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Avaliação fenotípica e funcional dos linfócitos T citotóxicos de indivíduos infectados pelo HTLV-1 com diagnóstico de HAM/TSPLima, Marcus Vinícius Alves January 2014 (has links)
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Previous issue date: 2014 / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / O Brasil representa uma das áreas endêmicas para o vírus linfotrópico de células T humanas
do tipo 1 (HTLV-1) e a cidade de Salvador, Bahia, possui a maior prevalência nacional da
infecção por este retrovírus (1,8%), com cerca de 50.000 pessoas infectadas. O HTLV-1 foi o
primeiro retrovírus humano descrito e está classicamente associado à leucemia/linfoma de
células T do adulto (ATLL) e à mielopatia associada ao HTLV-1/paraparesia espástica
tropical (HAM/TSP). A HAM/TSP é uma doença inflamatória do sistema nervoso central,
cujos mecanismos imunopatogênicos não estão completamente elucidados. O papel dos
linfócitos T citotóxicos na patogênese desta doença ainda não está bem definido. Neste
estudo, foram avaliados o fenótipo e a função de linfócitos T citotóxicos de pacientes
infectados pelo HTLV-1 com HAM/TSP. Ensaios de imunofenotipagem por citometria de
fluxo foram conduzidos para avaliar a proporção das subpopulações de memória dos
linfócitos T citotóxicos e mensurar potencial citotóxico destas células. Foram analisados 13
indivíduos não infectados e 49 infectados pelo HTLV-1 (18 sem mielopatia - ASS, 6
diagnosticados como HAM/TSP provável - HAM-PB - e 25 como HAM/TSP definido -
HAM-D). Os indivíduos infectados apresentaram aumento da proporção de linfócitos T
citotóxicos e de suas subpopulações de memória efetora em detrimento das células naive e de
memória central. Não foi observada diferença na distribuição das subpopulações de memória
dos CTLs entre os indivíduos infectados pelo HTLV-1. A quantidade de CTLs com atividade
de degranulação foi significativamente menor nos pacientes HAM-D em comparação aos
indivíduos ASS. O grupo HAM-D também apresentou redução (50%) da produção de IFN-γ
pelos CTLs em relação ao grupo ASS. O grupo HAM-PB apresentou resultados similares ao
grupo ASS quanto à atividade de degranulação e produção de IFN-γ. Aumento da expressão
de IL-15 em células mononucleares do sangue periférico e em células CD14+ foi observado
em todos os grupos de pacientes infectados em comparação com os indivíduos soronegativos
para o HTLV-1. Estes resultados sugerem que os pacientes infectados pelo HTLV-1 com
HAM/TSP apresentam prejuízo da resposta imune celular, caracterizado pela diminuição da
quantidade de linfócitos T CD8+ com atividade de degranulação. / Brazil represents one of the largest endemic areas for human T-lymphotropic virus cells type
1 (HTLV-1) infection and associated diseases. Salvador, Bahia, is considered as the Brazilian
city with the highest national HTLV-1prevalence (around 1.8% in the general population).
HTLV -1 was the first human retrovirus described and is classically associated with adult Tcell
leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical spastic
paraparesis (HAM/TSP). HAM/TSP is a chronic and progressive inflammatory disease of the
central nervous system and your immunopathogenic mechanisms are not completely
understood. The role of cytotoxic T-lymphocytes (CTLs) in the pathogenesis of this disease is
still undefined. In this study we evaluated the phenotype and function of cytotoxic Tlymphocytes
from HTLV-1-infected patients with HAM/TSP. Assays immunophenotyping by
flow cytometry were conducted to assess the proportion of cytotoxic T-lymphocytes memory
subsets and the cytotoxic potential of such cells. We analyzed 13 uninfected subjects
(controls) and 49 HTLV-1-infected patients (18 without myelopathy (asymptomatic-ASS), 6
diagnosed as probable-HAM/TSP (HAM-PB) and 25 as defined-HAM/TSP (HAMD).
Infected patients showed an increased proportion of cytotoxic T-lymphocytes and their
subpopulations of effector memory cells at the expense of naive and central memory cells.
The distribution of CTLs memory subsets resembled between HTLV-1-infected patients. The
amount of CTLs with recent degranulation activity was significantly lower in HAM-D
patients when compared to ASS group. The HAM-D group also showed IFN-γ production
decrease (50%) by CTLs relative to the ASS group. The degranulation activity and IFN-γ
production by cytotoxic T-lymphocytes were similar between the HAM-PB patients and ASS
patients. Increased expression of IL-15 on peripheral blood mononuclear cells and CD14+cells
was observed in all groups of infected patients when compared to not infected subjects. These
results suggest that HTLV-1-infected individuals with HAM/TSP have cellular immune
response impaired, characterized by decrease of CD8+ T-lymphocytes with degranulation
activity.
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The role of CD8+ T-lymphocyte mediated immunity in HIV-1 infectionWilson, Susan Elizabeth January 1999 (has links)
No description available.
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La D-cateslytine : un nouvel agent antifongique pour le traitement de la candidose buccale / D-Cateslytin : a new antifungal agent for the treatment of oral candidosisDartevelle, Pauline 25 March 2019 (has links)
L'utilisation excessive d'agents antifongiques, aggravée par la pénurie de nouveaux médicaments introduits sur le marché, provoque l'accumulation de phénotypes de multi-résistance de nombreuses souches fongiques. Dans ce contexte alarmant, le développement de nouvelles molécules alternatives aux agents antifongiques conventionnels constitue un enjeu majeur de santé publique afin de prévenir l’émergence de nouvelles résistances fongiques pour limiter les problèmes socio-économiques. Dans ce contexte, la cateslytine (CTL), un peptide naturel issu de la maturation endogène de la chromogranine A, et déjà décrit comme un agent antimicrobien efficace contre de nombreux agents pathogènes, dont Candida albicans, présente un intérêt particulier. Dans la présente étude, nous avons ainsi comparé l'activité antimicrobienne de deux conformations de CTL, L-CTL et D-CTL contre différentes souches de Candida. Nos résultats démontrent que D-CTL est l'agent antifongique le plus efficace et le plus sûr. De plus, contrairement à L-CTL, D-CTL n'est pas dégradé par les protéases sécrétées par Candida albicans et est également stable dans la salive. La vidéo-microscopie révèle une invasion rapide de Candida albicans par D-CTL, et démontre l’importance de la division cellulaire pour la propagation de D-CTL d'une cellule mère à une cellule fille. La microscopie électronique en transmission permet d’illustrer la perméabilisation de la membrane fongique induite par les deux peptides. Enfin, nos résultats révèlent un effet antifongique additif de la combinaison entre D-CTL et le voriconazole, un agent antifongique de référence dans le traitement des infections liées à Candida. En conclusion, D-CTL peut être considéré comme un agent antifongique efficace, sûr et stable et pourrait être utilisé seul ou en association avec le voriconazole pour traiter les infections orales liées à Candida et servir dans le futur à l’élaboration de biomatériaux actifs. / The excessive use of antifungal agents, compounded by the shortage of new drugs being introduced into the market, is causing the accumulation of multi-resistance phenotypes in many fungal strains. Consequently, new alternative molecules to conventional antifungal agents are urgently needed to prevent the emergence of fungal resistance. In this context, Cateslytin (CTL), a natural peptide derived from the processing of Chromogranin A, has already been described as an effective antimicrobial agent against several pathogens including Candida albicans. In the present study, we compared the antimicrobial activity of two conformations of CTL, L-CTL and D-CTL against various strains of Candida. Our results show that D-CTL was the most efficient and safe antifungal agent. Moreover, in contrast to L-CTL,D-CTL was not degraded by proteases secreted by Candida albicans and was also stable in saliva. Using video-microscopy, we also demonstrated that D-CTL can rapidly enter Candida albicans, but is unable to spread within a yeast colony unless from a mother cell to a daughter cell during cellular division. Besides, transmission electron microscopy illustrated the permeabilization of the fungal membrane induced by both peptides. Finally, we revealed that the antifungal activity of D-CTL could be synergized by voriconazole, an antifungal of reference in the treatment of Candida related infections. In conclusion, D-CTL can be considered as an effective, safe and stable antifungal and could be used alone or in a combination therapy with voriconazole to treat Candida associated infections including oral candidosis.
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Utility of envelope T cells in preventing AIDS: HIV-1 and SIV envelope-specific T cells: controlling HIV-1 and SIV infection in pigtail macaques and their utility as a T cell immunogenPeut, Vivienne Mary January 2008 (has links)
HIV/AIDS annually kills millions of people worldwide. Those claimed by the disease are quickly replaced by those newly infected. Three times as many new infections occur globally, as patients who are likely to have access to antiretroviral therapy. We need a HIV vaccine. However, the better HIV protein to target for this vaccine in unknown. Structural proteins such as Group specific antigen (Gag) and Envelope (Env) were thought likely candidates due to viral structural proteins usually being highly conserved and constrained in their ability to mutate to escape T cell attack. To establish if Env-specific T cells could control viraemia, 2 large vaccine trials were conducted with 66 pigtail macaques participating. Also, 2 reversion trials involving 4 pigtail macaques were undertaken. Env-specific T cell epitopes were mapped in both SHIV (simian/human immunodeficiency virus) and SIV (simian immunodeficiency virus)-infected macaques using IFNγ intracellular cytokine staining and flow cytometry.
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An alternative to conventional antibiotics : a new antimicrobial peptide derived from chromogranin A / Une alternative pour les antibiotiques conventionnels : un nouveau peptide antimicrobien dérivé de la chromogranine AZaet, Abdurraouf 09 March 2018 (has links)
Les peptides antimicrobiens (PAMs) représentent des composants importants de l`immunité innée. Ils sont présents dans la plupart des organismes multicellulaires et constituent la première ligne de défense contre les infections. Ils possèdent un large éventail d`activités, une non-toxicité contre les cellules de l`hôte et des effets synergiques avec les antibiotiques conventionnels. Par conséquent, ils peuvent être d`excellents candidats dans le développement de nouveaux antibiotiques pour lutter contre la résistance de microorganismes. Concernant les PAMs dérivés de la chromogranine A (CgA), la cateslytine (Ctl) présente des activités antimicrobiennes directes et des propriétés immunomodulatrices. Dans ma thèse, j`ai cherché à caractériser l`épipeptide D-Ctl, où tous les résidus en conformation-L ont été remplacés par des résidus en conformation-D. Tout d`abord, la stabilité dans les surnageants bactériens et des dosages de l`activité antimicrobienne ont été réalisés, ainsi que l`analyse de viabilité des cellules et des dosages des cytokines libérées par les cellules immunitaires. L`efficacité de D-Ctl a été comparée à celle de L-Ctl contre des souches bactériennes, puis les CMIs ont été déterminées et comparées dans le cas de combinaisons avec des antibiotiques conventionnels, afin de montrer un effet synergique et/ou additif. De plus, D-Ctl ne déclenche pas de résistance chez E. coli. Des tests de cytotoxicité ont été effectués sur plusieurs types de lignées cellulaires et de PBMCs. Les effets inflammatoires aussi ont été testés. Ensuite, le modèle bactérien E. coli MDR a été utilisé pour des analyses physico-chimiques, telles que la microscopie à épifluorescence, la spectroscopie ATR-FTIR et la microscopie à force atomique. Enfin, le brevet D-Ctl a été déposé en 2016 sous le numéro EP 16306539.4 « Nouveau peptide de cateslytine en conformation D ». En conclusion, D-Ctl est capable de tuer rapidement un large spectre de micro-organismes, et il pourrait potentialiser l`effet antimicrobien de plusieurs antibiotiques. / Antimicrobial peptides (AMPs) represent important components of innate immunity. They are present in most multicellular organisms and constitute the first line of defense against infections. They exhibit a large spectrum of activities, a non-toxicity against host cells and synergistic effects with conventional antibiotics. Therefore, they can be as excellent candidates in the development of new antibiotics to fight pathogens resistance. Concerning to AMPs derived from chromogranin A (CgA), Cateslytin (Ctl) represents a new antibiotic, which displays direct antimicrobial activities and immunomodulatory properties. In my thesis, I aimed to characterize the epipeptide D-Ctl, where all (L-conformation) residues were replaced by (D-conformation) residues. Firstly, antimicrobial assays were performed, cells viability, immune assays, and the stability in bacterial supernatant was tested. The efficiency of D-Ctl was compared with L-Ctl against bacterial strains, then MICs were determined and compared with combinations in presence of classical antibiotics in order to show synergistic or/and additive effect. Moreover, D-Ctl does not trigger resistance in E. coli. Also, cytotoxicity assays were performed on several types of cell line and PBMCs. Inflammatory effects were tested too. Then, bacterial model E. coli MDR was used for physicochemical analysis such as epifluorescence microscopy, ATR-FTIR spectroscopy and atomic force microscopy. Finally, D-Ctl patent has been deposited in 2016 under the number EP 16306539.4 “New D-configured cateslytin peptide”. To conclude: D-Ctl is able to rapidly kill a broad spectrum of microorganisms, and it could potentiate the antimicrobial effect of several antibiotics.
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Unwelcome guests: methods of pathologic escape from MHC class I-mediated immunityKhalsa, Harimander 09 July 2020 (has links)
Major histocompatibility complex class I (MHC-I) proteins are responsible for the presentation of intracellular protein fragments on the cellular surface and are thus the primary method for the broader immune system to recognize and respond to intracellular deformity or infection. A successful immune response against intracellular pathogens relies upon effective epitope presentation by MHC-I and recognition of this epitope by cytotoxic cluster of differentiation 8 positive (CD8+) T cells. Although MHC-I mediated immunity is a powerful mechanism which might resist infection by pathogens, many such pathogens have evolved methods of eluding or suppressing MHC-I mediated immune responses and are thereby able to persist within our cells. Close study of the fine details of the functionality of the MHC-I mediated antigen presentation system may yield important clues about how to best move forward in the quest to eliminate these problematic diseases. Although diseases such as tuberculosis, malaria, human immunodeficiency virus (HIV), and cancer may differ in many fundamental ways, it has become clear that the future of treating these elusive pathogens must involve utilization of the tools provided in the human immune system.
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Cytotoxic T lymphocytes in HIV-1 infectionPrice, David A. January 1999 (has links)
No description available.
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Activation of thymic T cells by MHC alloantigen can require syngeneic activated CD4 T cells and B cells as APCStrutt, Tara Marlene 07 April 2005
<p>An immunological mechanism to account for the regulation of peripheral self-reactive T cells, which escape central tolerance in the thymus, during the primary activation of naïve, foreign antigen-specific T cells remains to be established. Contemporary models of primary T cell activation that attempt to describe how this occurs differ significantly in the cellular interactions necessary for naïve CD4+ T helper cell activation. It is generally accepted that most CD8+ T cells are dependent upon CD4+ T helper cells for their activation. </p><p>The Infectious Non-Self and Danger Models of CD4+ T cell activation propose that interaction of a naïve T cell with an appropriately armed dendritic cell is sufficient, whereas the Two-step, Two-signal Model proposes additional cellular interactions are necessary. The major goal of this thesis was to establish and utilize an in vitro experimental system that would allow one to begin to delineate which model most validly describes the cellular interactions required for generation of primary immune responses from naïve T cells. Employing a population of naïve T cells uncontaminated with any partially or fully activated cells is essential for such a study.</p><p>The results presented in this thesis show, that when thymocytes are employed as a source of responding naïve T cells, cellular interactions, in addition to interaction with bone marrow derived dendritic cells, are required for the activation of naïve thymic T cells. The primary activation of thymic T cells to generate CD4+ IL-2 producing cells, and CD8+ IFN-g producing cells and cytotoxic T cells upon stimulation with splenic allogeneic stimulator cells is critically dependent upon the presence of a syngeneic population of radiation resistant, CD4+ T cells found in the spleen of normal mice. Additionally, when such cells are present as a source of help for thymocytes, allogeneic bone marrow derived dendritic cells fail to stimulate the generation of optimal cytotoxic and cytokine responses from naïve thymic T cells. However, they do stimulate thymocytes to cycle and up regulate the ligand for the costimulatory molecule CD40, CD40L.</p><p>The results presented within also show that the optimal activation of naïve thymic T cells to generate CD4+ IL-2 producing cells, and CD8+ IFN-g producing cells and cytotoxic T cells, requires the presence of allo-MHC bearing Ig+ B220+ B cells. The removal of B220+ cells by magnetic cell sorting from the allogeneic spleen reveals that the generation of CD8+ cytotoxic T cells and IFN-g producing cells from thymocytes is markedly reduced compared to unsorted allogeneic spleen cells. However, IL-2 and IL-4 cytokine producing cells are still detectable. Potential reasons for the generation of the latter cytokine producing cells are discussed. The results presented in this thesis have revealed insights into the cellular interactions involved in the activation of naïve thymic T cells.
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Rational Design and Testing of Novel HIV T Cell ImmunogensMothe Pujadas, Beatriz 17 April 2012 (has links)
Aquesta tesi doctoral té com a objectiu caracteritzar millor les respostes VIH específiques de les cèl·lules T (CTL), identificar les dianes virals implicades en el control del virus i desenvolupar com aquesta informació s'ha incorporat en el disseny d’un inmunogen per a una futura vacuna contra el VIH.
S’inicia amb una introducció actualitzada i àmpliament referenciada sobre el VIH/sida, inclosos aspectes històrics i epidemiològics de l’epidèmia, així com una visió des de la virologia i la immunologia de les dificultats en el desenvolupament de vacunes eficaces contra el VIH.
En el primer capítol, es revisa la interacció entre factors virals, característiques genètiques de l’hoste i mecanismes immunològics implicats en el control del VIH. S’han incorporat les troballes més recents sobre aspectes immunològics -especialment en CTL- correlacionats amb l’evolució de la malaltia. A més, s’exposen els nous coneixements sobre com l'evolució viral és modula per diferències en la freqüència de característiques genètiques de l'hoste en les diferents regions del món. Es desenvolupa alhora la importància de discernir millor entre causa i efecte dels marcadors immunològics associats amb el control relatiu de la infecció pel VIH, doncs els factors que són un mer reflex de la replicació continguda del virus per altres motius poden induir a errors de concepte que s’incorporin al disseny de noves vacunes.
Al llarg del segon capítol, s’exposa la identificació de 26 dianes virals (OLP) del VIH més potents per induir respostes CTL associades amb un millor control de la replicació viral en tres cohorts molt àmplies de pacients infectats. Es demostra que l'efecte dels OLP identificats en les càrregues virals dels pacients és tan fort com l'associat a la influència de l’ HLA individual. Alhora, les dianes identificades com a beneficioses van resultar trobar-se en regions més conservades dins del genoma viral, fet que està en relació amb treballs d’altres grups enfocats en els elements conservats del virus. Una contribució important del nostre treball és la incorporació d'una quantitat significativa de dades d’ immunogenicitat real, ja que no totes les regions conservades del proteoma viral són igualment immunogèniques i per tant, no totes poden considerar-se igualment beneficioses.
En el tercer capítol, es va associar l’avidesa funcional i la capacitat de reaccionar amb variants virals amb el control del VIH. En aquest treball, es va incloure un grup d'individus infectats pel VIH amb un fenotip de 'controlador' i ‘progressor’ del que es van excloure deliberadament tots els participants que expressaven alguns dels HLA prèviament coneguts com a favorables en la infecció per VIH, per tal d’evitar el possible biaix a causa de la dominància de CTLs dirigides a epítops restringits per aquests al·lels beneficiosos. La idea és trobar resultats que siguin el màxim de traduïbles a la població general, on aquests HLA es presenten a unes freqüències molt baixes. El nostre treball alhora complementa una visió més amplia de la funcionalitat de les CTL. Tot i la limitació de l'avaluació d'una sola funció efectora (excreció d’IFNγ) el fet que l'avidesa es mostri estar vinculada a la reactivitat creuada, pot ser determinant per la inducció de respostes amb gran ‘profunditat’ (reactivitat creuada a variants virals) i així ajudar a contenir l’escapament a la pressió immunològica així com respondre a l’enorme diversitat viral, alguns dels principals obstacles en el desenvolupament de vacunes.
Finalment, tots els resultats van ser incorporats per dissenyar una nova seqüència per a un immunogen reduccionista, que té com a objectiu cobrir un ampli repertori d’HLA, trencar amb la inmunodominància de respostes induïdes a regions que no apareixen com especialment beneficioses en les cohorts que hem testat alhora que tractar d'enfocar la inducció de respostes cap a les dianes virals identificades com a més beneficioses. Es va construir un plàsmid de DNA que expressa l’inmunogen dissenyat d’una forma estable in vitro. Es presenten els primers assaigs in vivo en ratolins C57BL/6 en els que l’immunogen va induir una resposta immunològica CTL particularment amplia. Al llarg de la discussió s’elaboren el punts forts i febles dels nostres resultats en un context més ampli del camp i es descriu la orientació futura del nostre treball. / This doctoral thesis aims to better characterize HIV specific T cell responses, define the viral targets most implicated in mediating viral control and discuss how this information has been incorporated into a rational immunogen design for a future HIV vaccine.
A well-researched and referenced introduction to HIV, including historical and epidemiological aspects of the infection as well as virological and immunological overview of the vaccine development field challenges is firstly provided.
In the first Chapter, a review of the important interplay between viral factors, host genetic and immune characteristics in HIV control is given. Some novel insights on immune correlates –specially on CTLs- elucidated over the last years to complete the work compiled in Chapter 1 are discussed. Also, new data is presenting regarding how viral evolution is shaped by differences in the frequency of different host genetic markers within different regions. New concepts to better discern between cause and effect of immune parameters associated with relatively controlled HIV infection will be discussed, as the factors that are a mere reflection of otherwise contained replication can mislead vaccine design.
Throughout the second Chapter, the most potent viral targets of the virus-specific T cell responses in controlling viral replication were identified in 26 regions over the HIV proteome. The relative effects of host genetics (i.e. HLA) and CTL specificity on HIV-1 control were assessed in large cohorts of HIV infected individuals. Importantly, the effect of T cell specificity towards the identified regions on viral loads was shown to be at least as strong as the associated with host HLA genetics. These preferred targets turned out to be in the most conserved regions of the viral genome, which is in accordance with other investigators work developing novel vaccine concepts focused on conserved elements. An important contribution of our work is the incorporation of a significant amount of immunogenicity data, as not all conserved regions of the viral proteome are equally immunogenic.
In the third chapter, functional avidity and the ability to react with viral variants were associated with controlled HIV infection. In the present work, a group of HIV infected individuals was chosen with a ‘controller’ and a ‘progressor’ phenotype, but those expressing some of the known favourable HLA were intentionally excluded from the cohort to avoid bias due to the presence of dominant CTL epitopes restricted by these beneficial alleles and find results more translatable to the general population. Our work complements recent data trying to have a bigger picture of CTL functionality. Despite the limitation of assessing a single effector function (IFNγ release) the fact that functional characteristics such as avidity are shown to be linked to cross-reactivity, can be determinant for the depth of vaccine induced T cell responses and therefore, help in dealing with escape and viral diversity, some of the major hurdles in vaccine development.
Lastly, all the compiled findings were incorporated into a new reductionistic HIV immunogen sequence with a broad HLA heterogeneity restriction that aims to break immunodominance to regions with potential non-beneficial effects in viral control and seek to focus the vaccine induced response to most protective viral targets. A DNA plasmid expressing the HIV T cell immunogen was first engineered , showed to have a stable expression in-vitro and induced a particularly broad T cell responses in the first in vivo immunogenicity studies in C57BL/6 mice. Strong and weaker points of our findings are elaborated in a larger context of the field and next future directions of our work are outlined throughout the Discussion of this Thesis.
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Activation of thymic T cells by MHC alloantigen can require syngeneic activated CD4 T cells and B cells as APCStrutt, Tara Marlene 07 April 2005 (has links)
<p>An immunological mechanism to account for the regulation of peripheral self-reactive T cells, which escape central tolerance in the thymus, during the primary activation of naïve, foreign antigen-specific T cells remains to be established. Contemporary models of primary T cell activation that attempt to describe how this occurs differ significantly in the cellular interactions necessary for naïve CD4+ T helper cell activation. It is generally accepted that most CD8+ T cells are dependent upon CD4+ T helper cells for their activation. </p><p>The Infectious Non-Self and Danger Models of CD4+ T cell activation propose that interaction of a naïve T cell with an appropriately armed dendritic cell is sufficient, whereas the Two-step, Two-signal Model proposes additional cellular interactions are necessary. The major goal of this thesis was to establish and utilize an in vitro experimental system that would allow one to begin to delineate which model most validly describes the cellular interactions required for generation of primary immune responses from naïve T cells. Employing a population of naïve T cells uncontaminated with any partially or fully activated cells is essential for such a study.</p><p>The results presented in this thesis show, that when thymocytes are employed as a source of responding naïve T cells, cellular interactions, in addition to interaction with bone marrow derived dendritic cells, are required for the activation of naïve thymic T cells. The primary activation of thymic T cells to generate CD4+ IL-2 producing cells, and CD8+ IFN-g producing cells and cytotoxic T cells upon stimulation with splenic allogeneic stimulator cells is critically dependent upon the presence of a syngeneic population of radiation resistant, CD4+ T cells found in the spleen of normal mice. Additionally, when such cells are present as a source of help for thymocytes, allogeneic bone marrow derived dendritic cells fail to stimulate the generation of optimal cytotoxic and cytokine responses from naïve thymic T cells. However, they do stimulate thymocytes to cycle and up regulate the ligand for the costimulatory molecule CD40, CD40L.</p><p>The results presented within also show that the optimal activation of naïve thymic T cells to generate CD4+ IL-2 producing cells, and CD8+ IFN-g producing cells and cytotoxic T cells, requires the presence of allo-MHC bearing Ig+ B220+ B cells. The removal of B220+ cells by magnetic cell sorting from the allogeneic spleen reveals that the generation of CD8+ cytotoxic T cells and IFN-g producing cells from thymocytes is markedly reduced compared to unsorted allogeneic spleen cells. However, IL-2 and IL-4 cytokine producing cells are still detectable. Potential reasons for the generation of the latter cytokine producing cells are discussed. The results presented in this thesis have revealed insights into the cellular interactions involved in the activation of naïve thymic T cells.
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