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Wyant, Tiana L. "Influence of Anti-CD44 on Murine B Cell Activation." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/1004.
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Lymphocyte activation and trafficking are indispensable to the immune system. CD44, an adhesion molecule, plays important roles in T cell activation, lymphocyte homing/trafficking, and tumor metastasis. Although the functions of CD44 have been shown in T cells and other leukocytes, little is known about its role in B cells. The effects of CD44 cross-linking on murine B cell activation via CD40L/IL-4 was explored using the anti-CD44 mAbs RK3G9 and IM7. Immobilized RK3G9 and IM7 could strongly inhibit B cell proliferation and Ig production, with IgE inhibition being prominent. Soluble anti-CD44 had no effect. The inhibitory effect of RK3G9 was not influenced by addition of anti-FCγRII, indicating no role for the inhibitory receptor. The effects of delayed addition of immobilized anti-CD44 mAbs were studied, and the results indicated no inhibition after 96 hrs of culture. B cells were also activated by either LPS or anti-IgM F(ab')2. While LPS-induced B cell activation was inhibited by immobilized anti-CD44 mAbs, anti-IgM activation was refractory. Interestingly, addition of both anti-IgM and CD40L or LPS resulted in some modulation of the inhibitory activity. Additionally, FACS and Elispot revealed that RK3G9-treated cells had reduced numbers of plasma cells. Taken together, these results suggest that CD44 cross-linking could control polyclonal B cell activation by CD40L, but allow sIgM/CD40L activation to continue.
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Fournier-Conge, Anne-Marie. "Anomalies de l'activation des lymphocytes B circulants au cours de l'infection par le VIH-1 : implications physiopathologiques et cliniques." Montpellier 1, 1996. http://www.theses.fr/1996MON1T025.
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DiSanto, James Philip. "Molecular events in human T cell activation : CD4, CD8 and the human Lyt-3 molecules /." Access full-text from WCMC, 1989. http://proquest.umi.com/pqdweb?did=745024391&sid=1&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Sutherland, Claire Louise. "Structure/function analysis of CD40, a key activator of B lymphocytes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0027/NQ38986.pdf.
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Delli, Joe. "Coreceptor and costimulatory signals organize proteins within the immunological synapse and augment proximal T cell signaling events /." Connect to full text via ProQuest. IP filtered, 2006.
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Thesis (Ph.D. in Immunology) -- University of Colorado, 2006.Typescript. Includes bibliographical references (leaves 277-285). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Hermann, Patrice. "Recherche du ligand du CD40 : étude du rôle de son interaction avec le CD40 dans la réponse lymphocytaire B." Lyon 1, 1995. http://www.theses.fr/1995LYO1T120.
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Evans, Dean E. "CD40 Sustains T Cell Activation During Cognate Communication with Resting B Cells: a Dissertation." eScholarship@UMMS, 1998. http://escholarship.umassmed.edu/gsbs_diss/178.
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T and B-lymphocytes play an important role in an adaptive immune response. Communication between these two cells may result in either a humoral immune response or tolerance. Communication between T and B-lymphocytes involves a number of inducible cell surface molecules on both T and B-lymphocytes. It was the aim of this project to gain a greater understanding of the role of CD40 in the dynamic communication that occurs between naïve T-lymphocytes and resting B-lymphocytes during cognate communication. Because in vivo antigen specific T-lymphocytes are at low frequency, it is difficult to examine antigen-specific naïve T-lymphocytes. Thus, an in vitro system employing naïve antigen-specific T cell receptor (TCR) transgenic T cells and small resting B-lymphocytes that did not express CD40 was devised to examine the role of CD40 in cognate communication between naïve T-lymphocytes and resting B-lymphocytes.
Upon recognition of antigen on resting B-lymphocytes that expressed CD40, T-lymphocytes proliferated, expressed the activation antigens CD69 and CD25, and remained responsive to subsequent antigen challenge. In the absence of CD40, resting B-lymphocytes did not induce sustained proliferation or sustained expression of the activation markers CD69 and CD25 on naïve T-lymphocytes, and their recovery was decreased compared to naïve T-lymphocytes that recognized antigen on resting B-lymphocytes that expressed CD40. Naïve T-lymphocytes, however, remained responsive to subsequent antigen challenge after recognition of antigen on resting CD40-/- B-lymphocytes. Recognition of antigen on resting CD40-/- B-lymphocytes also resulted in increased recovery and antigen responsiveness of T-lymphocytes when compared to controls without antigen, The role of CD40 in sustaining activation of naïve T-lymphocytes may be unique to resting B-lymphocytes, since proliferation of naïve T-lymphocytes in response to dendritic cells that did not express CD40 was similar to proliferation of naïve T-lymphocytes in response to dendritic cells that expressed CD40. The mechanism by which CD40 sustained activation of naïve T-lymphocytes was investigated by examining the induction of various costimulatory molecules on resting CD40+/- and CD40-/- B-lymphocytes during cognate interaction with naive T-lymphocytes. Induction of B7-1, upregulation of CD44 and ICAM-1, and sustained but not initial induction of B7-2 required that CD40 be expressed on resting B-lymphocytes. Expression of B7-1 and CD44H was not required for proliferation of naïve T-lymphocytes in response to antigen presented on resting B-lymphocytes. However, sustained expression of B7-2 was crucial for proliferation of naïve T-lymphocytes in response to antigen presented on resting B-lymphocytes.
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Esquerré, Michael. "Influence des lymphocytes T CD4+ CD25+ régulateurs sur la dynamique de formation de la synapse immunologique entre un lymphocyte T CD4+ effecteur et une cellule présentatrice d'antigène." Toulouse 3, 2007. http://thesesups.ups-tlse.fr/51/.
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La rencontre entre un lymphocyte T et une cellule présentatrice d'antigène (CPA) est un évènement central dans l'initiation et le développement de la réponse immunitaire adaptative. L'interaction entre ces deux cellules entraîne de nombreuses réorganisations moléculaires au niveau de l'aire de contact intercellulaire conduisant à la formation d'une structure dynamique et spécialisée remplissant diverses fonctions biologiques : la Synapse Immunologique (SI). Cette interaction permet à un lymphocyte T CD4+ helper (TH) de s'activer et de mettre en place une signalisation intracellulaire nécessaire à la production de cytokines. Le second aspect crucial de cette interaction consiste en la polarisation de la machinerie sécrétoire du lymphocyte TH vers la CPA permettant ainsi une activation sélective de la CPA présentant l'antigène spécifique et donc une amplification sélective de la réponse immunitaire. Les lymphocytes T CD4+ CD25+ régulateurs naturels (Treg) jouent un rôle capital dans le maintien de la tolérance périphérique au soi, leur absence conduisant au développement de syndromes lymphoprolifératifs auto-immuns. Les Treg sont également impliqués dans le contrôle des réponses immunitaires anti-infectieuses et ont un rôle délétère lors des réponses immunitaires anti-tumorales. Différents mécanismes de régulation impliquant le contact cellulaire ou bien la sécrétion de molécules effectrices solubles ont à ce jour été décrits. Mon travail de thèse a été de déterminer si les Treg humains pourraient inhiber les réponses immunitaires en altérant la polarisation des lymphocytes TH vers les CPA. Afin de répondre à cette question, nous avons utilisé des approches de microscopie confocale afin de visualiser un Treg et un lymphocyte TH interagissant simultanément avec une même CPA. Nous avons pu observer que les Treg inhibent la polarisation de la machinerie sécrétoire des lymphocytes TH (appareil de Golgi et cytosquelette de tubuline) vers la CPA via la production locale de TGF-bêta. L'obtention de ces résultats nous a permis d'identifier un nouveau mécanisme de suppression, qui pourrait permettre de mieux appréhender l'incroyable potentiel des Treg à réguler finement les réponses immunitairesThe encounter between a T lymphocyte and an antigen presenting cell (APC) is a central event in the initiation and development of adaptative immune responses. Interaction between these two cells leads to multiple molecular reorganizations of the intercellular contact site leading to the formation of a dynamical and specialized structure filling diverse biological functions: the Immunological Synapse (IS). This interaction enables a CD4+ T helper lymphocyte (TH) to activate and to put into place an intracellular sustained signaling necessary for cytokine production. The second key feature of this interaction consists in TH lymphocyte secretory machinery polarization towards APC thereby allowing a selective activation of the APC presenting the specific antigen and thus a selective amplification of the immune response. CD4+ CD25+ natural regulatory T lymphocytes (Treg) play a pivotal role in the maintenance of peripheral self tolerance, their absence leading to the development of autoimmune lymphoproliferative disorders. Treg are also involved in controlling anti-infectious immune responses and have a deleterious role during anti-tumoral immune responses. To date, different regulation mechanisms involving cellular contact or the secretion of soluble effector molecules have been described. My thesis work was to determine if human Treg could inhibit immune responses by altering polarization of TH lymphocytes towards APC. In order to answer this question we used confocal microscopy approaches so as to visualize a Treg and a TH lymphocyte simultaneously interacting with a same APC. We were able to observe that Treg inhibit secretory machinery polarization of TH lymphocytes (Golgi apparatus and tubulin cytoskeleton) towards APC via local TGF- production. These results enabled us to identify a novel suppression mechanism that could allow to better apprehend the incredible potential of Treg to finely regulate immune responses
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Liu, Anquan. "Proinflammatory factor mediated lymphocyte activation - the pivotal role of leukotriene B4 /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-391-7/.
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Jellison, Evan Robert. "CD4 T Cell-Mediated Lysis and Polyclonal Activation of B Cells During Lymphocytic Choriomeningitis Virus Infection: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/349.
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CD4 T cells and B cells are cells associated with the adaptive immune system. The adaptive immune system is designed to mount a rapid antigen-specific response to pathogens by way of clonal expansions of T and B cells bearing discrete antigen-specific receptors. During viral infection, interactions between CD4 T cells and B cells occur in a dynamic process, where B cells that bind to the virus internalize and degrade virus particles. The B cells then present viral antigens to virus-specific CD4 T cells that activate the B cells and cause them to proliferate and differentiate into virus-specific antibody-secreting cells. Yet, non-specific hypergammaglobulinemia and the production of self-reactive antibodies occur during many viral infections, and studies have suggested that viral antigen-presenting B cells may become polyclonally activated by CD4 T cells in vivo in the absence of viral engagement of the B cell receptor. This presumed polyclonal B cell activation associated with virus infection is of great medical interest because it may be involved in the initiation of autoimmunity or contribute to the long-term maintenance of B cell memory.
In order to directly examine the interactions that occur between T cells and B cells, I asked what would happen to a polyclonal population of B cells that are presenting viral antigens, if they were transferred into virus-infected hosts. I performed these studies in mice using the well-characterized lymphocytic choriomeningitis virus (LCMV) model of infection. I found that the transferred population of antigen-presenting B cells had two fates. Some antigen-expressing B cells were killed in vivo by CD4 T cells in the first day after transfer into LCMV-infected hosts. However, B cells that survived the cytotoxicity underwent a dynamic polyclonal activation manifested by proliferation, changes in phenotype, and antibody production.
The specific elimination of antigen-presenting B cells following adoptive transfer into LCMV-infected hosts is the first evidence that MHC class II-restricted killing can occur in vivo during viral infection. This killing was specific, because only cells expressing specific viral peptides were eliminated, and they were only eliminated in LCMV-infected mice. In addition to peptide specificity, killing was restricted to MHC class II high cells that expressed the B cell markers B220 and CD19. Mice depleted of CD4 T cells prior to adoptive transfer did not eliminate virus-specific targets, suggesting that CD4 T cells are required for this killing. I found that CD4 T cell-dependent cytotoxicity cannot be solely explained by one mechanism, but Fas-FasL interactions and perforin are mechanisms used to induce lysis.
Polyclonal B cell activation, hypothesized to be the cause of virus-induced hypergammaglobulinemia, has never been formally described in vivo. Based on previous studies of virus-induced hypergammaglobulinemia, which showed that CD4 T cells were required and that hypergammaglobulinemia was more likely to occur when virus grows to high titer in vivo, it was proposed that the B cells responsible for hypergammaglobulinemia may be expressing viral antigens to virus-specific CD4 T cells in vivo. CD4 T cells would then activate the B cells. However, because the antibodies produced during hypergammaglobulinemia are predominantly not virus-specific, nonvirus-specific B cells must be presenting viral antigens in vivo.
In my studies, the adoptively transferred B cells that survived the MHC class II-restricted cytotoxicity became polyclonally activated in LCMV-infected mice. Most of the surviving naïve B cells presenting class II MHC peptides underwent an extensive differentiation process involving both proliferation and secretion of antibodies. Both events required CD4 cells and CD40/CD40L interactions to occur but B cell division did not require MyD88-dependent signaling, type I interferon signaling, or interferon γ signaling within B cells. No division or activation of B cells was detected at all in virus-infected hosts in the absence of cognate CD4 T cells and class II antigen. B cells taken from immunologically tolerant donor LCMV carrier mice with high LCMV antigen load became activated following adoptive transfer into LCMV-infected hosts, suggesting that B cells can present sufficient antigen for this process during a viral infection. A transgenic population of B cells presenting viral antigens was also stimulated to undergo polyclonal activation in LCMV-infected mice. Due to the high proportion of B cells stimulated by virus infection and the fact that transgenic B cells can be activated in this manner, I conclude that virus-induced polyclonal B cell activation is independent of B cell receptor specificity. This approach, therefore, formally demonstrates and quantifies a virus-induced polyclonal proliferation and differentiation of B cells which can occur in a B cell receptor-independent manner.
By examining the fate of antigen-presenting B cells following adoptive transfer into LCMV-infected mice, I have been able to observe dynamic interactions between virus-specific CD4 T cells and B cells during viral infection. Adoptive transfer of antigen-presenting B cells results in CD4 T cell-mediated killing and polyclonal activation of B cells during LCMV infection. Studies showing requirements for CD4 T cells or MHC class II to control viral infections must now take MHC class II-restricted cytotoxicity into account. Polyclonal B cell activation after viral infection has the potential to enhance the maintenance of B cell memory or lead to the onset of autoimmune disease.
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Peters, Anna Louisa. "Dysregulation of CD40 signaling pathways in enhanced B cell activation and autoimmunity." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1055.
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CD40 signals are required for productive immune responses but also play a role in autoimmune disease pathogenesis. The major goal of this research was to investigate the contribution of two receptors to the development of autoimmune disease: (1) LMP1, an oncogenic EBV-encoded mimic of CD40 and (2) a naturally-occurring polymorphism in CD40, P227A, which appears to confer LMP1-like properties to the CD40 receptor.
Interestingly, hCD40-P227A is overrepresented in individuals of Mexican and South American descent. Although this allele is not directly associated with SLE incidence in Hispanic populations, patients of Hispanic ethnicity have a tendency toward increased severity of SLE symptoms, particularly lupus nephritis. This work reports the initial genetic description of CD40-P227A and characterizes its gain-of-function signaling properties in mouse and human B cells. In comparison to Wt-CD40 signaling, CD40-P227A signaling results in increased binding of TRAF3, TRAF5, and Act1, as well as enhanced secretion of IL-6, TNF-α, and Ig due to a selective hyperactivation of the JNK pathway. Whereas TRAF3 is normally a negative regulator of Wt-CD40 signaling, TRAF3 is a required positive regulator of CD40-P227A signaling as demonstrated in TRAF3-deficient B cells.
LMP1 is an EBV-encoded CD40 mimic which signals in an amplified and sustained manner. Although EBV is latent in >90% of humans, EBV infection is associated with autoimmunity, particularly SLE. Upon flares of autoimmunity, EBV reactivates and LMP1 is expressed, yet the contribution of LMP1 to exacerbation of disease is unknown. LMP1 transgenic mice generated in our lab have an autoreactive phenotype but do not die early due to autoimmune disease. To test the hypothesis that LMP1 cooperates with other genes in the host to exacerbate autoimmunity, mCD40-LMP1 transgenic mice were bred to two lupus-prone strains of mice. LMP1 signaling was able to enhance the autoimmune phenotype of the B6.Sle1, but not the B6.Sle3 strain. These data suggest that LMP1 is redundant with genes within the Sle3 interval, but acts cooperatively with genes within the Sle1 interval to exacerbate autoimmunity.
Together, the research foci of this dissertation examine how the CD40 pathways of B cell activation can be amplified and dysregulated, by either a viral mimic of CD40, a polymorphism in its signaling domain, or its cooperation with additional gene products. Differential usage of TRAF3 as a positive, rather than a negative, regulator of signaling appears to be one common mechanism by which this occurs. In conditions where enhanced CD40 signaling may be desirable such as during chronic infections, manipulation of TRAF3-CD40 signaling may serve to enhance immune responses. It is hoped that these studies can additionally reveal important information about the normal regulation of this powerful activation pathway.
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Filippi, Christophe. "Cellules dentritiques : activation et différenciation des lymphocytes T CD4+ in vivo." Nice, 2003. http://www.theses.fr/2003NICE4028.
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Au cours de ma thèse, j'ai tenté de comprendre pourquoi certains individus sont plus sensibles que d'autres à l'infection par certains pathogènes. Je me suis intéressé à la présentation de l'antigène parasitaire LACK ainsi qu'à l'activation et la différenciation des lymphocytes T (LT) CD4+ spécifiques de cet antigène chez des souris infectées par le parasite Leishmania (L. ) major. Les travaux que nous avons effectués nous ont permis de montrer que les cellules responsables de l'initiation des réponses T CD4 anti-LACK chez les souris sensibles BALB/c comme chez les souris résistantes B10. D2 sont des cellules dendritiques (DC) qui expriment la molécule CD11b. Toutefois, alors que les DC issues de souris B10. D2 infectées induisent préférentiellement des réponses de polarité Th1, les mêmes cellules issues de souris BALB/c induisent des réponses de type Th2, probablement en raison de défaillances dans leur capacité à produire de l'IL-1b. De plus, ce phénomène est une propriété intrinsèque des DC des souris BALB/c et B10. D2, indépendante de l'infection, et pouvant être observée avec d'autres antigènes que LACK indépendament de l'haplotype des souris. Ainsi, la capacité de différents individus à monter des réponses T CD4 de polarité différente serait sous le contrôle de gènes exprimés par les DC. Au cours d'une autre étude, nous avons montré que les cinétiques d'activation et d'expansion des LT CD4+ anti-LACK sélectionnés consécutivement à l'infection chez les souris sensibles et résistantes sont comparables, mais que leurs propriétés phénotypiques sont différentes. Alors que ces cellules sont de type Th1 et expriment des récepteurs T (TCR) de haute affinité chez les souris B10. D2, elles sont de type Th2 et expriment des TCR d'affinité plus faible chez les souris BALB/c. Ces résultats suggèrent l'existence d'un lien entre l'affinité des TCR exprimés par les LT CD4+ et leur capacité à se différencier en effecteurs Th1 ou Th2. Enfin, une troisième étude nous a permis de démontrer que le blocage des signaux de co-stimulation fournis par CD86 permet de renverser la polarité des LT CD4+ anti-LACK des souris BALB/c infectées par L. Major sans pour autant modifier la nature et l'affinité du TCR qu'ils expriment. L'ensemble de nos résultats nous a permis de suggérer l'existence de gènes et mécanismes des compartiments "T" et "non T" modulant de façon indépendante la polarité des réponses T CD4 in vivoDuring my Ph. D, I tried to understand why some individuals are more susceptible than others to specific infectious diseases. I focused on the presentation of the Leishmania (L. ) LACK antigen and the activation and differentiation of LACK-specific CD4+ T cells in L. Major-infected mice. The results we obtained indicated that the cells which are responsible for the initiation of LACK-specific CD4 T cell responses in both resistant and susceptible mice are dendritic cells (DCs) which express the surface molecule CD11b. However, while DCs from infected B10. D2 mice preferentially induce Th1 responses, DCs from BALB/c mice induce Th2 responses, probably due to defects in their ability to produce IL-1b. Moreover, this phenomenon is an intrinsic property of BALB/c and B10. D2 DCs, is independant of infection, and can be observed with other antigens than LACK, independently of the haplotype of the mice. Thus, the ability of different individuals to mount Th1 or Th2 responses may be governed by genes which are expressed by DCs. In another study, we showed that the kinetics of activation and expansion of LACK-specific CD4+ T cells from infected resistant and susceptible mice are similar while their phenotypic properties are different. While these cells are high-affinity T cell receptor (TCR)-expressing Th1 cells in B10. D2 mice, they are Th2 cells and express lower affinity TCR in BALB/c mice. These results suggest the existence of a linear relationship between the affinity of the TCR expressed by CD4+ T cells and theire ability to differentiate into Th1 or Th2 effectors. Finally, we showed in a third study that the blockade of the co-stimulatory signals provided by CD86 is able to reverse the polarity of LACK-sepcific CD4+ T cells without modifying the type and affinity of their TCR. The whole of our results enabled us to suggest the existence of genes and mechanisms from both "T" and non "non-T" cell compartments which independently modulate the polarity of CD4 T cell responses in vivo
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Fournel, Sylvie. "Étude des mécanismes de contrôle de l'activation, de l'anergie et de l'apoptose des cellules T par la molécule CD4." Lyon 1, 1996. http://www.theses.fr/1996LYO1T124.
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Malin, Stephen. "Deciphering mechanisms of transcriptional activation and repression in B lymphocytes /." Stockholm : Karolinska institutet, 2004. http://diss.kib.ki.se/2004/91-7349-958-7/.
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Hernandez, Maria Genevieve H. "The Role of CD40 in Naïve and Memory CD8+ T Cell Responses: a Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/346.
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Stimulation of CD40 on APCs through CD40L expressed on helper CD4+ T cells activates and “licenses” the APCs to prime CD8+ T cell responses. While other stimuli, such as TLR agonists, can also activate APCs, it is unclear to what extent they can replace the signals provided by CD40-CD40L interactions. In this study, we used an adoptive transfer system to re-examine the role of CD40 in the priming of naïve CD8+ T cells. We find an approximately 50% reduction in expansion and cytokine production of TCR-transgenic T cells in the absence of CD40 on all APCs, and on dendritic cells in particular. Moreover, CD40-deficient and CD40L-deficient mice fail to develop endogenous CTL responses after immunization and are not protected from a tumor challenge. Surprisingly, the role for CD40 and CD40L are observed even in the absence of CD4+ T cells; in this situation, the CD8+T cell itself provides CD40L. Furthermore, we show that although TLR stimulation improves T cell responses, it cannot fully substitute for CD40.
We also investigated whether CD40-CD40L interactions are involved in the generation, maintenance, and function of memory CD8+ T cells. Using a virus infection system as well as a dendritic cell immunization system, we show that the presence of CD40 on DCs and other host APCs influences the survival of activated effector cells and directly affects the number of memory CD8+ T cells that are formed. In addition, memory CD8+ T cell persistence is slightly impaired in the absence of CD40. However, CD40 is not required for reactivation of memory CD8+ T cells. It seems that CD40 signals during priming also contribute to memory CD8+ T cell programming but this function can be independent of CD4+T cells, similar to what we showed for primary responses.
Altogether, these results reveal a direct and unique role for CD40L on CD8+ T cells interacting with CD40 on APCs that affects the magnitude and quality of primary as well as memory CD8+ T cell responses.
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Clay, Elizabeth. "The effects of environmental oxygen on CD4+ T lymphocyte activation and responses." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5795/.
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The organs in which lymphocytes function are low in oxygen (<5% oxygen) and even lower oxygen levels may be more prevalent in inflammatory tissues. In this thesis the effects of environmental oxygen on human CD4+ memory T lymphocyte function in vitro have been investigated. The level of oxygen in normal air (21%) which historically has been used for most in vitro experiments with immune cells was found result in suboptimal responses of this cell type, especially with regards to proliferation. At physiologically more appropriate oxygen levels of 8.5%, optimal proliferation was observed which coincided with an increase in Th2-associated markers. At 3% oxygen, the average level found in the inflamed joint in rheumatoid arthritis, a more sustained pro-inflammatory response was observed. In 1% oxygen, cytokine production was not maintained over time paralleling observations of CD4+ T lymphocyte behaviour in both the tumour and chronic inflammatory environment. This comparison was further supported by the increased expression of the activation marker CD69 and the depression of CD4+ T lymphocyte proliferation. A model of reperfusion injury also highlighted the effect that varying oxygen levels can have on CD4+ memory T lymphocytes. Proximal T cell receptor signalling was found to be altered after equilibration at different oxygen levels, and preliminary experiments investigating the potential role that redox plays in regulating CD4+ memory T lymphocyte functions were performed. It is concluded that environmental oxygen levels significantly influence CD4+ memory T lymphocyte responses, have implications for their function in inflammatory sites in vivo, and need to be considered when designing or interpreting in vitro experiments.
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Mayack, Shane Renee. "The role of Janus Kinase 3 in CD4+ T Cell Homeostasis and Function: A Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/94.
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This dissertation addresses the role for Janus Kinase 3 (Jak3) in CD4+ T cell homeostasis and function. Jak3 is a protein tyrosine kinase whose activity is essential for signals mediated by the γc dependent cytokines IL-2, -4, -7, -9, -15, and -21. Previous data have demonstrated that peripheral CD4+ T cells from Jak3-deficient mice have a memory phenotype and are functionally impaired in both proliferative and IL-2 responses in vitro. Interestingly, Jak3/γc activity has been previously shown to play a role in the prevention of T cell anergy.
These studies were initiated to more precisely define the role for Jak3/γc cytokines in the prevention of T cell anergy and the maintenance of functional CD4+ T cell responses. We began to address this question by assessing global gene expression changes between wild type and Jak3-/- CD4+ T cells. These data indicate that Jak3-/- CD4+ T cells have an increase in gene expression levels of inhibitory surface receptors as well as immunosuppressive cytokines.
Further analyses confirmed that Jak3-deficient T cells express high levels of PD-1, secrete a Trl-type cytokine profile following direct ex vivo activation, and suppress the proliferation of wild type T cells in vitro. These characteristics indicate that CD4+ Jak3-/- T cells share properties with regulatory T cell subsets that have an important role in peripheral tolerance and the prevention of autoimmunity.
We next addressed whether these regulatory characteristics were T cell intrinsic or rather the result of expanding in a Jak3-deficient microenvironment characterized by a number of immune abnormalities and a disrupted splenic architecture. Jak3-/- CD4+ T cells proliferate in vivoin a lymphopenic environment and selectively acquire regulatory T cell characteristics in the absence of any additional activation signals. While the precise mechanism by which Jak3-deficient T cells acquire these characteristics remains unclear, our data indicate that one important component is a T cell-intrinsic requirement for Jak3 signaling.
These findings indicate several interesting aspects of T cell biology. First, these studies, demonstrate that the homeostatic proliferation of CD4+ T cells is not dependent on signaling via γc-dependent cytokine receptors. And, second, that the weak activation signals normally associated with homeostatic expansion are sufficient to drive Jak3-/- T cells into a non-conventional differentiation program. Previous data indicate that, for wild type T cells, signaling through both the TCR as well as γc-dependent cytokine receptors promote the homeostatic proliferation of T cells in lymphopenic hosts. Since Jak3-/- T cells are unable to receive these cytokine signals, their proliferation is likely to be wholly dependent on TCR signaling. As a consequence of this TCR signaling, Jak3-/- T cells proliferate, but in addition, are induced to up regulate PD-1 and to selectively activate the IL-10 locus while shutting off the production of IL-2. Since this fate does not occur for wild type T cells in a comparable environment, it is likely that the unique differentiation pathway taken by Jak3-/- T cells reflects the effects of TCR signaling in the absence of γc-dependent cytokine signaling.
Interestingly, wild type T cells undergoing homeostatic expansion in lymphopenic hosts show many common patterns of gene expression to freshly-purified unmanipulated Jak3-/- T cells. For instance, micro array analysis of gene expression in wild type CD4+ T cells after lymphopenia induced homeostatic expansion show a similar pattern of upregulation in surface markers (PD-1 and LAG-3), and cytokine signaling molecules (IL-10 and IFN-γ cytokine, receptors, and inducible gene targets) to that of Jak3-/- CD4+ T cells immediately ex vivo. These data suggest that the process of homeostatic proliferation normally induces immune attenuation and peripheral tolerance mechanisms, but that full differentiation into a regulatory T cell phenotype is prevented by γc-dependent cytokine signals.
Taken together these data suggest that Jak3 plays an important role in tempering typical immune attenuation mechanisms employed to maintain T cell homeostasis and peripheral tolerance.
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Bonnefoix, Thierry. "Les lymphocytes T intra-tumoraux dans les lymphomes malins non hodgkiniens B : activation, prolifération et production de facteurs de régulation des cellules B." Grenoble 1, 1991. http://www.theses.fr/1991GRE10153.
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Les lymphocytes t sont constamment presents dans les ganglions envahis par un lymphome malin non hodgkinien b. Ce travail a permis de reunir des arguments en faveur de l'implication de ces cellules t dans le processus tumoral: diminution de la capacite des cellules t a produire de l'interleukine 2 (il2) et a proliferer en presence de pha; pourcentages eleves de cellules t dr+ (activees), et cd4+cd45ra-(memoires), ainsi que de cellules t cd25+ (p55 du recepteur de l'il2); a partir des cellules t cd25+ totales, il a ete obtenu des clones t capables de proliferer au contact des cellules b malignes autologues, mais pas au contact des cellules b normales (b-ebv) autologues; la nature des relations fonctionnelles entre les cellules t intra-tumorales et les cellules b malignes autologues reste a determiner: en utilisant des cellules b normales comme cibles des cellules t, il n'a pu etre mis en evidence aucune anomalie de production d'activites bcgf et bcdf mu et gamma
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Costa, Priscilla Ramos. "Avaliação do perfil de ativação de células T nas fases recente e estabelecida de infecções por subtipos C e não C do vírus HIV-1." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-11052017-161346/.
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A pandemia Hiv/ Aids já resultou em mais de 34 milhões de pessoas infectadas pelo vírus no mundo até o momento. Causada pelo HIV, de caráter crônico que evolui para um quadro clínico de imunodeficiência (Aids), pode tornar o indivíduo susceptível a infecções oportunistas potencialmente letais. Diferentes fatores foram identificados por ativar o sistema imune, incluindo genótipos do hospedeiro (HLAB-27, HLA-B57, CCR5delta32), co-infecções (GBV-C) e alguns fatores virais como a capacidade de replicação (fitness) e tropismo celular. O HIV-1 possui diversidade genética extensa e dinâmica. Considerando a variabilidade genética dentro do cenário da epidemia no Brasil, as clades do HIV-1 predominantes são B, F e C, além de formas recombinantes. Contudo, ainda não foi completamente estabelecido se essa diversidade genética possa influenciar o curso clínico da doença. O objetivo deste trabalho foi avaliar o perfil de ativação celular induzido encontrado em indivíduos infectados por subtipos virais C e Não- C do HIV-1, durante o primeiro ano de infecção (analisando as fases recente e estabelecida). A análise comparativa dos dois grupos (subtipos C vs. Não-C), identificou no grupo do subtipo-C uma maior frequência de células T CD4+ totais ativadas, como também uma maior frequência e ativação nas subpopulações de células T CD4+ de memória, principalmente memória efetora e efetora terminal, na fase estabelecida. Em relação às células T CD8+, deparamos na fase estabelecida com uma maior frequência de células T CD8+ de memória efetora e ativação das mesmas no grupo do subtipo-C em relação ao grupo do subtipo Não-C. Investigamos também a presença de células T CD4+ que se diferenciaram em células T reguladoras, e foi encontrada uma frequência diminuída dessas células no grupo do subtipo C em relação ao Não- C tanto na fase recente como na fase estabelecida. Na análise comparativa das fases recente e estabelecida, o grupo do subtipo Não-C apresentou um declínio tanto na quantidade de células T CD4+ como na frequência de células T CD8+ ativadas após um ano de infecção. Com base nos resultados encontrados, os dois grupos apresentaram perfis de ativação e diferenciação celular diferentes no primeiro ano de infecção pelo HIV-1, o que aponta para diferentes histórias naturais quando comparamos infecção por clades virais distintasThe Hiv/ Aids pandemic has affected more than 34 million people worldwide, reaching men, women and children. Caused by the HIV virus, a chronic infection that develops into a clinical picture of immunodeficiency (Aids), it can make the individual susceptible to opportunistic infections and result in death. Different factors were identified by activating the immune system, including host genotypes (HLAB-27, HLA-B57, CCR5delta32), co-infections (GBV-C) and some viral factors such as fitness and cellular tropism. The HIV-1 presents an extensive and dynamic genetic diversity, favoring the production of variants with molecular differences. Considering the genetic variability within the scenario of the epidemic in Brazil, the predominant subtypes of HIV-1 are B, F and C. However, it has not yet been completely established if this genetic diversity can impact the clinical course of the disease. The objective of this study was to evaluate the induced cellular activation profile found in HIV-1 C and non-C viral subtypes groups in the first year of infection (analyzing the recent and established phases). The comparative analysis of the two groups (subtypes C vs. Non-C) identified a higher frequency of activated CD4+ T cells in the C-subtype group, as well as a higher frequency and activation in CD4+ T-cell subsets of memory, mainly effector memory and terminal effector on the established phase. About CD8+ T cells, we found in the established phase a higher frequency and activation in the effector memory subset in the C- subtype group compared to the non- C subtype group. We also investigated the presence of CD4+ T cells differentiated into regulators T cells, and a decreased frequency of these cells was found in the subtype C group over non- C in both the recent and established phases. In the recent and established phase comparative analysis evidenced that the non-C subtype group presented a decline in both the number of CD4+ T cells and the CD8+ T-cell activated frequency after 1 year of infection, however, it presented a positive correlation between the viral load and frequency of activated CD4+ and CD8+ T cells in both phases. Based on the results found, the two groups presented different activation and differentiation profiles in the first year of HIV-1 infection, which points to different natural histories when comparing infection with different viral clades
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Vazquez, Aimé. "Activation des lymphocytes B humains : interactions entre signaux spécifiques et non spécifiques." Paris 6, 1986. http://www.theses.fr/1986PA066436.
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Lafarge, Sandrine. "Signalisation dans le lymphocyte B humain au décours de son activation in vitro via les molécules de l'immunité innée." Saint-Etienne, 2008. http://www.theses.fr/2008STET007T.
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Une activation lymphocytaire B anormale ou déréglée est souvent la cause de nombreuses maladies auto-immunes ou cancéreuses, en particulier onco-hématologiques. Cette activation cellulaire est sous le contrôle de différentes voies de signalisation intracellulaire d'où l'émergence de nombreux axes d'études sur le rôle et la modulation de la signalisation. L'objectif de mon travail de thèse était donc d'étudier la signalisation dans les lymphocytes B in vitro dans un contexte expérimental inflammatoire. Les cytokines/chimiokinies et les TLR ayant un rôle majeur dans l'inflammation, nous avons dans un premier temps, détecté l'expression du TLR9 par les lymphocytes B. Ainsi, nous avons identifié deux populations lymphocytaires B distinctes (naïve et mémoire) exprimant toutes deux le TLR9 membranaire. Après stimulation par le sCD40L, l'IL-2, l'IL-10 et des oligonucléotides de type CpG-ODN, ces populations produisaient d'importantes quantités d'IL-6. Cette dernière induisant la différenciation des lymphocytes B en plasmocytes, ces données montrent le rôle indirect de la signalisation via le TLR9 dans la production d'anticorps en réponse à un signal de danger. Par la suite, nous nous sommes posé la question des mécanismes sous-jacents entrant en jeu lors de l'activation des lymphocytes B et nous sommes donc intéressés plus précisément à la signalisation intracellulaire. Tout d'abord, nous avons développé une technique d'analyse de cytométrie en flux permettant d'observer les voies de signalisation NF-κB et STAT3. Ensuite nous avons cherché à savoir si la voie de signalisation STAT3 était impliquée dans la production d'IgA lorsque le BCR n'était pas engagé par un antigène c'est à dire en cultivant des lymphocytes B en présence de sCD40L, IL10 et TGF-β. Nous avons tout d'abord montré que la production d'IgA, dans ce modèle, ne nécessitait pas d'ajout de TGF-β exogène et que cette production dépendait bien des voies intracellulaires NF-κB et STAT3. De plus, la voie STAT3 était directement activée par l'IL-10 sans dépendance vis à vis de IL-6 et coopérait avec la voie NF-κB, ce qui rendait la voie STAT3 encore plus sensible à l'IL-10 en augmentant l'expression d' IL-10R par les lymphocytes B. Ces travaux montrent une fois de plus l'importance de la voie intracellulaire STAT3 dans les réponses immunitaires. Le rôle prépondérant de la voie STAT3 dans le développement lymphocytaire B la désigne comme une cible potentielle pour le développement de vaccins muqueux, en particulier pour l'obtention de réponses humorales (IgA) aux interfaces muqueuses.
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Forni, Luciana. "Recepteurs membrananires des lymphocytes b : interactions entre recepteurs et physiologie des cellules b." Paris 6, 1987. http://www.theses.fr/1987PA066375.
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Pozzi, Lu-Ann M. "Macrophages Directly Prime Naïve CD8+ T Cells: a Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/117.
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Professional antigen presenting cells (APCs) represent an important link between the innate and adaptive immune system. Macrophages (MΦs) and dendritic cells (DCs) serve as sentinels in the periphery collecting samples from their environment and processing this information. These cells then present antigenic fragments to T cells in the context of self-MHC molecules. Although a clear role for both of these APCs in the stimulation of already activated or memory T cells has been established, the ability of MΦs to activate naive T cells is still unknown. In this thesis the ability of bone marrow-derived MΦs and DCs to prime naive CD8+ and CD4+ T cells was investigated. Using adoptively transferred transgenic CFSE-Iabeled P-14 T cells, specific for gp33 from lymphocytic choriomeningitis virus in the context of Db, we were able to demonstrate the ability of both MΦs and DCs to induce naive CD8+ T cells proliferation. Once primed by MΦs these T cells gained effector function as shown by interferon- γ (IFN-γ) production and in vivo cytolysis. In addition, immunization of wild type animals with gp33-pulsed MΦs, as well as DCs, led to greater than a 95% reduction in lymphocytic choriomeningitis virus titers. To rule out the role of cross-presentation in the observed priming, two models were used. In the first model, lethally irradiated F1 bxs chimeras reconstituted with either H-2s or H-2b bone marrow were used as host for the adoptive transfer experiments. Since the gp33 peptide binds to Db, the H-2s reconstituted animals should be unable to cross-present the peptide to the P-14 T cells. Using this model, we were able to clearly demonstrate the ability of MΦs to activate naive P-14 T cells to undergo division. Additional experiments, demonstrated that these MΦ primed T cells went on to develop into effector cells. Finally, the ability of the MΦ primed T cells to develop into functional memory cells was demonstrated. To confirm the chimera results, these experiments were repeated using β2 microglobulin deficient animals (whose cells don't express MHC I) as host in adoptive experiments. MΦs were able to stimulate the naive P-14 T cells to divide and gain effector function as demonstrated by the ability to produce IFN-γ. In contrast to the CD8 system, MΦ were poor stimulators of D011.10 CD4+ T cell proliferation. Additionally, D011.10 T cells stimulated by DCs were able to produce interleukin-2 (IL-2), IL-4, tumor necrosis factor and granulocyte-macrophage colony stimulating factor where as MΦ stimulated D011.10 T cells were only able to produce IL-2. In conclusion this body of work clearly demonstrates the in vivo ability of MΦ to stimulate CD8+ T cell proliferation, effector function, as well as the formation of functional CD8+ T cell memory. Whether or not the nature of the memory pools stimulated by the two APCs is exactly the same is still unknown and needs further investigation. The ability of APCs other than DCs to stimulate functional protective memory needs to be considered in the quest to design vaccines that offer broad-spectrum protection.
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Westerberg, Lisa. "Regulation of B cell motility and adhesion in health and disease /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-694-4.
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Donati, Daria. "Malaria, B lymphocytes and Epstein-Barr virus : emerging concepts on Burkitt's lymphoma pathogenesis /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-403-1/.
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Huard, Bertrand. "Caracterisation structurale et fonctionnelle d'une nouvelle molecule apparentee a cd4, lag-3 (lymphocyte activation gene 3)." Paris 7, 1995. http://www.theses.fr/1995PA077123.
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Le gene lag-3 est considere comme un cousin germain de cd4. Ces deux genes sont localises sur une meme bande (12p13) du chromosome 12 humain, presentent des similarites dans leur organisation genomique, et les produits proteiques possedent un meme ligand, les molecules du cmh ii. Toutes ces observations suggerent que lag-3 et cd4 proviennent d'un ancetre commun, et constitue donc une sous-famille, sous famille cd4, a l'interieur de la famille des immunoglobulines. Plag-3 est une glycoproteine monomerique de 70 kda, associee a la membrane cellulaire a une (ou plusieurs) gp(s) 45. Cette expression est restreinte aux cellules t et nk activees. Lag-3 est implique dans la desactivation de clones t cd4+. En effet, lag-3 transduit un signal desactivateur en aggregant les molecules du cmh ii exprimees par les cellules t activees. En conclusion, lag-3 et cmh ii representent un couple recepteur-ligand implique dans un phenomene de desactivation autocrine de la reponse t
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Aucher, Anne. "Étude des caractéristiques de la capture de fragments de membrane par trogocytose par les lymphocytes T et B." Toulouse 3, 2008. http://thesesups.ups-tlse.fr/752/.
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La mise en place des réponses immunitaires a lieu via l'échange de facteurs solubles et la transmission de signaux intracellulaires. Ces dernières années, un nouveau mode de communication a été découvert, mettant en jeu l'échange de fragments de membrane entre cellules en contact. Ce processus, nommé trogocytose, initialement décrit chez les lymphocytes T, est rapide, efficace et présente une spécificité de passage. Mais ses mécanismes et ses rôles physiologiques sont encore mal définis. Mon travail de thèse s'est orienté sur deux axes : mener une étude comparative des mécanismes de la trogocytose entre les lymphocytes T et B et identifier les bases de la sélectivité de capture par trogocytose. En utilisant des inhibiteurs de différentes voies d'activation lymphocytaire, nous avons déterminé que si la trogocytose est un phénomène actif, dépendant du cytosquelette d'actine et de la signalisation dans les lymphocytes T, c'est un phénomène passif dans les lymphocytes B, qui a lieu dans toutes les conditions testées. Cette différence, intrinsèque au type cellulaire, est une première étape vers la compréhension du phénomène dans son ensemble. Dans les travaux sur la sélectivité de passage par trogocytose nous avons tout d'abord montré que les glycoconjugués membranaires étaient capturés efficacement par les lymphocytes par trogocytose. L'étude a alors été complétée par une approche plus fine de criblage de protéines individuelles. Nos résultats préliminaires confirment l'existence d'une sélectivité de passage et identifient des protéines candidates, dont l'étude permettra de comprendre les bases du transfert sélectif et donc de mieux appréhender les mécanismes de la trogocytoseEstablishment of immune responses takes place through soluble factors exchange and intracellular signals transmission. Recently, a new mode of communication has been discovered, involving the exchange of plasma membrane fragments between cells in contact. This phenomenon, called trogocytosis, originally described in T cells, occurs rapidly and efficiently and is a selective process. However, its mechanisms and physiological roles are not well defined yet. My thesis work has focused on two main areas: first to compare the mechanisms of trogocytosis in T and B lymphocytes and second to identify the criteria that determine the selectivity of transfer. Using a large panel of inhibitors of various cellular activities, we determined that trogocytosis is an active phenomenon in T cells, dependent on actin cytoskeleton and signalisation, and that it is a passive phenomenon in B cells, that can takes place in all conditions we tested. This difference, intrinsic to the cell type, is a first step towards understanding the phenomenon of trogocytosis as a whole. Concerning selectivity of molecules transfer, we first showed that glycoconjugates were captured from the target cells with the same efficiency as proteins or lipids during trogocytosis by T and B cells. In a second study, we are currently working to define the criteria of transfer selectivity of membrane components by following the transfer of unique proteins. Our initial results confirm that there is a selectivity of transfer and identify candidate proteins, whose study will enable us to understand the factors determining the transfer of molecules, and thus to advance our understanding of the mechanism(s) of trogocytosis
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Hmama, Zakaria. "Propriétés de différents extraits de Klebsiella pneumoniae : antigénicité, liaison aux membranes, activation des monocytes et des lymphocytes B." Lyon 1, 1992. http://www.theses.fr/1992LYO1H177.
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Anis, Mursalin M. "Modulation of naive CD4+ Tcell activation and dendritic cell function in the lungs during pulmonary mycobacterial infection." Connect to text online, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1184427168.
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Siracusa, Francesco. "Maintenance and re-activation of antigen-specific CD8+ and CD4+ memory T lymphocytes in the bone marrow." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19335.
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Das Knochenmark (BM) beherbergt wesentliche Komponenten des adaptiven Immunsystems, die einen langfristigen Schutz gegen wiederkehrende Pathogene vermitteln können, sodass es sich als Reservoir für ein immunologisches Gedächtnis qualifiziert. Neben langlebiger Antikörper-produzierender Plasmazellen bleiben auch Antigen (Ag)-spezifische CD8+ und CD4+ T-Gedächtniszellen dauerhaft im Knochenmark erhalten, auch wenn sie in den sekundären lymphoiden Organen (SLOs) und im Blut abwesend sind. Es wird angenommen, dass diese T-Gedächtniszellen bei erneutem Kontakt mit den gleichen systemischen Pathogenen schnell reagieren können. Allerdings sind die biologischen Mechanismen für ihre langfristige Aufrechterhaltung immer noch umstritten und demnach ungeklärt. Unklar ist auch, wie die T-Gedächtniszellen des Knochenmarks bei erneuter Konfrontation mit demselben Antigen reagieren. Hier wird dieser Frage begegnet, indem durch klassiche Immunisierung mit definieren Antigenen eine stabile Population Ag-spezifischer CD8+ und CD4+ T-Gedächtniszellen im Knochenmark erzeugt wird.The bone marrow (BM) harbors critical components of the adaptive immune system being able to provide long-lasting protection against previously encountered pathogens, thus qualifying as a reservoir of immunological memory. In addition to long-lived antibody producing plasma cells, antigen (Ag)-specific CD8+ and CD4+ memory T lymphocytes are maintained long-term in the BM even when they are absent from secondary lymphoid organs (SLOs) and blood. Those memory T cells are thought to respond fast upon re-encounter of systemic pathogens. However, the biological mechanisms behind their long-term maintenance in the BM are still a matter of debate and thus remain unclear. Similarly, it is also unclear how the memory T cells of the BM react to antigenic re-challenge. Here we address these issues by generating a stable pool of Ag-specific CD8+ and CD4+ memory T lymphocytes in the BM by classical immunizations with defined antigens.
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Schmidt, Madelyn R. "Virus-Lymphocyte Interactions: Virus Expression Is Differentially Modulated by B Cell Activation Signals: A Dissertation." eScholarship@UMMS, 1991. https://escholarship.umassmed.edu/gsbs_diss/51.
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It is shown here that the ability of B lymphocytes to act as supportive host cells for virus infections requires they be activated from the resting Gostage of the cell cycle. I have used a series of activation regimens, which allow B cells to progress to different stages in their activation/differentiation pathway toward antibody secretion, in order to evaluate the extent of activation required to support vesicular stomatitis or Newcastle disease virus infections.
At least three distinct phases during B cell activation which affected VSV infection were defined. Freshly isolated resting murine splenic B cells in the Go phase of the cell cycle do not support VSV, assessed by protein synthesis, infectious center formation, and PFU production. Small B cells cultured for 48 hours without stimulation still do not support VSV. B cells stimulated with the lymphokines found in Con A activated supernatants from splenic T cells or cloned T cell lines transited into the G1 phase of the cell cycle but remain refractory to VSV. These VSV non-supportive B cell populations do take up virus particles and transcribe viral mRNAs which can be translated in vitro, suggesting a translational block to VSV. B cells stimulated into the S phase of the cell cycle with anti-immunoglobulin synthesize VSV proteins and increased numbers of infectious centers, but only low level PFU synthesis (center) is observed. Co-stimulation with anti-Ig and lymphokines, which supports differentiation to antibody secretion, enhanced PFU synthesis without further increasing the number of infected B cells. LPS, which activates B cells directly to antibody secretion by a pathway different from anti-Ig, induced infectious centers, and PFUs at levels comparable to those seen when stably transformed permissive cell lines are infected. Co-stimulation of LPS activated B cells with the same lymphokine populations that enhance PFU production when anti-Ig is used as a stimulator suppresses PFU production completely, suggesting that anti-Ig and LPS activated B cells are differentially responsive to lymphokines.
NDV infection of murine B cells differed markedly from VSV infection, as all B cell populations examined gave a similar response pattern. NDV viral proteins were synthesized by B cells in each of the activation states previously described, even freshly isolated B cells. Infectious center formation increased up to 5-fold over the levels observed with unstimulated B cells after anti-Ig or LPS activation. However, PFU synthesis was low (center) for all B cell populations.
These results suggest that these two similar viruses may be dependent on different host cell factors and that these factors are induced for VSV but not NDV by the B cell activators employed here or that the process of infection of B cell by these two viruses induces different cellular responses.
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De, Milito Angelo. "Immune activation during HIV-1 infection : implication for B cell dysfunctions and therapy monitoring /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-170-5.
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Murera, Uwanyirigira Diane. "Study of lymphocyte autophagy in normal and autoimmune responses." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ068.
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L’autophagie est un processus catabolique lié aux lysosomes, essentiel à la l’homéostasie cellulaire notamment dans les lymphocytes. Elle est impliquée dans la pathogenèse de nombreuses maladies et pourrais jouer un rôle dans le développement de maladies auto-immunes. Nous avons voulu étudier son rôle in vivo dans les lymphocytes B et T. Nous avons généré des souris déficientes en autophagie spécifiquement dans ces cellules et montré que l’autophagie n’est pas essentielle au développement des LB, mais que dans un contexte auto-immun la persistance de plasmocytes et la production d’autoanticorps été diminuée. Cela démontre un rôle de l’autophagie dans les réponses à long terme. Les réponses humorales à long-terme T dépendantes sont également impactées. De plus des souris transplantées avec des LT CD4+ déficients en autophagie montrent une réponse humorale mémoire diminuée. Nous nous sommes également intéressé aux voies de signalisation conduisant à l’induction de l’autophagie en réponse à une stimulation du TCR dans des LT normaux et pathologiques. Nos résultats préliminaires montrent une implication de la voie calciqueAutophay is a catobolic lysosomal process essentail for cellular maintenance and fucntion such as lymphocyte homeosatsis. The generation of mice models with an Atg5 conditional knock-out in B and T cells respectively, have allowed us to study autophagy requirements of those immune cells in vivo. We have demonstrated that autophagy was dispensable for B cell development but that in autoimmune settings B cell autophagy was required for the maintenance of long-lived plasma cells and for the production of autoantibodies. In mice deficient for autophagy in T cells, long-term tumoral response to a T-dependent antigen is decreased. We also showed that in mice adoptively transferred with autophagy deficient CD4 T cells, the antigen specific memory humoral immune response was impaired. We also investigated the signaling pathways leading to autophagy induction upon TCR stimulation in normal and lupus T cells and showed that the calcium signaling is highly involved
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Thedrez, Aurélie. "Modalités d'activation des lympocytes T non conventionnels iNKT et Vgamma9Vdelta2." Paris 7, 2009. http://www.theses.fr/2009PA077026.
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Les lymphocytes non conventionnels iNKT (invariant Natural Killer 7) et T Vγ9Vδ2 humains constituent deux sous-populations T relativement bien représentées en périphérie, qui sont impliquées dans la défense anti-tumorale et la réponse immunitaire à divers agents infectieux. Suite à la reconnaissance d'une cible cellulaire, ces cellules sécrètent rapidement des quantités importantes de cytokines variées, peuvent lyser leur cible, moduler l'activité d'autres effecteurs de l'immunité, et proliférer intensément en présence d'IL-2. Chez l'homme, les cellules iNKT (CD4⁺, CD4⁻CD8⁻ ou CD8αα⁺) expriment un TCR Vα24Jα18-Vβ11 semi-invariant restreint par des molécules CD1d non polymorphes, et spécifique d'antigènes glycolipidiques, incluant l'a-galactosylcéramide (a-GalCer). Quant aux cellules humaines T Vγ9Vδ2 (principalement CD4⁻CD8⁻ ), elles expriment un TCR Vγ9Vδ2 de diversité restreinte qui leur permet d'être activées spécifiquement, selon un mécanisme encore non défini, par de petits intermédiaires pyrophosphatés des voies de biosynthèse des isoprénoïdes, communément appelés « phosphoantigènes » (PhosphoAg). Lors de ce travail, nous nous sommes intéressés aux modalités d'activation de ces deux sous-populations. Tout d'abord, nous avons étudié l'implication de la molécule CD4 au cours du processus d'activation des lymphocytes iNKT CD4⁺ par des complexes CD1d/α-GalCer. De façon surprenante, nous avons montré que, comme pour les lymphocytes T CD4 conventionnels, la molécule CD4 peut jouer un rôle de co-récepteur de l'activation de cellules iNKT CD4⁺ : elle potentialise l'activation TCR-dépendante d'une fraction significative de cellules iNKT CD4+, en s'engageant avec les molécules CD1d. Par la suite, nous avons étudié les réponses des lymphocytes T Vγ9Vδ2 activés ex vivo pan des PhosphoAgs synthétiques (Phosphostim® / Picostim®) et cultivés en présence de différentes cytokines : IL-7, IL-15, IL-18, IL-21, IL-23 ou IFN-α, versus IL-2. D'une part, nous avons constaté que seule l'IL-15 est capable de conduire à une prolifération intense des lymphocytes T Vγ9Vδ2 stimulés ex vivo par les PhosphoAgs synthétiques, de façon comparable à l'IL-2. D'autre part, de façon particulièrement intéressante, nous avons démontré que l'amplification des populations T Vγ9Vδ2 en présence d'IL-21 + IL-2/ IL-15 conduit à une potentialisation de leurs propriétés proinflammatoires (irréversible) et de leur potentiel cytotoxique anti-tumoral (réversible). En conclusion, cette étude révèle l'IL-21 comme une cytokine candidate de choix qui pourrait être utilisée en conjonction avec de NL-2/IL-15 et les PhosphoAgs synthétiques pour « renforcer» les propriétés anti-tumorales des lymphocytes T Vγ9Vδ2, dans le cadre de stratégies immunothérapeutiques passives et activesHuman iNKT (invariant Natural Killer T) and Vgamma9Vdelta2 (Vy9Vô2) non-conventional lymphocytes are two T cell subsets well represented in periphery, implicated in immune responses against a variety of tumor cells and infectious pathogens. After recognition of a target cell, these lymphocytes quickly and strongly secrete various cytokines, can lyse their target, modulate the activity of other immune effectors, and intensely proliferate in the presence of IL-2. Human iNKT cells (CD4⁺, CD4⁻CD8⁻ or CD8αα⁺) express a semi-invariant Vα24Jα18-Vβ11 TCR which is restricted by non-polymorphic CD1d molecules, and specific of glycolipidic antigens, including a-galactosylceramide (a-GalCer). Human Vγ9Vδ2 lymphocytes (mainly CD4⁻CD8⁻) express a Vγ9Vδ2 TCR of restricted diversity that confers them the capacity to be specifically activated, using a mechanism yet undefined, by small pyrophosphate intermediates produced through the isoprenoid biosynthetic pathways, referred to as Phosphoantigens (PhosphoAg). In this work, we investigated the activation modalities of these two subsets. First, we studied the involvement of the CD4 molecule during the activation process of iNKT lymphocytes by CD1d/a-GalCer complexes. Surprisingly, we showed that, as for conventional CD4⁺ T lymphocytes, CD4 can play a role of co-receptor during activation of CD4⁺ iNKT cells : it potentiates TCR-dependent activation of a significant fraction of CD4⁺ iNKT cells, binding CD1d molecules. Later, we studied the responses of Vγ9Vδ2 T cells activated ex vivo by synthetic PhosphoAg (Phosphostim® / Picostim®) and maintained in the presence of different candidate cytokines : IL-7, IL-15, IL-18, IL-21, IL-23, or IFN-a, versus IL-2. On one hand, we noticed that only IL-15 is able substain an optimal proliferation of Vγ9Vδ2 T lymphocytes stimulated ex vivo by synthetic PhosphoAg, similarly to IL-2. On the other hand, we demonstrated that amplification of Vγ9Vδ2 cells in the presence of IL-21 and IL-2/ IL-15 leads to a potentiation of their pro-inflammatory properties (irréversible) and anti-tumoral cytotoxic potential (réversible). In conclusion, this study reveals IL-21 as a candidate cytokine of choice that could be used in conjunction with IL-2/ IL-15 and synthetic PhosphoAgs to strengthen the anti-tumoral properties of the Vγ9Vδ2 lymphocytes, in the setting of active and passive immunotherapeutic strategies
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Meunier, Sylvain. "Impact de l’interaction CD40/CD40L sur les différents intervenants de la réponse immunitaire T CD8." Paris 5, 2011. http://www.theses.fr/2011PA05T039.
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Mon sujet de thèse consiste à étudier le rôle des différentes voies possible à l’interaction CD40/CD40L au cours de la réponse primaire des lymphocytes T CD8 et à caractériser la réponse des lymphocytes T CD8 CD40-/-. Les résultats obtenus jusqu’à présent semblent montrer deux effets à une interaction CD40/CD40L en fonction de la localisation de la molécule CD40 selon le type cellulaire (sur les lymphocytes T CD8 ou sur les cellules présentatrices d’antigène). Le premier effet est la mis en place d’une réponse primaire optimale de la part des lymphocytes T CD8 et est dû à l’expression de CD40 par les cellules présentatrices d’antigène. Le deuxième effet est la génération de la mémoire immunitaire T CD8 au cours de la réponse primaire et est dû à l’expression de CD40 par les lymphocytes T CD8. Nos résultats montrent que l’interaction CD40/CD40L passant par les cellules présentatrices d’antigène envoie les signaux suffisants pour la prolifération et la cytotoxicité de la réponse primaire T CD8. En revanche, l’interaction CD40/CD40L passant par les lymphocytes T CD8 est indispensable à la génération de la mémoire T CD8. Si la déficience en CD40 par les lymphocytes T CD8 n’affecte pas la réponse primaire, ce n’est pas le cas de la réponse secondaire. En effet, dans ce cas, les lymphocytes T CD8 présentent une réponse secondaire altérée. Comparé à une réponse secondaire classique, les lymphocytes T CD8 CD40-/- présentent une amplitude de réponse diminuée et un pic de réponse décalé, une réponse plus proche d’une réponse primaire. Ces cellules présentent également une cytotoxicité et une survie altérées, ainsi qu’une sensibilité aux facteurs immunorégulateurs accrueMy thesis project is to study the role of different possible pathways possible for the CD40/CD40L interaction during the primary response of CD8 T cells and to characterize the response of CD8 T cell CD40-/-. The results suggest two CD40/CD40L interaction effects depending on the location of the CD40 molecule expressed on different cell types (on CD8 T cells or on antigen presenting cells). The first effect is to set up an optimal primary response from the CD8 T cells and is due to the expression of CD40 by antigen presenting cells. The second effect is the generation of memory CD8 T cells during the primary response and is due to the expression of CD40 by CD8 T cells. Our results show that the CD40/CD40L interaction via the antigen presenting cells sends signals sufficient for proliferation and cytotoxicity of CD8 primary response. However, the CD40/CD40L interaction via the CD8 T cells is essential for the generation of memory CD8 T cells. If the deficiency of CD40 by CD8 T cells does not affect the primary response, it is not the case of the secondary response. Indeed, in this case, CD8 T cells exhibit altered secondary response. Compared to a classical secondary response, the CD8 T cells CD40-/- exhibit a decreased response amplitude and delayed peak response, a response closer to a primary response. These cells also exhibit impaired cytotoxicity and survival. Finally these cells have a more sensitivity to immunoregulatory factors
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Nayrac, Manon. "Persistance du VIH-1 et reconstitution des lymphocytes T CD4+ dans la muqueuse intestinale sous traitement antirétroviral." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30110.
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Chez les individus infectés par le VIH-1, le traitement antirétroviral a pour but de supprimer durablement la réplication virale, et de préserver et/ou restaurer les fonctions immunitaires. Néanmoins, le virus persiste sous forme de provirus intégrés latents dans le génome de cellules réservoirs à longue durée de vie qui sont un obstacle majeur à l'éradication et donc à la guérison du VIH-1. La persistance d'une réplication virale résiduelle pourrait également contribuer à ré-ensemencer le réservoir viral et contribuer à sa stabilité. L'intestin est le compartiment clé dans la physiopathologie de l'infection VIH-1 car il contient de nombreux lymphocytes T CD4+ mémoires effecteurs particulièrement permissifs à la réplication virale. Les travaux présentés dans ce manuscrit ont porté sur l'analyse comparée des compartiments intestinaux et sanguins d'individus infectés par le VIH-1 sous traitement antirétroviral prolongé. Nos résultats démontrent: (i) une compartimentation entre le sang et l'intestin de la quasiespèce virale, avec un enrichissement en virus utilisant le corécepteur d'entrée CCR5 dans l'intestin; (ii) une production virale résiduelle dans le compartiment intestinal qui ré-ensemence ce réservoir; (iii) une stimulation antigénique chronique par la production virale résiduelle et contrôle immunitaire du réservoir. La persistance du VIH-1 dans la muqueuse intestinale semble également impliquée dans le défaut de reconstitution immunitaire de ce compartiment sous traitement antirétroviral. La réponse T effectrice induite par la persistance virale est en effet associée à une diminution d'expression par les entérocytes de CCL25, chimiokine nécessaire au recrutement des lymphocytes T CD4+CCR9+ dans la muqueuse intestinale. Parmi les sous-populations de lymphocytes T CD4+ intestinaux, la fréquence des Th17 reste diminuée sous traitement antirétroviral, alors que celle des Th22 est normale. Les Th17 dépendent de l'axe CCR6-CCL20 pour migrer dans l'intestin; axe déficitaire du fait d'une diminution de l'expression de la chimiokine CCL20 par les entérocytes. Nous avons mis en évidence que les lymphocytes Th22 peuvent utiliser alternativement les axes CCR10-CCL28 ou CCR6-CCL20, selon le ratio CCL28/CCL20 présent dans le micro-environnement intestinal. L'IL-22 produite par les Th22 participe au défaut de production de CCL20 par les entérocytes, par un mécanisme indirect faisant intervenir l'IL-18, alors que la production de CCL28 est maintenue, permettant donc le recrutement préférentiel des Th22 dans la muqueuse intestinale par cet axeCurrent antiretroviral therapies control HIV-1 replication allowing subsequent reconstitution of the immune system. However, the persistence of integrated proviruses in long-lived reservoir cells precludes virus eradication. Residual virus replication could also replenish the reservoir and contributes to its stability. The gut is a key compartment during HIV-1 infection as it contains numerous effector memory CD4+ T cells that are highly permissive to HIV-1 replication. Here we characterized the blood and intestine compartments of HIV-1-infected individuals on prolonged antiretroviral therapy and showed: (i) a compartmentation of viral quasispecies between the blood and gut compartments, with an enrichment of CCR5-using virus in the gut; (ii) the persistence of a residual production in gut which replenishes the viral reservoir; (iii)a chronic antigenic stimulation exerted by residual virus production; (iv) a dynamic equilibrium between the residual production and immune control of the reservoir. HIV-1 persistence in the intestine mucosa under antiretroviral therapy also contributes to the default of immune reconstitution in this compartment. The HIV-1-specific immune response is associated with the reduction of CCL25 expression by enterocytes, a chemokine required for CD4+CCR9+ T cell migration in the intestine. Among gut CD4+ T cell subsets, th17 cells remain depleted contrasting with a normal frequency of Th22 cells. Th17 cells migration to the gut remains impaired because of the reduced production of CCL20 by enterocytes. Th22 cells could alternatively use the CCR10-CCL28 and CCR6-CCL20 chemotactic axes, depending on the CCL28/CCL20 ratio in the intestinal microenvironment. Th22 cells produce IL-22 that reduces CCL20 production by an IL-18-dependant mechanism, thus blunting Th17 cells recruitment to the gut mucosa. By contrast, CCL28 production is maintained and allows Th22 cells to be recruited along this axis
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Patterson, Andrew R. "Gimap5: A Critical Regulator of CD4+ T Cell Homeostasis, Activation, and Pathogenicity." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1544098387129747.
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Karray, Saoussen. "Heterogeneite fonctionnelle des lymphocytes b de leucemie lymphoide chronique de type b : interactions entre signaux non specifiques." Paris 7, 1988. http://www.theses.fr/1988PA077083.
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Marie-Cardine, Anne, and P. A. CAZENAVE. "Activation et endocytose de la proteine tyrosine kinase p561ck au cours de la stimulation du lymphocyte t via cd2 ou cd45." Paris 6, 1994. http://www.theses.fr/1994PA066644.
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La phosphorylation de proteines sur des residus tyrosine represente un des phenomenes precoces consecutifs a l'activation des lymphocytes t. Elle peut etre obtenue, entre autres, par activation des recepteurs tcr/cd3 ou cd2 a la surface cellulaire. Ces recepteurs ne possedant pas d'activite kinase intrinseque, leur association avec des proteines tyrosine kinases intracellulaires a rapidement ete suggeree. Ainsi, il a ete etabli que l'activation des lymphocytes t avec une combinaison d'anticorps anti-cd2 conduit a une augmentation transitoire de l'activite kinase de p56#l#c#k, la proteine tyrosine kinase majoritairement exprimee dans le lymphocyte t. Au cours de ce travail, nous avons montre que cette augmentation d'activite est associee a une delocalisation d'une fraction activee de lck de la membrane plasmique vers les endosomes. Cette modification de localisation est specifique de la voie d'activation passant par cd2. De plus, l'analyse des proteines phosphorylees sur tyrosine au niveau des endosomes nous a permis de detecter la presence de zap-70 et de deux autres proteines non identifiees dont le degre de phosphorylation varie au cours du temps. De nombreuses etudes ont suggere l'existence d'un couplage fonctionnel entre les recepteurs cd2, la proteine tyrosine phosphatase cd45 et p56#l#c#k. Nous avons demontre que l'incubation de cellules jurkat avec une combinaison d'anticorps anti-cd45 resulte en l'activation de lck et en son endocytose. Cette augmentation d'activite est correlee, in vivo, a la dephosphorylation du site negatif de regulation de la kinase (tyr 505) ce qui reflete probablement la stimulation de l'activite phosphatase de cd45. Des resultats similaires ont ete obtenus en utilisant une combinaison d'anticorps anti-cd2 et anti-cd45, ce qui est en faveur d'un role preponderant de cd45 dans la voie d'activation passant via cd2
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Petit, Frédéric. "Effets du VIH-1 sur la modulation des mécanismes de mort cellulaire programmée dans les lymphocytes T CD4." Paris 6, 2002. http://www.theses.fr/2002PA066294.
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Saison, Julien. "Étude de la réponse immunitaire au traitement antirétroviral au cours de l'infection par le virus de l'immunodéficience humaine." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10108/document.
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Plus de 30 ans après la découverte du virus de l'immunodéficience humaine (VIH), entre 20 et 30% des patients sous trithérapie anti rétrovirale (TARV) ne récupèrent pas un taux normal de lymphocytes (LT) CD4, ce qui est associé à une plus grande morbi-mortalité. Il existe de nombreux résultats discordants dans la littérature concernant le rôle joué par l'activation immunitaire des LT CD4 et CD8, ainsi que des incertitudes sur celui des LT régulateurs (Treg), dans cette non réponse immunologique (NRI). Dans le but de clarifier les liens entre NRI, activation immunitaire et Treg, nous avons formulé deux hypothèses : (i) il existe un lien entre le pourcentage de Treg, l'activation immune des LT CD4 et/ou LT CD8, et NRI; et (ii) le pourcentage de Treg mesuré à l'introduction de la TARV est utilisable en tant que marqueur indépendant de risque de NRI à la TARV. Afin de tester nos hypothèses, nous avons dans un premier temps amélioré le phénotypage des Treg en pratique quotidienne, d'abord en comparant différents phénotypes de Treg, puis en validant dans des échantillons cliniques une nouvelle méthode de marquage de FoxP3 intracellulaire en un temps. Puis nous avons analysé dans une étude transversale les liens entre NRI, activation immune, différentes sous populations de Treg et la détection d'une virémie résiduelle, au sein d'une population de patients infectés par le VIH-1, en succès virologique sous TARV depuis de nombreuses années. Les facteurs prédictifs associée à la NRI ont été analysés au moyen d'une analyse multivariée. Nous avons parallèlement étudié au moyen d'une étude prospective le rôle pronostic de la mesure du pourcentage de Treg à l'introduction de la TARV, sur la réponse immune en LT CD4 dans les 2 ans suivant le début du traitement. Nous avons montré que la NRI après 7 ans de TARV en moyenne était associée de façon indépendante au nadir de LT CD4 et au pourcentage de Treg. Nous avons retrouvé une augmentation significative de l'activation immune des LT CD4 en cas de NRI, mais pas des LT CD8. Enfin, nous avons montré que le pourcentage de Treg était, avec le nadir de LT CD4, un facteur prédictif de NRI dans les 2 ans suivant le début de la TARV, et que son impact sur la réponse immune était d'autant plus marqué que le nadir de CD4 était bas. La mesure du pourcentage de Treg à l'introduction de la TARV pourrait être un outil simple et facilement utilisable en routine pour mieux cibler les patients à risque de NRI, en association avec la mesure du nadir des LT CD4. Un suivi de la cohorte permettra de confirmer ces résultats à plus long terme. D'autres études devront être conduites, en se focalisant sur les patients avec un nadir de LT CD4 bas, ainsi que chez des patients plus âgés, afin d'explorer les interactions entre immunosénescence, activation immune et TregMore than 30 years after the discovery of HIV, between 20 and 30% of patients on highly active antiretroviral therapy (ART) do not recover normal levels of CD4 T lymphocytes (CD4). This immunological non response (INR) to ART is associated with an increased morbidity and mortality. There are many conflicting results in the literature related the role of T cells immune activation of T regulator cells (Treg), in INR. In order to clarify the links between INR, immune activation and Treg, we made two hypotheses: (i) there is a link between Treg’s percentage, immune activation of CD4 and / or CD8, and INR; and (ii) the percentage of Treg measured at ART introduction can be used as an independent predictor for INR. To test our hypotheses, we initially improved the immunophenotyping of Treg in daily practice, by comparing different Treg’s phenotype, and by validating in clinical samples a new « one step» staining method of intracellular FoxP3. Then we analyzed in a crosssectionnal study the links between INR, immune activation, different Treg’s subpopulations and detection of very low level viremia, in a population of HIV-1 infected patients, under suppressive ART for many years. Predictive factors associated with the INR were analyzed using multivariate analysis. Simultaneously, we performed a prospective study to analyse the prognostic role of Treg’s percentage at ART introduction on the CD4 reconstitution within 2 years. We have shown that INR after 7 years of ART was independently associated with CD4 nadir and Treg’s percentage. We found in INR patients a significant increase of CD4 immune activation, but not of CD8. Finally, we showed that the Treg’s percentage and the CD4 nadir were independant predictors of INR within 2 years from the start of ART. The effect of Treg at baseline on CD4 evolution was as lower as the CD4 nadir was higher. Measuring the percentage of Treg at ART introduction could be a simple and easy tool to use in daily routine. It could help to better target patients at risk of INR in association with the measurement of CD4 nadir. A follow-up of the cohort will confirm these results in the long term. Further studies will be conducted, focusing on patients with a low CD4 nadir, and on older patients, in order to explore the interactions between immunosenescence, immune activation and Treg
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Giret, Maria Teresa Maidana [UNIFESP]. "Infecção pelo vírus GB-C (GBV-C) em recém infectados pelo vírus da imunodeficiência humana tipo 1 (HIV-1): prevalência, incidência e modulação da ativação celular." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9671.
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Publico-062b.pdf: 1669897 bytes, checksum: 5ca81b8b1f9a75f45902de9ce4bc36f7 (MD5)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O GB vírus C (GBV-C) está constituído por uma fita única de RNA de polaridade positiva e pertence à família Flaviviridae. Possui uma seqüência e organização genómica parecida ao vírus da hepatite C, (HCV). A infecção pelo GBV-C não foi associada a nenhuma patologia, embora, na co infecção com o HIV, tenha sido associada a uma sobrevida maior e retardo no desenvolvimento da imunodeficiência. O efeito benéfico do GBV-C parece ser mediado por alterações na resposta imune celular; contudo, os possíveis mecanismos para explicar esse efeito ainda não foram esclarecidos. Neste trabalho investigamos a freqüência e características genotípicas assim como o impacto da infecção pelo GBV-C nos indivíduos infectados pelo HIV-1. No primeiro manuscrito examinamos os conhecimentos descritos na literatura referentes à coinfecção e propusemos algumas hipóteses para explicar esses efeitos. Posteriormente, descrevemos a taxa de infecção, a prevalência, incidência e características genotípicas do GBV-C nesta população. Assim, uma considerável freqüência de infecção pelo GBV-C foi observada e a análise filogenética dos isolados de GBV-C mostraram ser do genótipo 1 e 2. Foi observada também uma correlação inversa entre a carga viral do GBV-C e a carga viral do HIV na inclusão e um ano depois, assim como uma correlação positiva, mas não significativa, entre a carga viral do GBV-C e a contagem de linfócitos T CD4+. Finalmente, avaliamos o efeito da viremia pelo GBV-C na ativação celular em recém infectados pelo HIV-1. Os pacientes foram agrupados em GBV-C viremicos e não virémicos e foram avaliados para a contagem de linfócitos T, marcadores de ativação celular e carga viral do GBV-C e HIV-1. Foram realizadas análises de univariada e multivariada para identificar variáveis associadas com ativação celular. Demonstramos que a viremia pelo GBV-C foi correlacionada com uma diminuição da ativação celular nos indivíduos HIV positivos e este efeito mostrou se independente da carga viral do HIV. Assim, esta associação entre a replicação do GBV-C e menor ativação celular pode explicar, pelo menos em parte, a proteção conferida pelo GBV-C na progressão da doença nos indivíduos infectados pelo HIV-1.
GB virus C (GBV-C) is a single stranded positive sense RNA virus, which is a member of the Flaviviridae. It has a close sequence homology and genomic organization to hepatitis C virus (HCV). No disease has been associated with GBV-C infection but coinfection with human immunodeficiency virus (HIV) leads to improved morbidity and mortality for the HIV infected subjects. The mechanism of the beneficial effect of GBV-C appears to be mediated by alterations in the cellular immune response. In this study we investigated the frequency and genotyping characteristics as well as the impact of the GBV-C infection among recently HIV-1 infected individuals. In the first manuscript we examined the current knowledge concerning this co-infection and developed hypotheses to explain its effects. Subsequently, we described the rate of infection, the prevalence, incidence and genotypic GBV-C characteristics in this population. In that regard, a considerable frequency of GBV-C infection was observed and the phylogenetic analysis of the GBVC isolates revealed the predominance of genotypes 1 and 2. Also, it was observed an inverse correlation between GBV-C load and HIV-1 load at the enrollment and after one year of follow-up, and a positive, but not statistically significant, correlation between GBV-C load and CD4+ T lymphocyte counts. Finally, we have investigated the effect of GBV-C viremia on T cell activation in early HIV-1-infection. The volunteers were enrolled into two groups: GBV-C viremic and non viremic, all co-infected with HIV-1. They were evaluated for T cell counts, cellular activation markers, GBV-C RNA detection, and HIV-1 viral load. Non-parametric univariate and multivariate analyses were carried out to identify the variables associated with cellular activation. We demonstrated that the GBV-C viremia is correlated with a lower T cell activation in HIV-1-infected individuals and this effect was independent of HIV-1 viral load. The association between GBV-C replication and lower T-cell activation may explain, at least in part, the protection conferred by this virus against disease progression to immunodeficiency in HIV-1-infected patients.
TEDE
BV UNIFESP: Teses e dissertações
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Leclercq, Lise. "Analyse du mode d'action du lymphocyte T "helper" : son rôle dans les phases précoces de l'activation de la cellule B et sa contribution à la régulation isotypique." Paris 7, 1985. http://www.theses.fr/1985PA077058.
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Lors d'une stimulation par un antigène protéique soluble, les lymphocytes B reconnaissent l'antigène grâce à leurs immunoglobulines (Ig) de surface et collaborent avec des lymphocytes T helper (Th) également spécifiques de cet antigène. Ces interactions cellulaires complexes conduisent la cellule B à produire des anticorps qui représentent la forme soluble de l'Ig de surface. Bien que tous dirigés contre l'antigène, ces anticorps peuvent néanmoins appartenir à différentes classes que l'on appelle isotypes et qui se distinguent par la nature de leur région constante. Notre travail réalisé dans un modèle murin utilisant des clones de lymphocytes Th spécifiques d'un antigène synthétique, le GAT (poly (G1u60 Ala30 Tyr ¹º)), a tenté d'analyser le mode d'action du lymphocyte Th, en particulier son rôle dans les phases précoces de l'activation de la cellule B et sa contribution à la régulation isotypique. Après avoir testé différents clones de lymphocytes Th pour leur capacité à induire une stimulation polyclonale de lymphocytes B vierges, nous avons concentré nos efforts sur le clone le plus actif, appelé 52. 3. Nous avons préparé du surnageant (SN) de culture du clone 52. 3 activé et montré que les lymphocytes B au repos, syngéniques ou allogéniques, prolifèrent en présence de ce SN et en l'absence de tout autre stimulus tel que celui délivré par des anticorps anti-Ig. Par cytométrie de flux, nous avons démontré qu'après stimulation avec du SN du clone 52. 3, la quasi-totalité des lymphocytes B hyperexpriment les antigènes Ia, augmentent de taille (30% d'entre eux devenant blastiques) et passent de G₀ en G₁, mais que seuls 20% d'entre eux atteignent les phases S et G₂/M du cycle cellulaire. Ces résultats nous ont conduits à postuler l'existence dans le SN d'une lymphokine agissant sur les lymphocytes B au repos en provoquant leur passage du stage G₀ au stade G₁ du cycle cellulaire et ceci d'une manière qui n'est pas restreinte par les gènes du complexe majeur d'histocompatibilité (CMH). Après stimulation avec le clone de lymphocytes Th 52. 3, des lymphocytes B spléniques IgM⁺ IgG⁻ (isolés par passage au trieur de cellules) sont capables de produire, en plus de l'isotype dominant IgM, des Ig appartenant aux différentes sous-classes d'IgG (avec une nette prédominance des IgG1). Des résultats analogues concernant la sécrétion des IgA ont été obtenus avec des lymphocytes IgM⁺ IgA⁻ isolés par adhérence sur une boîte recouverte d'anticorps anti-IgA. La stimulation de cellules B IgM⁺ IgG⁻ IgA⁻ par du SN du clone 52. 3 induit une réponse plus faible que celle induite par les cellules 52. 3 elles-mêmes, mais elle conduit néanmoins à une production des isotypes IgM, IgG et IgA. Parmi l'isotype IgG la sous-classe IgGi est dominante. Les expériences conduites sur des cellules B IgM⁺ IgG⁻ IgA⁻ semblent indiquer que des cellules Th spécifiques d'isotype ne sont pas indispensables pour qu'une cellule B primaire stimulée par une cellule Th spécifique d'un antigène produise des anticorps d'un isotype autre que IgM.
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Li, Cheng-Rui Michael. "The Role of Tec Kinases in CD4+ T Cell Activation: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/3.
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The Tec family tyrosine kinases Itk, Tec and Rlk are expressed in T cells. Previous studies have established that these kinases are critical for TCR signaling, leading to the activation of PLCγ1. To further understand the functions of Tec kinases in T cell activation, we took three different approaches. First, we performed a thorough analysis of CD28-mediated signaling events and functional responses with purified naïve T cells from Itk-/- mice and a highly controlled stimulation system. Data from this set of studies definitively demonstrate that CD28 costimulation functions efficiently in naïve CD4+ T cells in the absence of Itk. Second, in order to further study the functions of Tec kinases in vivo, we generated transgenic mouse lines expressing a kinase-dead (KD) mutant of Tec on the Itk-/-Rlk-/- background, hoping to study mice that are functionally deficient for all three Tec kinases. The results hint the importance of the Tec kinases in T cell development and/or survival. Finally, in order to identify potential transcriptional targets of Itk, we used microarray technology to compare global gene expression profiles of naïve and stimulated Itk-/- versus Itk+/- CD4+ T cells. This analysis provided a short list of differentially expressed genes in Itk-/- versus Itk+/- CD4 T cells, providing a starting point for further studies of Itk in T cell activation. Collectively, these studies clarified the role of Itk in CD28 signaling, revealed some unexpected aspects of Tec family kinases in T cells, and indicated potential targets of Itk-dependent signaling pathways in T cells.
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Chen, Meilan [Verfasser], and Friedrich [Akademischer Betreuer] Thaiss. "Role for IKK2- and NEMO-Kinase Mediated Nuclear Factor kappa B (NF-κB) Activation in CD4+ T Lymphocytes in Nephrotoxic Serum Nephritis (NTN) Induced Glomerulonephritis Mice / Meilan Chen ; Betreuer: Friedrich Thaiss." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1121783317/34.
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Chen, Meilan Verfasser], and Friedrich [Akademischer Betreuer] [Thaiss. "Role for IKK2- and NEMO-Kinase Mediated Nuclear Factor kappa B (NF-κB) Activation in CD4+ T Lymphocytes in Nephrotoxic Serum Nephritis (NTN) Induced Glomerulonephritis Mice / Meilan Chen ; Betreuer: Friedrich Thaiss." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://nbn-resolving.de/urn:nbn:de:gbv:18-82333.
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Grandvaux, Nathalie. "Etude structurale et fonctionnelle de la protéine p40phox : étude d'une fonction potentielle dans les lymphocytes B." Université Joseph Fourier (Grenoble), 1999. http://www.theses.fr/1999GRE10185.
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La destruction des microorganismes par les cellules phagocytaires necessite l'activation de la nadph oxydase productrice d'ions superoxyde et de derives microbicides. La formation d'un complexe nadph oxydase actif resulte de l'association d'un flavocytochrome b et de proteines cytosoliques, p67phox, p47phox, p40phox et rac. Le role du facteur p40phox dans ce complexe reste encore enigmatique. Une activite nadph oxydase a egalement ete mise en evidence dans les lymphocytes b qui sont des acteurs de l'immunite specifique, par opposition aux cellules phagocytaires qui sont responsables de la reaction immunitaire non specifique. L'importance quantitative des facteurs cytosoliques par rapport au flavocytochrome b reste egalement inexpliquee. Le travail experimental decrit ici a ete centre sur le facteur p40phox qui a ete surexprime et purifie pour realiser des etudes structurales par les technique de diffusion de neutrons. Et de cristallogenese afin d'obtenir des informations sur la structure tridimensionnelle des complexes et d'apprehender le role de p40phox dans leur formation. Dans une deuxieme partie le role de p40phox, et des facteurs cytosoliques en general, dans les lymphocytes b a ete aborde par la methode du double-bybride. La proteine ku70, qui controle l'activite de la proteine kinase adn dependante (dna-pk), a ete identifiee comme partenaire de p40phox. Cette interaction a ete confirmee par liaison in vitro et copurification. L'etude de la localisation des proteines p40phox et ku70, ainsi que de p47phox et p67phox, a montre leur presence dans le noyau des lymphocytes b. Il a egalement ete montre que p47phox et p67phox sont des substrats potentiels de la dna-pk. Ces resultats, ainsi que l'implication de la dna-pk dans la reparation de l'adn ainsi que dans les recombinaisons v(d)j des lymphocytes, suggerent l'implication des facteurs cytosoliques de l'oxydase dans des processus de signalisation lies a l'immunite specifique. Finalement, l'etude de la phosphorylation de p40phox a ete abordee aussi bien dans les cellules differenciee en pseudo neutrophiles que dans les lymphocytes b soumis a un stress oxydant. Les premiers resultats obtenus montrent une phosphorylation de p40phox en reponse a la stimulation des cellules par le peroxyde d'hydrogene.
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Cholley-Cohen, Tanugi Laurence. "La NADPH oxydase des lymphocytes B immortalisés par le virus d'Epstein-Barr : étude d'un cas de granulomatose chronique lié à un déficit en facteur cytosolique d'activation p67phox." Université Joseph Fourier (Grenoble), 1994. http://www.theses.fr/1994GRE10153.
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Ce travail a pour objectif l'analyse de la nadph oxydase des lymphocytes b immortalises par le virus d'epstein-barr (lb-ebv). Dans la premiere partie du memoire, le systeme de production des ions superoxyde des lymphocytes b immortalises est compare a celui des polynucleaires neutrophiles. La mise au point d'un test d'activation de l'enzyme en milieu acellulaire et en systeme heterologue, complete par l'utilisation de techniques immunochimiques montre des proprietes similaires du complexe oxydase dans les deux modeles cellulaires bien que l'activite enzymatique engendree dans les lymphocytes b-ebv stimules soit faible. Dans une deuxieme partie un cas particulier de granulomatose chronique presentant un deficit en facteur cytosolique de 67 kda est analyse au niveau moleculaire. L'anomalie genetique a l'origine de la maladie est mise en evidence sur l'arn messager et l'adn genomique de la patiente grace aux techniques de biologie moleculaire (amplification par polymerisation de chaine, clonage et sequencage) en utilisant les lymphocytes b immortalises comme materiel de travail. Les resultats experimentaux revelent une mutation ponctuelle au niveau du site d'epissage (extremite 5') de l'intron 3 ; cette mutation est a l'origine de l'absence de rna messager codant le facteur p67#p#h#o#x
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Landires, Ivan. "Mécanismes de l'altération des réponses à l'interleukine-7 pendant l'infection à VIH." Paris 7, 2011. http://www.theses.fr/2011PA077078.
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L'Interleukine-7 (IL-7) est une cytokine qui joue un rôle central dans le contrôle de l'homéostasie des lymphocytes T CD4+ à la fois dans le thymus et la périphérie. Les voies de signalisation déclenchées par l'IL-7 sont modifiées suite à l'infection par le VIH, ce qui peut contribuer à la perte des cellules T CD4+. Il a été précédemment démontré que chez les individus infectés par le VIH, la voie de signalisation JAK/STAT déclenchée par l'IL-7 est modifiée par une fonction transcriptionnelle défectueuse de STAT, comme indiqué par l'induction limitée du gène anti-apoptotique Bcl-2, et peut contribuer à la perte de cellules T CD4+. Les réactions de signalisation, mesurée par la phosphorylation de STAT5 dans Y694 et S726, ont été montrées dans les cellules T CD4+ naïves des patients virémiques, avec une phosphorylation de STAT5 plus élevée que celle détectée chez les donneurs sains. Pour tenter d'expliquer l'induction défectueuse des gènes cibles de la voie JAK/STAT chez les patients virémiques, nous nous sommes demandés si STAT5 pouvait migrer efficacement dans le compartiment nucléaire. L'analyse d'imagerie quantitative a révélé que cette étape était altérée chez les patients virémiques, avec les deux formes phosphorylées de STAT5,. , montrant une relocalisation défectueuse dans le noyau après la stimulation par IL-7. Nous avons confirmé ces résultats par la constatation d'une anomalie de relocalisation nucléaire spécifique de l'isoforme STAT5B chez les patients virémiques en réponse à la stimulation par 1TL-7. Le défaut de relocalisation nucléaire de STAT5 est en corrélation avec l'activation immunitaire chez les patients virémiques. Nous avons également mis en évidence chez les patients virémiques, que STÀT3 n'était pas non plus relocalisé de façon appropriée dans le noyau des cellules T CD4+. Ainsi, nous avons montré que l'infection par le VIH perturbe la transduction du signal de l'IL-7 à deux niveaux : en induisant une hyper-phosphorylation de STAT5 et en provoquant un blocage de la fonction nucléaire de STAT5. D'autre part, nous avons constaté que les kinases JAK1 et JAK3 sont présentes dans le noyau des cellules T CD4 +. Au cours de l'infection par le VIH, les patients virémiques présentent une hyper-phosphorylation de JAK3 dans le noyau en corrélation avec l'activation immunitaire chronique. Nous avons trouvé un dysfonctionnement global dans la voie de signalisation JAK/STAT dépendante de PIL-7 pendant l'infection par le VIH. Ces mécanismes peuvent avoir des conséquences profondes sur la perte des cellules T CD4+ caractéristique du sidaInterleukin-7 (IL-7) is a cytokine that plays a central role in controlling the homeostasis of CD4+ T cells both in the thymus and the periphery. Importantly, the signaling pathways triggered by IL-7 are altered following HIV infection, which may contribute to the loss of CD4+ T cells. It has been previously shown that in HW infected individuals, the JAK/STAT signaling pathway triggered by IL-7 is altered with defective STAT transcriptional function, as indicated by limited induction of the anti-apoptotic gene Bcl-2, which may contribute to the loss of CD4+ T cells. The early signaling response, measured by the phosphorylation of both STAT5 at Y694 and S726 has been shown to be unexpectedly efficient in naive CD4+ T cells from viremic patients, with an induction of phosphorylated STAT5 that was even higher than that detected in healthy donors. To try to explain the defective induction of targets genes for the JAK/STAT pathway in viremic patients, we then asked whether activated STAT5 could efficiently migrate into the nuclear compartment. Quantitative image analysis revealed that this step was impaired in viremic patients, with both forms of phosphorylated STAT5 showing a defective relocalization to the nucleus after IL-7 stimulation. We have confirmed these results by the finding of an specific nuclear relocalization defect of the STAT5 isoform in viremic patients in response to the IL-7 stimulation. The STAT5 defect of nuclear relocalization correlates with immune activation in viremic patients. We also showed STAT3 does not relocalize appropriately to the nucleus of CD4+ T cells from viremic patients. Thus, HIV infection perturbed IL signal transduction at two levels, by inducing an early hyper-phosphorylation and causing a late block STAT5 nuclear function. Additionally we have found that JAK1 and JAK3 proteins localize to the nucleus CD4+ T cells and that viremic patients exhibit a higher extent of phosphorylated JAK3 in the nucleus correlating also with chronic immune activation during HIV infection. We have found an overall dysfunction in the IL-7 dependent JAK/STAT pathway in HW infection. These mechanisms may have profound consequences on the loss of CD4+ T cell homeostasis characteristic of AIDS
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Perez, Patrigeon Santiago. "Fonctions lymphocytaires T dans l'infection à VIH : altération des réponses chimiotactiques chez les patients virémiques : activation et différentiation des lymphocytes T CD4+ chez les patients "HIV controllers"." Paris 7, 2009. http://www.theses.fr/2009PA077126.
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Le travail présenté ici porte sur la réponse migratoire et adaptative à l'infection par le virus de rimmunodéficience Humaine (VIH). En analysant les réponses chimiotactiques chez les patients infectés, nous avons observé un défaut de migration à CCL19, un ligand de CCR7, chez les patients virémiques. Ce défaut est indépendant de l'expression de CCR7, suggérant une perturbation de la signalisation en aval du récepteur. L'altération de la réponse chimiotactique via CCR7 risque de limiter la migration des lymphocytes T dans les ganglions lymphatiques, ce qui pourrait contribuer à enrayer la réponse immune adaptative chez ces patients. Nous avons également étudié les réponses T CD4+ spécifiques du VIH chez les rares patients qui contrôlent spontanément l'infection, désignés de ce fait comme « HIV controllers ». Nous observons que les cellules T CD4+ des HIV controllers se caractérisent par un compartiment "mémoire centrale" préservé, avec une augmentation de l'expression de CCR7, ce qui pourrait conférer un avantage de survie et une migration plus efficace dans les ganglions, avec en conséquence une meilleure réponse immune adaptative. De plus, les T CD4+ "effecteur mémoires" des Controllers présentent des signes d'activation et des réponses antigéniques polyfonctionnelles, ce qui pourrait être lié à un contrôle antiviral plus efficace. Enfin, notre travail montre que les cellules T CD4+ des patients HIV controllers présentent une forte avidité pour un épitope p24 Gag du VIH, ce qui pourrait expliquer leur capacité à répondre et à proliférer en présence de faibles concentrations d'antigènes viraux circulants. Du fait de cette forte avidité, les cellules T CD4+ des patients HIV controllers pourraient réagir plus rapidement à un pic de réplication virale, limitant ainsi la destruction progressive du système immunitaire par le VIHOur work analyses the migratory and adaptative immune response to Human Immunodeficiency Virus (HIV). By analyzing the chemotactic responses of T lymphocytes in HIV infected patients, we found a CCR7-dependent migration defect in T lymphocytes from viremic patients. This defect is independent of their CCR7 expression suggesting the signalling cascade of CCR7 is disturbed. An altered chemotactic response could perturb lymphocyte migration into lymph nodes, thus disturbing adaptative immune response of T cells in these patients. We also studied specific T CD4+ responses from those rare HIV infected patients able to spontaneously control viral replication, thus called HIV controllers. We observed that T CD4+ cells of Controller patients have a preserved T CD4+ Central Memory compartment with an overexpression of CCR7, which could enhance their migration to lymph nodes and confer them with a more effective adaptative immune response. On the other hand, T CD4+ Effector Memory cells from HIV controllers present a moderated activation and polyfunctional antigenic responses, which could be related to an effective viral control. Finally, our work shows that HIV controllers present specific T CD4+ cells with increased antigen avidity to an HIV p24-Gag epitope. This might explain their effective response and proliferation in the presence of very low levels of circulating viral antigens. The presence of high avidity specific T CD4+ cells could allow HIV controllers to react early to a burst of viral replication thus limiting HIV related progressive damage to the immune System