the intestinal nematode Heligmosomoides polygyrus and with the blood trematode Schistosoma mansoni. Functionally, ICOS was required for the optimal expansion of lymphoid Treg numbers during early stage H. polygyrus infection and following the onset of the acute egg phase of S. mansoni infection suggesting common pathways for Treg induction by diverse helminth species. Whilst helminth induced proliferation and activation of Foxp3+ Treg was ICOS independent, ICOS was essential for Treg survival in settings of homeostasis and helminth infection. In contrast to the lymph node, Treg responses in the intestinal lamina propria (LP) of ICOS-/- mice were increased due to expanded natural Treg. Following H. polygyrus infection Foxp3+ Helios- CD4+ T cells preferentially expanded in wild-type (WT) mice but not in ICOS deficient mice suggesting ICOS is required for the expansion of adaptive Treg at the site of intestinal nematode infection. Functionally, ICOS supports Treg, but not effector T cells (Teff), H. polygyrus induced IL- 10 production suggesting ICOS differentially regulates Treg and Teff. At the H. polygyrus infection site, ICOS acted to downregulate CD4+ T cell Th2 cytokine production. Conversely, in the reactive lymph node ICOS signalling promoted Th2 immune responses, possibly by maintaining the pool of IL-4 secreting type 2 follicular helper T cells. Thus, ICOS has different effects on Th2 immunity depending on tissue location. Because Th2 immunity governs expulsion of H. polygyrus parasites, the differences in Th2 responses between lymph node and infection site could explain why ICOS deficiency did not impact worm burden. Protective immunity to long-lived helminth infection can be quenched in the initial days of infection by the action of Treg. Whether Treg expand and suppress protective immunity during S. mansoni larvae lung transit has not been investigated. We found that in contrast to H. polygyrus and L. sigmodontis infection, early S. mansoni infection did not induce a Treg response suggesting other mechanisms are employed for immune subversion. During the acute egg-phase of S. mansoni infection, Foxp3+ Treg protect the host from damaging egg-induced hepatic immunopathology. Despite reduced Foxp3+ Treg responses, ICOS deficiency did not impact egg-induced immunopathology. Thus, ICOS co-stimulation contributes to early expansion and the continued maintenance of Treg during helminth infection, both in the local lymph node and at the infection site. ICOS is required for Treg function during helminth infection by promoting IL-10 production, whilst its contribution to Th2 effector immunity is tissue specific. In addition, ICOS is dispensable for protective immunity and pathology during helminth infection. As ICOS controls both positive and negative immune responses and can have opposing roles depending on tissue location, an understanding of the consequences of these contradictory effects will be important when considering targeting ICOS therapeutically.
7

Regulatory T cells in Wiskott-Aldrich syndrome and after allogeneic transplantation with nonmyeloablative conditioning.

Humblet, Stéphanie 26 May 2009 (has links)
Etude des Treg dans la physiopathologie du syndrome de Wiskott-Aldrich et étude de la reconstitution des Treg dans les greffes de cellules souches hématopoïétiques après un conditionnement nonmyéloablateur.
8

The Function of LAT in T Cell Activation and Autoimmunity

Chuck, Mariana January 2010 (has links)
<p>LAT (linker for activation of T cells) is an important transmembrane adaptor protein in TCR-mediated signaling. Upon TCR engagement, LAT associates with multiple proteins which allows for the activation of downstream signaling pathways. The interaction between LAT with phospholipase C (PLC-gamma1) is especially critical for T cell receptor (TCR)-mediated Ca2+ signaling and MAPK activation. Knock-in mice harboring a mutation at the PLC-gamma1 binding site (Y136) of LAT develop a severe lymphoproliferative syndrome. These mice have defective thymic development and selection and lack natural regulatory T cells, implicating a breakdown of both central and peripheral tolerance. The phenotype observed in LAT-/- mice is even more severe.T cells are absent in the periphery of these mice due to a complete block in thymocyte development at the DN3 stage thereby making it difficult to study the physiological role of LAT in the activation and function of mature T cells. In order to bypass the developmental defects exhibited by LAT-/- and LATY136F mice, we developed conditional knock-in lines in which only a nonfunctional (ERCreLATf/-) or a LATY136F-mutated allele (ERCreLATf/m) of LAT is expressed in mature T cells after deletion of the wildtype LAT allele.</p><p>Analysis of ERCreLATf/m T cells after LAT deletion indicated that the interaction between LAT and PLC-gamma1 plays an important role in TCR-mediated signaling, proliferation, and IL-2 production. Furthermore, the deletion of LAT induced the development of the LATY136F lymphoproliferative syndrome in these mice. Although Foxp3+ natural Treg cells were present in these mice after deletion, they were unable to suppress the proliferation of conventional T cells. Our data indicated that the binding of LAT to PLC-gamma1 is essential for the suppressive function of CD4+CD25+ regulatory T cells. </p><p>We have also performed studies using ERCreLATf/- T cells to demonstrate that total LAT deficiency reduced the expression of Foxp3, CTLA4, and CD25 in peripheral Treg cells. Interestingly, mice with LAT deleted in peripheral T cells developed a lymphoproliferative syndrome similar to that observed in LATY136F mice although the disease caused by the LATY136F mutation was more severe. These data implicate LAT in both the positive and the negative regulation of mature T cells. Moreover, our findings indicate that LAT is essential in the maintenance of the regulatory T cell profile in the periphery, thereby aiding in the prevention of lymphoproliferative autoimmune disease.</p> / Dissertation
9

The role of ADAM10, ADAM17, and Spag6 in humoral immunity and secondary lymphoid tissue architecture

Cooley, Lauren Folgosa 01 January 2015 (has links)
ADAM10, ADAM17, and SPAG6 contribute significantly to humoral immunity and secondary lymphoid tissue architecture. ADAM10 and ADAM17 are two closely related zinc-metalloproteinases. Through cleavage of their ligands CD23 and TNF, respectively, they greatly influence IgE production and secondary lymphoid tissue architecture maintenance. Th1 prone WT strains initially exhibit increased ADAM17 and TNF yet reduced ADAM10 relative to Th2 prone WT strains. In the absence of B cell ADAM10, a compensatory increase in ADAM17 and TNF cleavage is noted only in Th1 prone C57Bl/6, not Th2 prone Balb/c. B cell TNF homeostasis is important for maintaining secondary lymphoid tissue architecture. We show for the first time that excessive B cell TNF production in C57-ADAM10B-/- lymph nodes contributes to loss of B/T segregation, increased HEV number and size, fibrosis, loss of FDC networks, and impaired germinal center formation. Furthermore, B cell ADAM10, which enhances IgE production through CD23 cleavage, is shown to be a marker of Th2 susceptibility. B cell ADAM10 is elevated in Th2 prone mouse strains and allergic patients compared to Th1 prone controls and as B cell ADAM10 level increases, so does IgE production. Lastly, the B cell profile of allergic patients is determined to be B cell ADAM10highADAM17lowTNFlow. Furthermore, the mechanism underlying reduced class-switched antibody production in C57-ADAM10B-/- mice is explored. C57-ADAM10B-/- B cells exhibit a B10, or IL-10 producing, phenotype, which is linked to reduced antibody production. Furthermore, increased Tregs noted in C57-ADAM10B-/- mice contributed to reduced class switched IgE production and disease parameters following a house dust mite airway inflammation challenge. SPAG6, a component of the central apparatus of the “9+2” axoneme, plays a central role in flagellar stability and motility. Immune cells lack cilia, but the immunological synapse is a surrogate cilium as it utilizes the same machinery as ciliogenesis including the nucleation of microtubules at the centrosome. We demonstrate that Spag6 localizes in the centrosome and is critical for centrosome polarization at and actin clearance away from the synapse between CTL and target cells. Furthermore, improper synapse formation and function likely explains reduced CTL function and class-switched antibody production in Spag6KO mice.
10

The Immunoregulatory Role of FGL2 as a Novel Effector Molecule of Treg Cells

Shalev, Itay 18 June 2009 (has links)
Background and Aim: CD4+CD25+ regulatory T (Treg) cells are important in the maintenance of self-tolerance, regulation of T cell homeostasis, prevention of allograft rejection and in the modulation of immune responses to pathogens. Several groups have recently reported an increased expression of fgl2 in Treg cells by microarray analysis. FGL2, a member of the fibrinogen-like family, was previously shown to act as an immunomodulator by inhibiting DC maturation and T cell proliferation. Based on these findings, the immunoregulatory role of FGL2 as a novel effector molecule of Treg cells was investigated. Results: In agreement with previous studies, high levels of fgl2 transcripts were detected in Treg cells by real-time PCR. In fgl2-/- mice, an increased number and percentage of Treg cells were found with a greater expression of Foxp3 compared with fgl2+/+ Treg cells; however, the suppressive activity of fgl2-/- Treg cells was significantly impaired. Antibody to FGL2 completely inhibited the activity of fgl2+/+ Treg cells in vitro. Consistent with FGL2 contribution to Treg cell activity, targeted deletion of the gene led to an increased immune reactivity of DC, T cells and B cells, and the manifestation of glomerular autoimmunity in aged fgl2-/- mice. The importance of FGL2 as an effector of Treg cells was also demonstrated in MHV-3-induced fulminant hepatitis. Uninfected susceptible BALB/cJ mice had increased numbers of Treg cells and expression of FGL2 compared to uninfected resistant A/J mice. Following MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with an increased percentage of Treg cells. Treatment with anti-FGL2 antibody completely inhibited Treg cell activity and protected susceptible BALB/cJ mice against MHV-3-induced liver injury and mortality. Adoptive transfer of fgl2+/+ Treg cells into resistant fgl2-/- mice increased their mortality following MHV-3 infection. Finally, FGL2 treatment led to prolonged skin graft survival in a murine allotransplant model. The suppressive activity of FGL2 was mediated through binding to the inhibitory FcγRIIB receptor expressed on APCs, resulting in inhibition of DC maturation and induction of B cell apoptosis. Conclusion: These studies indicate that FGL2 plays an important immunoregulatory role as an effector cytokine of Treg cells; targeting FGL2 may provide a novel therapeutic approach for the treatment of patients with viral hepatitis, autoimmunity and transplant rejection.

Page generated in 0.0614 seconds