945 resultados para CD4 T lymphocyte count
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Limportance respective des lymphocytes T rgulateurs naturels gnrs dans le thymus ou induits en priphrie dans la rgulation immunitaire et la rsolution de linflammation est dsormais bien tablie. Nous avons contribu mettre en vidence une nouvelle voie dinduction de lymphocytes T rgulateurs priphriques partir de cellules T humaines CD4+CD25- naves et mmoires. Nous avons montr que lengagement de la molcule ubiquitaire transmembranaire CD47 sur la cellule T par un anticorps monoclonal ou par le peptide 4N1K (peptide driv du domaine carboxy-terminal de la thrombospondine-1 et spcifique du site de liaison CD47) induisait des lymphocytes T CD4+ rgulateurs exerant une fonction suppressive sur les lymphocytes T effecteurs. Les proprits suppressives induites par la thrombospondine-1 confortent les fonctions anti-inflammatoires de cette protine de la matrice extracellulaire. Linhibition exerce par les lymphocytes T rgulateurs induits dpend du contact intercellulaire entre les cellules T rgulatrices et leurs cibles, et est indpendante du TGF-. Nos rsultats dmontrent galement le rle de CD47 sur le lymphocyte T CD4+ dans la rponse immunitaire spcifique de lantigne in vivo. En effet, les souris BALB/c dficientes pour CD47 prsentent un biais de la scrtion danticorps et de cytokines de type Th1, alors que les souris BALB/c sont dcrites comme exprimant un profil de production de cytokines de type Th2. Nos travaux mettent en vidence le rle de CD47 dans linhibition du dveloppement dune rponse cellulaire et humorale de type Th1 in vivo, confirmant de prcdentes tudes in vitro ralises avec des cellules T CD4+ humaines. Nous prsentons galement le rle inhibiteur de lengagement de CD28 in vitro sur la diffrenciation en cellules Th17 des lymphocytes T CD4+ nafs isols de souris BALB/c. Le mcanisme propos est dpendant de la production de lIL-2 et de lIFN- et indpendant de la prsence de lymphocytes T rgulateurs. Notre tude du rle de deux molcules transmembranaires CD47 et CD28 exprimes sur la cellule T CD4+, contribue une meilleure connaissance des mcanismes impliqus dans la tolrance immunologique, la rsolution de linflammation et la diffrenciation des cellules T "helper" CD4+.
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Le diabte auto-immun rsulte de la destruction des cellules bta pancratiques scrtrices dinsuline par les lymphocytes T du systme immunitaire. Il sensuit une dficience hormonale qui peut tre comble par des injections quotidiennes dinsuline dorigine exogne, toutefois il demeure ce jour impossible de gurir les patients atteints de la maladie. De faon gnrale, un systme immunitaire sain reconnat une multitude dantignes diffrents et assure ainsi notre dfense lgard de diffrents pathognes ou encore de cellules tumorales. Il arrive cependant que, pour des raisons gntiques et/ou environnementales, les lymphocytes T puissent sactiver de faon aberrante suite la reconnaissance dantignes provenant du soi. Cest ce bris de tolrance qui mne au dveloppement de pathologies auto-immunes telles que le diabte auto-immun. Afin de limiter lauto-immunit, des mcanismes de slection stricts permettent dliminer la majorit des lymphocytes T prsentant une forte affinit envers des antignes du soi lors de leur dveloppement dans le thymus. Certains de ces lymphocytes russissent toutefois chapper lapoptose et migrent en priphrie afin dy circuler en qute dun antigne spcifiquement reconnu. Il est alors primordial que des mcanismes priphriques assurent le maintien de la tolrance immunitaire en faisant obstacle lactivation et la prolifration des lymphocytes T auto-ractifs. Lune des avenues afin dinhiber le dveloppement de rponses immunitaires aberrantes est la gnration de lymphocytes T rgulateurs. Ces cellules, dorigine thymique ou priphrique, peuvent arborer diffrents phnotypes et agissent via de multiples mcanismes afin dinactiver et/ou liminer les cellules impliques dans lapparition de pathologies auto-immunes. Lutilisation de modles murins transgniques a permis la mise en vidence dune population peu caractrise de lymphocytes T au potentiel rgulateur. En effet, la proportion de ces cellules T nexprimant pas les corcepteurs CD4 et CD8 (double ngatives, DN) a t inversement corrle la prdisposition lauto-immunit chez ces ii souris. Lobjectif principal de cette thse est de dmontrer la fonction immuno-rgulatrice des lymphocytes T DN, tout en investiguant les facteurs gntiques responsables du maintien de cette population cellulaire. Nous avons observ que les lymphocytes T DN exercent une activit cytotoxique lgard des lymphocytes B de faon spcifique lantigne, via la libration de granules cytolytiques contenant du granzyme B et de la perforine. Par ailleurs, nous avons tabli quun unique transfert adoptif de ces cellules est suffisant afin dinhiber le dveloppement du diabte auto-immun chez des htes transgniques prdisposs la maladie. Le recours des souris dficientes pour lexpression du gne CD47 a permis de constater que la voie de signalisation CD47-Sirp est essentielle dans le maintien de la proportion des lymphocytes T DN. De plus, le locus murin de prdisposition au diabte auto-immun Idd13, qui contient le gne Sirp, a t identifi pour son rle dans la rgulation de la proportion de ces cellules. Finalement, une analyse gntique a rvl que dautres intervalles gntiques sont impliqus dans le contrle de la population des lymphocytes T DN. Parmi ceux-ci, un locus situ en rgion proximale du chromosome 12 a t valid grce la cration de souris congniques. Grce aux rsultats prsents dans cette thse, notre comprhension de la biologie ainsi que de la rgulation des lymphocytes T DN est approfondie. Ces connaissances constituent un pas important vers la cration de thrapies cellulaires novatrices permettant de prvenir et de gurir diverses pathologies auto-immunes.
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Une petite population de lymphocytes T exprimant les deux corcepteurs CD4 et CD8 et appele double positive (DP), a t dtecte dans le sang priphrique de donneurs sains et de patients atteints de diverses pathologies dont la sclrose en plaques (SEP). Nous avons mis lhypothse quil sagissait de lymphocytes T hautement activs pouvant contribuer linflammation chronique prsente dans la SEP. Nous avons compar les cellules T DP obtenues du sang de donneurs sains et de patients atteints de la SEP et non traits. La frquence des cellules DP tait similaire chez les patients et les donneurs sains. La proportion de lymphocytes T DP qui exprimaient les chaines du rcepteur de linterleukine-15 (IL-15) tait plus leve que pour les autres populations lymphocytaires. Des mesures dinduction de la phosphorylation du STAT5 (signal transducer and activator of transcription) ont dmontr que les cellules DP ont rpondu des doses plus faibles et pour de plus longues priodes lIL-15 comparativement aux autres lymphocytes T. Le pourcentage de lymphocytes T DP ayant la capacit de produire linterfron-gamma et des enzymes lytiques tait lev chez les tmoins sains mais ces niveaux taient significativement rduits chez les patients atteints de la SEP. La caractrisation phnotypique de cellules DP a suggr que ces cellules ont des proprits similaires aux lymphocytes T activs. Bien quil ne sagisse que dune caractrisation partielle, il semble que les lymphocytes T DP perdent une partie de leurs proprits chez les patients atteints de la SEP.
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Lymphocyte subsets, activation markers and apoptosis were assessed in 20 HIV-exposed noninfected (ENI) children born to HIV-infected women who were or not exposed to antiretroviral (ARV) drugs during pregnancy and early infancy. ENI children and adolescents were aged 6-18 years and they were compared to 25 age-matched healthy non-HIV-exposed children and adolescents (Control). ENI individuals presented lower CD4(+) T cells/mm(3) than Control group (control: 1120.3 vs. ENI: 876.3; t-test, p=0.030). ENI individuals had higher B-cell apoptosis than Control group (Control: 36.6%, ARV exposed: 82.3%, ARV nonexposed: 68.5%; Kruskal-Wallis, p < 0.05), but no statistical difference was noticed between those exposed and not exposed to ARV. Immune activation in CD4(+) T, CD8(+) T and in B cells was comparable in ENI and in Control children and adolescents. Subtle long-term immune alterations might persist among ENI individuals, but the clinical consequences if any are unknown, and these children require continued monitoring.
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Fish oil supplementation has been shown to improve the cachectic state of tumor-bearing animals and humans. Our previous study showed that fish oil supplementation (1 g per kg body weight per day) for 2 generations had anticancer and anticachetic effects in Walker 256 tumor-bearing rats as demonstrated by reduced tumor growth and body weight loss and increased food intake and survival. In this study, the effect of fish oil supplementation for 2 generations on membrane integrity, proliferation capacity, and CD4/CD8 ratio of lymphocytes isolated from mesenteric lymph nodes, spleen, and thymus of Walker 256 tumor-bearing animals was investigated. We also determined fish oil effect on plasma concentration and ex vivo production of cytokines [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, and IL-10]. Lymphocytes from thymus of tumor-bearing rats presented lower viability, but this change was abolished by fish oil supplementation. Tumor growth increased proliferation of lymphocytes from all lymphoid organs, and fish oil supplementation abolished this effect. Ex vivo production of TNF-alpha and IL-6 was reduced in supplemented animals, but IL-4 and IL-10 secretion was stimulated in both nontumor and tumor-bearing rats. IL-10 and IFN-gamma plasma levels was also decreased in supplemented animals. These results suggest that the anticachetic effects of fish oil supplementation for a long period of time (2 generations) in Walker 256 tumor-bearing rats may be associated to a decrease in lymphocyte function as demonstrated by reduced viability, proliferation capacity, and cytokine production.
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Lymphotoxin alpha (LTA) is a member of the TNF cytokine superfamily, produced principally by lymphocytes. It plays an important role in immune and inflammatory responses. Many TNF superfamily members have functionally important isoforms generated by alternative splicing but alternative splicing of LTA has never been studied. The known LTA protein is encoded by a transcript containing four exons. Here we report seven new LTA splice variants, three of them evolutionary conserved. We demonstrate their presence in cytoplasmic RNA suggesting that they could be translated into new LTA isoforms. We observed that their expression is differentially regulated upon activation of peripheral blood mononuclear cells and lymphocyte subpopulations (CD4+, CD8+, and CD19+). Our data suggest that the new LTA splice variants might play a role in the regulation of the immune response. (C) 2007 Elsevier Ltd. All rights reserved.
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Dendritic cells (DCs) are the most important antigen-presenting cells of the immune system and have a crucial role in T-lymphocyte activation and adaptive immunity initiation. However, DCs have also been implicated in maintaining immunological tolerance. In this study, we evaluated changes in the CD4(+) CD25(+) Foxp3(+) T-cell population after co-culture of lymph node cells from BALB/c mice with syngeneic bone marrow-derived DCs. Our results showed an increase in CD4(+) CD25(+) Foxp3(+) T cells after co-culture which occurred regardless of the activation state of DCs and the presence of allogeneic apoptotic cells; however, it was greater when DCs were immature and were pulsed with the alloantigen. Interestingly, syngeneic apoptotic thymocytes were not as efficient as allogeneic apoptotic cells in expanding the CD4(+) CD25(+) Foxp3(+) T-cell population. In all experimental settings, DCs produced high amounts of transforming growth factor (TGF)-beta. The presence of allogeneic apoptotic cells induced interleukin (IL)-2 production in immature and mature DC cultures. This cytokine was also detected in the supernatants under all experimental conditions and enhanced when immature DCs were pulsed with the alloantigen. CD4(+) CD25(+) Foxp3(+) T-cell expansion during co-culture of lymph node cells with DCs strongly suggested that the presence of alloantigen enhanced the number of regulatory T cells (Tregs) in vitro. Our data also suggest a role for both TGF-beta and IL-2 in the augmentation of the CD4(+) CD25(+) Foxp3(+) population.
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Fundao de Amparo Pesquisa do Estado de So Paulo (FAPESP)
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Background: Cryptococcus neoformans causes meningitis and disseminated infection in healthy individuals, but more commonly in hosts with defective immune responses. Cell-mediated immunity is an important component of the immune response to a great variety of infections, including yeast infections. We aimed to evaluate a specific lymphocyte transformation assay to Cryptococcus neoformans in order to identify immunodeficiency associated to neurocryptococcosis (NCC) as primary cause of the mycosis.Methods: Healthy volunteers, poultry growers, and HIV-seronegative patients with neurocryptococcosis were tested for cellular immune response. Cryptococcal meningitis was diagnosed by India ink staining of cerebrospinal fluid and cryptococcal antigen test (Immunomycol-Inc, SP, Brazil). Isolated peripheral blood mononuclear cells were stimulated with C. neoformans antigen, C. albicans antigen, and pokeweed mitogen. The amount of H-3-thymidine incorporated was assessed, and the results were expressed as stimulation index (SI) and log SI, sensitivity, specificity, and cut-off value (receiver operating characteristics curve). We applied unpaired Student t tests to compare data and considered significant differences for p<0.05.Results: The lymphotoxin alpha showed a low capacity with all the stimuli for classifying patients as responders and non-responders. Lymphotoxin alpha stimulated by heated-killed antigen from patients with neurocryptococcosis was not affected by TCD4+ cell count, and the intensity of response did not correlate with the clinical evolution of neurocryptococcosis.Conclusion: Response to lymphocyte transformation assay should be analyzed based on a normal range and using more than one stimulator. The use of a cut-off value to classify patients with neurocryptococcosis is inadequate. Statistical analysis should be based on the log transformation of SI. A more purified antigen for evaluating specific response to C. neoformans is needed.
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Infected dogs are urban reservoirs of Leishmania chagasi, which is a causative agent of visceral leishmaniasis (VL). Dogs exhibit immune suppression during the course of this disease, and lymphocyte apoptosis is involved in this process. To investigate apoptosis and the expression levels of FAS-FAS-associated death domain protein (CD95 or APO-1), FASL-FAS ligand protein (CD178), and TRAIL-TNF-related apoptosis-inducing ligand (CD253) receptors in peripheral blood mononuclear cells and spleen leukocytes from 38 symptomatic dogs with moderate VL and 25 healthy dogs were evaluated by flow cytometry. The apoptosis rate of blood and splenic CD4+ and CD8+ cells was higher in infected dogs than in healthy dogs. The expression levels of FAS and FASL in blood and splenic CD4+ cells were lower in infected dogs than in healthy dogs. FAS expression in CD8+ cells was higher in infected dogs than in healthy dogs; in contrast, FASL expression was lower in infected dogs. The expression of the TRAIL receptor increased only in splenic CD8+ cells from infected dogs. The FAS and FAS-L blocking antibodies confirmed the importance of these receptors in apoptosis. Our results enhance the current understanding of the immune response in dogs infected with L. chagasi, facilitating the future development of therapeutic interventions to reduce lymphocyte depletion. 2013 Elsevier B.V.
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Fundao de Amparo Pesquisa do Estado de So Paulo (FAPESP)
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Coordenao de Aperfeioamento de Pessoal de Nvel Superior (CAPES)
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Ps-graduao em Biocincias e Biotecnologia Aplicadas Farmcia - FCFAR
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Fundao de Amparo Pesquisa do Estado de So Paulo (FAPESP)
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Ps-graduao em Biocincias e Biotecnologia Aplicadas Farmcia - FCFAR
