Submitted by Hiolanda Rêgo (hiolandarego@gmail.com) on 2016-07-27T15:42:04Z No. of bitstreams: 1 Dissertação_ICS_ Ana Luiza Dias Angelo.pdf: 1143787 bytes, checksum: 4f198dcfcd707a8f0ed1c85f8673c9cc (MD5) / Made available in DSpace on 2016-07-27T15:42:04Z (GMT). No. of bitstreams: 1 Dissertação_ICS_ Ana Luiza Dias Angelo.pdf: 1143787 bytes, checksum: 4f198dcfcd707a8f0ed1c85f8673c9cc (MD5) / CAPES / A contagem de células T CD4+ é o principal marcador imunológico usado para definir o momento adequado para início da terapia antiretroviral e profilaxia para infecções oportunistas em pacientes portadores do vírus HIV. Seu alto custo limita o uso desta técnica em muitos locais no mundo. O objetivo deste estudo foi avaliar a utilidade da TLC em substituir a contagem de células T CD4+ como marcador imunológico para detectar os pacientes com necessidade de profilaxia contra infecções oportunistas (CD4 < 200 cel/mm3), e aqueles com CD4 < 350 cel/mm3 (limite brasileiro que define AIDS). Nós analisamos a TLC e contagem de células T CD4 de 1174 pacientes infectados pelo HIV provenientes do HUPES durante o período de maio/2003 a setembro/2004. A contagem de células T CD4+ foi realizada por citometria de fluxo e a contagem total de linfócitos por contador hematológico automatizado. Foram analisadas um total de 1510 amostras. A contagem de células T CD4+ teve valor mínimo de 4 cel/mm3 e valor máximo de 2531 cel/mm3, TLC teve mínimo de 300 cel/mm3 e máximo de 6200 cel/mm3. O melhor valor de TLC, capaz de predizer CD4 < 200 cel/mm3, foi ≤ 1700 cel/mm3 (SE=76,3%; SPE=65,2%, NPV=93,1%), mas PPV de somente 31,1%. Resultados semelhantes foram encontrados para contagem de células T CD4+ < 350 cel/mm3, entretanto observou-se menor sensibilidade (SE= 59,4%, SPE=96,6%, PPV= 57,3% e NPV= 79,4%). Estes resultados indicam que apesar da forte associação existente entre TLC e contagem de células T CD4+, a contagem total de linfócitos não é um bom indicador da contagem de células T CD4+ em pacientes portadores do vírus HIV, mas pode ser um útil indicador para dispensar a realização da contagem de células T CD4+.

Trichuris trichiura is a gastrointestinal dwelling nematode that infects almost 500 million people worldwide. T. muris occurs naturally in mice and is very closely related the human whipworm, making it a suitable model to dissect the immune response against the parasite. Studies using the Trichuris muris system have identified CD4+ T cells as dictators of the outcome of infection. In wild type mice, infection with a high dose of T. muris eggs leads to resistance and worm expulsion, which are dependent on a Th2 response and the secretion of type 2 cytokines especially interleukin (IL) 13. Chronicity is dependent on a Th1 response and occurs when mice are infected with a low dose of T. muris eggs. It is well established that metabolic changes are essential to promoting T cell activation and effector function. Moreover, during chronic infection the host immune system is continuously exposed to parasite antigen, which represents a metabolic challenge. This thesis has investigated the importance of T cell metabolism during response against T. muris. Data presented here show that low and high dose T. muris infections promote upregulation of the glycolytic pathway in CD4+ T cells. During later stages of chronic infection, CD4+ T cells displayed supressed glycolysis and mitochondrial respiration, and may be due to metabolic modulation imposed by the parasite. Leucine uptake via the amino acid transporter Slc7a5 was previously shown to be required for mTORC1 activation and for T cell effector function. Data presented here show that in early stages following a high dose T. muris infection, mice that lack Slc7a5 in T cells have delayed worm expulsion, impaired production of antibodies, and lower levels of IL-13. Their CD4+ T cells present reduced glycolytic rates when compared to cells from cohoused infected wild type mice. However, at later stages of infection, antibody, IL-13 and glycolytic levels were restored together with worm expulsion. CD4+ T cells from the early stage of infection showed reduced phosphorylation of mTOR, which suggested that impairment of function was mTOR dependent. Indeed, mice lacking mTOR in T cells fail to expel a high dose of parasites. They showed abrogation of IL-13 production, impairment in antibody class switching and their CD4+ T cells failed to upregulate glycolysis. Thus, this thesis shows that mTOR is essential for the proper functioning of T cells during T. muris infection and efficient amino acid transport plays a significant role. Taken together, these data show that metabolic orchestration of T cell function influences the capacity to effectively control helminth infection and that even subtle changes in T cell metabolic control can have a major effect on response phenotype.

Submitted by Hiolanda Rêgo (hiolandar@gmail.com) on 2013-08-13T16:57:51Z No. of bitstreams: 1 Tese_ISC_Alex José Leite Torres.pdf: 1506694 bytes, checksum: 5e8d47ad1e02ea0fc8fe10e9e6543865 (MD5) / Made available in DSpace on 2013-08-13T16:57:51Z (GMT). No. of bitstreams: 1 Tese_ISC_Alex José Leite Torres.pdf: 1506694 bytes, checksum: 5e8d47ad1e02ea0fc8fe10e9e6543865 (MD5) / Departamento Nacional DST e AIDS e Hepatites Virais / RACIONAL: Tropismo viral e carga proviral do HIV possuem papel fundamental para o auxílio da introdução de terapia e avaliação da patogênese do vírus, respectivamente, os quais são determinados, atualmente, por técnicas de genotipagem e fenotipagem. Outro importante parâmetro para monitoramento laboratorial do sistema imune do paciente HIV positivo é a determinação de valores de referências dos linfócitos T, dados esses inexistente para a população brasileira que é caracterizada por uma grande diversidade étnica e cultural. OBJETIVOS: Determinar a sensibilidade e especificidade da citometria de fluxo para detecção intracitoplasmática do HIV-1, identificando o tropismo viral e carga proviral deste vírus e estabelecer valores de referências das subpopulações dos linfócitos T na população brasileira. MÉTODOS: Para a detecção do vírus intracelular, foram avaliados 102 pacientes soropositivos para o HIV-1, atendidos no Hospital Universitário Professor Edgard Santos, estratificado em estágios de viremia diferenciados e para a determinação dos valores de referências das células T, foram triados 645 doadores de sangue de 03 hemocentros e 02 hospitais universitários, das cinco regiões brasileiras, além de 280 crianças atendidas em dois hospitais universitários, um no Rio de Janeiro e outro na Bahia. Amostras foram submetidas a marcação através de anticorpos monoclonais anti-CD3+, anti-CD4+, anti-CD8+, anti-CD45+, anti-CCR5+ e anti- CXCR4 e probe complementar das regiões gag e pol do HIV para a avaliação da imunofenotipagem celular.RESULTADOS: A determinação do tropismo viral por imunofenotipagem obteve uma elevada correlação com os resultados comparados com geno2pheno representando 97.2% de especificidade e 95% de intervalo de confiança com variação entre 85.8%-99.5%. Pacientes controladores de elite apresentaram uma siginificante diferença da carga proviral em comparação com pacientes com cargas virais plasmáticas indetectáveis e detectáveis em terapia. Pacientes com tropismo CCR5 e carga viral indetectável há menos de cinco anos apresentaram carga proviral mais elevada em comparação aos indetectáveis há mais de cinco anos. Os valores de referência dos linfócitos T CD4+ na população brasileira mostraram-se variáveis entre as regiões, sendo São Paulo e Rio Grande do Sul superiores em comparação às demais regiões, o que caracteriza a importância da influência étcnica e cultural entre a diversidade das populações. CONCLUSÃO: Os testes de tropismo viral e carga proviral por citometria de fluxo apresentaram-se como importantes ferramentas tendo significante diminuição do custo e do tempo de procedimento e também devem ser adotados valores de referências diferenciados nas regiões do Brasil, devido a características peculiares regionais em suas populações. / Salvador

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-12-05T18:04:29Z No. of bitstreams: 1 Marcelo Dos Santos Teixeira Obtencao de celulas... 2003.pdf: 28318419 bytes, checksum: a1e439159f78f314897b74a003f09de9 (MD5) / Made available in DSpace on 2012-12-05T18:04:29Z (GMT). No. of bitstreams: 1 Marcelo Dos Santos Teixeira Obtencao de celulas... 2003.pdf: 28318419 bytes, checksum: a1e439159f78f314897b74a003f09de9 (MD5) Previous issue date: 2003 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil

Made available in DSpace on 2016-04-15T12:58:15Z (GMT). No. of bitstreams: 2 jesuito_dantas_ioc_mest_2015.pdf: 8011040 bytes, checksum: c494775b2a194ca3921d445d202df24a (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Os pacientes infectados pelo vírus HIV apresentam alta frequência de dermatoses, sendo essas a primeira (sinal precoce) e, às vezes, a única manifestação do estágio da doença. Para tanto, torna-se imprescindível conhecer a distribuição dessas doenças cutâneas nos pacientes acometidos pelo HIV/AIDS no Instituto de Doenças Tropicais Natan Portella \2013 IDTNP, considerado hospital de referência para o tratamento do HIV no Estado do Piauí. O objetivo deste trabalho foi, portanto, identificar as dermatoses que afetam os pacientes com HIV/AIDS no IDTNP, segundo o grau de imunossupressão por eles apresentado, e correlacioná-las com variáveis clínicas e epidemiológicas. O estudo foi descritivo do tipo relato de série de casos. Foram analisados 151 pacientes com HIV/AIDS, atendidos no IDTNP no período de janeiro a abril de 2015. As doenças cutâneas foram caracterizadas, do ponto de vista clínico-epidemiológico, em sete grupos: I) fúngicas; II) virais; III) bacterianas; IV) por protozoários; V) por artrópodes; VI) neoplasias cutâneas; e VII) miscelânea, assim entendidas aquelas não enquadradas nas categorias anteriores. Para o diagnóstico das dermatoses, foram utilizados exames clínicos e laboratoriais, dos quais se podem destacar: micológico direto, cultura de bactérias e fungos, estudo anatomopatológico, contagem de linfócitos CD4, carga viral etc. Constatou-se que, entre os pacientes, a maioria eram homens (n=110 72,8%). A média de idade dos homens (40,9 ± 11,9 anos) foi ligeiramente inferior à das mulheres (41,4 ± 10,2 anos). Entre os homens, 31% declararam manter relações sexuais com homens. O grau de instrução predominante foi o Ensino Fundamental. Cerca de um quarto dos pacientes atendidos não residia no Piauí Entre estes, predominaram pacientes do estado do Maranhão (22,5%) e, entre os municípios, da cidade de Teresina/PI (58,3%). Foram frequentes os estágios avançados da infecção pelo HIV. As médias de contagem de linfócitos CD4 foram 272,6 ± 271,1 entre os homens e 338,9 ± 351 entre as mulheres. De acordo com a categoria etiológica, 93 (61,6%) tinham afecções do grupo miscelânea, 50 (33,1%) tinham infecções cutâneas de etiologia fúngica, 40 (26,4%) tinham infecções bacterianas, 35 (23,2%) apresentavam dermatoses virais, 16 (10,6%) dos pacientes tinham dermatoses neoplásicas, 5 (3,3%) tinham doenças causadas por artrópodes e 4 (2,6%) doenças causadas por protozoários. As dermatoses prevalentes nos pacientes observados foram prurigo do HIV com 35 pacientes acometidos, seguida de onicomicose (n=28), dermatite seborréica (n=18), hanseníase (n=17), herpes simples (n=14), candidose oral (n=12) e farmacodermia (n=10). Os grupos de dermatoses neoplásicas e virais foram mais comumente vistos em casos avançados de imunossupressão. Esta tendência não foi observada em pacientes com dermatoses bacterianas ou fúngicas. Observaram-se médias de contagem de CD4 inferiores e cargas virais superiores no grupo de pacientes com sarcoma de Kaposi e prurigo do HIV quando comparados com os pacientes com sífilis e hanseníase A candidose oral foi a patologia isolada que mais suscitou o médico a pedir o teste diagnóstico de infecção pelo HIV nos pacientes que ainda desconheciam seu estado sorológico e o sarcoma de Kaposi a patologia que mostrou maior correlação inversa entre número de linfócitos CD4 e superfície corpórea atingida. Percebeu-se uma média de número de dermatoses por pacientes superior nos pacientes com contagem de linfócitos CD4 inferior. Pretendeu-se com este estudo contribuir para o conhecimento sobre as doenças cutâneas encontradas nos pacientes com HIV/AIDS e propor uma melhor atenção a esses pacientes, por meio sobretudo de uma visão holística/interdisciplinar da doença / Abstract: Patients infected with HIV often have skin diseases such as dermathosis, this being the first (early sign) and sometimes the only manifestation of the disease. To this end, it is essential to know the distribution of these skin diseases in patients affected by HIV / AIDS at the Instituto de Doenças Tropicais Natan Portella - IDTNP, considered a reference whe it comes to hospitals for the treatment of HIV in the state of Piaui, Brazil. The objective of this study was therefore to identify the skin diseases that affect patients with HIV / AIDS in IDTNP according to the degree of immunosuppression they presented, and correlate them with clinical and epidemiological variables. The study was descriptive of the kind reported case series. This study analyzed 151 patients with HIV / AIDS who were attended at IDTNP from January to April 2015. Skin diseases have been characterized, from a clinical and epidemiological point of view, into seven groups: I) yeast; II) virus; III) bacterial; IV) by protozoa; V) by arthropods; VI) skin cancer; and VII) miscellany, understood those not falling into the above categories. For the diagnosis of skin diseases, they used clinical and laboratory tests, of which the following stand out: mycological, culture of bacteria and fungi, pathological studies, CD4 count, viral load, etc. It was found that, among patients, most were men (n = 110 72.8%). The average age of men (40.9 ± 11.9 years) was slightly lower than that of women (41.4 ± 10.2 years). Among men, 31% reported having sex with men. The predominant degree of education was elementary school. About a quarter of the patients seen were not resident in Piauí. Among these, the predominant patients were from the State of Maranhão (22.5%) and among the municipalities, the city of Teresina / PI (58.3%) It was quite frequente cases of advanced stages of HIV infection. The average CD4 count was 272.6 ± 271.1 for men and 338.9 ± 351 among women. According to etiological category 93 (61.6%) were miscellaneous group of diseases, 50 (33.1%) had skin infections fungal etiology, 40 (26.4%) had bacterial infections, 35 (23.2 %) had viral dermatoses, 16 (10.6%) patients who had neoplastic dermatoses 5 (3.3%), diseases caused by arthropod and 4 (2.6%) protozoal diseases. The prevalent dermatoses in patients observed were prurigo HIV with 35 patients affected, followed by onychomycosis (n = 28), seborrheic dermatitis (n = 18), leprosy (n = 17), herpes simplex (n = 14), oral candidiasis (n = 12) and adverse drug (n = 10). The groups of neoplastic and viral dermatoses are commonly seen in advanced cases of immunosuppression. This trend was observed in patients with bacterial or fungal skin diseases They observed mean CD4 count and viral load higher in patients with Kaposi's sarcoma and prurigo HIV compared with patients with syphilis and leprosy. Oral candidiasis was isolated pathology that most provoked the doctor to ask for the diagnosis of HIV infection in the patients still unaware of their HIV status and Kaposi's sarcoma pathology which showed higher inverse correlation between the number of CD4 lymphocytes and affected body surface. It was realized an average number of dermatoses per patient higher in patients with lower CD4 lymphocyte count. It was intended with this study contribute to knowledge about skin diseases found in patients with HIV / AIDS and offer better care to these patients, especially through a holistic / interdisciplinary view of the disease

Humoral immunity provides protection against subsequent infections. Antigen-specific, high-affinity, class-switched antibodies are produced by B cells through rounds of proliferation, B cell receptor rearrangement and selection in the germinal centres (GC). T cells play an essential and indispensable role in this process and in the recent years the term T follicular helper cells (TFH) was coined to describe this cell subset. The aim of my thesis is to investigate whether there is more than one type of T cells within the TFH population and whether it has important functional consequences. Firstly, I use sheep red blood cell immunisation (SRBC) and Salmonella enterica infection to show phenotypical differences between TFH expressing high and low level of surface molecule PD-1. In order to investigate the relationship between different TFH populations gene profiling was carried out on the microarray platform. Detailed transcriptome analysis revealed the discrete nature of isolated TFH cell subsets and provided an overview of their genetic landscape. Secondly, I have investigated the dependence of TFH subsets on cognate interactions with B cell in SRBC model by generating BM chimeras. I have demonstrated that generation of PD-1HI TFH, but not of PD-1LO TFH, depends on antigen presentation by B cells. Furthermore, I have shown that provision of wild-type but not MHC II knock-out B cells rescues PD-1HI formation in BM chimeras after SRBC immunisation. Finally, I have explored plasticity within TFH subsets and showed that none of the populations is in a terminally differentiated state, as they can convert into one another. Thirdly, experiments with S. enterica model revealed that the absence of PD- 1HI TFH is independent of the splenic architecture disruption present within the first week of the response. Surprisingly, co-immunisation studies showed that PD-1HI population is not only present but even enhanced in the group which received both SRBC and S. enterica when compared to single immunisations. The work presented in the thesis documents that there is a significant and previously unappreciated heterogeneity within TFH subset. This knowledge is important for designing optimal vaccine strategies and treating autoimmune diseases, as in both processes the antibody production plays a crucial role and its manipulation (either enhancing or blocking antibody production, respectively) can significantly improve clinical interventions.

La génération et/ou le recrutement de cellules immuno-suppressives fait partie des mécanismes majeurs utilisés par les tumeurs afin d’échapper aux réponses anti-tumorales du système immunitaire. Parmi les cellules capables d’inhiber les réponses anti-tumorales, les lymphocytes T CD4+ régulateurs et les macrophages de type II tiennent un rôle de premier ordre dans le contexte tumoral. Au cours de ma thèse, j’ai pu étudier l’impact de ces deux populations dans la suppression des réponses immunitaires anti-tumorales dans le modèle MT/ret de mélanome spontané métastatique. L’ensemble de nos résultats met en avant plusieurs niveaux d’immuno-suppression dans le modèle MT/ret. D’une part, les lymphocytes T CD4+ régulateurs, de par leur localisation dans les ganglions drainants et dans la peau, semblent impliqués dans la suppression des réponses anti-tumorales aux localisations et aux moments où les tumeurs nécessitent une forte inhibition des effecteurs anti-tumoraux. D’un autre côté, les macrophages de type II présentent, en plus de leurs capacités immuno-suppressives, des fonctions importantes pour la croissance et la dissémination tumorale justifiant leur localisation dans le microenvironnement tumoral. Dans un second temps, nos données suggèrent pour la première fois un rôle des monocytes Ly-6Cfort dans le contrôle tumoral via la lyse de ces dernières ou encore le maintien de la dormance des cellules tumorales disséminées. En conséquence, nous proposons de les ajouter à la liste des acteurs immunitaires directement impliqués lors des phases d’élimination et d’équilibre de la théorie de l’immuno-éditing. De plus, nous mettons en évidence leur inhibition par les lymphocytes T CD4+ régulateurs, ce qui n’avait pas non plus été décrit précédemment. Ceci nous pousse à suggérer de prendre plus en compte l’impact des lymphocytes T CD4+ régulateurs sur d’autres populations immunitaires que les lymphocytes T dans le contexte tumoral / Pas de résumé en anglais

La reprogrammation métabolique est un événement critique dans la fonction et la différenciation des lymphocytes T. Les lymphocytes T quiescents reposent principalement sur la phosphorylation oxydative qui leur permet de produire de grandes quantités d’énergie. Cependant, après activation antigénique, les lymphocytes T subissent une reprogrammation métabolique caractérisée par une augmentation de la glycolyse. Cette situation unique permet aux lymphocytes T activés de diriger rapidement les intermédiaires métaboliques vers la synthèse de macromolécules requises pour leur prolifération et leur fonction effectrice. Néanmoins, l’exposition à un antigène persistant modifie très fortement la fonction lymphocytaire. Les lymphocytes T CD4+ stimulés chroniquement développent un état de non-réponse caractérisé par une perte apparente de leur capacité proliférative et de leurs fonctions effectrices. Le récepteur inhibiteur PD-1 (Programmed cell Death-1) a été identifié comme un régulateur majeur de cet état de non-réponse. L’objectif de notre travail a été de caractériser le métabolisme énergétique des lymphocytes T CD4+ stimulés chroniquement par un antigène. Nous avons, pour cela, développé un modèle murin d’exposition antigénique chronique dans lequel des lymphocytes T CD4+ anti-mâle de souris femelles sont adoptivement transférés dans des receveurs mâles. L’analyse du profil protéomique des lymphocytes T anti-mâle stimulés chroniquement par leur antigène a montré que plusieurs enzymes impliquées dans le métabolisme cellulaire étaient sous-exprimées par ces cellules en comparaison avec des cellules naïves. Nous avons ensuite montré que ces lymphocytes T stimulés chroniquement présentaient un flux glycolytique bas et une capacité respiratoire limitée comparativement à des lymphocytes T effecteurs. De plus, l'expression du transporteur de glucose GLUT1 ainsi que la masse mitochondriale étaient réduites dans ces lymphocytes T CD4+ stimulés chroniquement. Suite à leur activation, ces cellules présentaient une capture de glucose et une synthèse d’ATP limitées. Le blocage de la voie inhibitrice PD-1/PD-L1 a permis de restaurer rapidement la fonction effectrice, et en particulier la sécrétion d’interféron gamma, des lymphocytes T CD4+ soumis à une stimulation antigénique chronique. Cependant, ce blocage n’a induit aucune reprogrammation métabolique en faveur de la glycolyse aérobique dans ces cellules. Par contre, l'absence de régulation médiée par PD-1 a entraîné une perturbation de la chaîne mitochondriale de transport des électrons, une augmentation de la production de superoxyde mitochondrial et une réduction de la survie et de la capacité effectrice des lymphocytes T CD4+ exposés à un antigène persistant. En conclusion, nos observations démontrent que l'inhibition médiée par PD-1 limite la production de superoxyde mitochondrial dans les lymphocytes T CD4+ stimulés chroniquement, améliorant ainsi leur viabilité et leur capacité à développer des fonctions effectrices. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Solid organ transplantation is now an established and effective treatment option for end-stage organ failure. Whilst early outcomes have improved significantly over recent decades, longer-term outcomes have changed little. Despite advances in immunosuppression, most transplanted organs suffer an inevitable decline in function attributed to chronic rejection. It is evident that the alloimmune response remains incompletely characterised. Crucially, despite description several decades ago, the precise contribution that the direct (recognition of intact allogeneic MHC) and indirect (recognition of self-MHC restricted allopeptide) pathways make to allograft rejection remains incompletely understood. In this thesis, murine models of heterotopic cardiac transplantation have been utilised to analyse these pathways. The key findings of this work are as follows: 1) If able to evade NK cell killing, passenger donor CD4 T cells can make cognate, direct-pathway, interactions with recipient B cells. This interaction results in augmentation of all arms of the alloimmune response and acceleration of allograft rejection. 2) Direct-pathway CD4 T cell allorecognition is restricted to the immediate post transplantation period. Donor APCs are the major source of MHC class II for direct-pathway priming, and these are cleared rapidly by both innate and adaptive responses of the recipient, effectively limiting the longevity of direct allorecognition. 3) The duration of indirect-pathway responses against different alloantigens is variable, limited by availability of donor antigen. Expression of donor MHC class II is restricted to APCs and possibly endothelium (where expression is transient) limiting the duration of indirect-pathway allorecognition against MHC class II alloantigen. Indirect-pathway CD4 T cell responses targeted against parenchymal alloantigen are long-lived, and can provide help for generating alloantibody against different MHC alloantigens. 4) In response to continual presentation of target epitope indirect-pathway CD4 T cell responses against parenchymal expressed alloantigen are long-lived. The continual division of these cells results in greatly increased numbers of alloantigen-specific CD4 T cells in the chronic phase of the response, but despite this, memory responses are impaired. 5) Generating indirect-pathway regulatory T cells specific for parenchymal expressed alloantigen appears to be the most effective strategy to ameliorating chronic rejection.

Les cytokines jouent un rôle essentiel dans la réponse immunitaire ; elles modulent les propriétés et la survie de nombreuses cellules immunitaires. Les lymphocytes T (LT) sont régulés par un large spectre de cytokines. Néanmoins certaines sous-populations de LT restent peu définies à ce jour tout comme l’impact de cytokines sur ces cellules en conditions physiologiques et pathologiques. Une population de LT caractérisée par la double expression des corécepteurs CD4 et CD8 a été identifiée en périphérie chez des donneurs sains et sa fréquence est augmentée chez les patients atteints de certaines pathologies. Cependant, peu d’études ont déterminé le phénotype et les fonctions de ces cellules. Nous avons caractérisé le phénotype ex vivo des LT CD4+CD8+ issus de sujets sains et étudié la réponse de ces cellules à plusieurs cytokines importantes dans l’homéostasie et l’activation des lymphocytes. Notre étude révèle que les LT CD4+CD8+ forment une population hétérogène présentant de nombreuses caractéristiques des cellules mémoires. De plus, notre étude montre que ces cellules ont une capacité accrue de produire des cytokines et enzymes lytiques comparée aux LT CD4 et CD8. Finalement, nous avons observé qu’une plus grande proportion de LT CD4+CD8+ répond aux cytokines IL-2, IL-15 et IL-7 comparée aux LT CD4 et CD8 simples positifs. Plusieurs études ont révélé que certaines cytokines participent à la pathobiologie de maladies auto-immunes notamment la sclérose en plaques (SEP). La SEP est une maladie inflammatoire chronique du système nerveux central (SNC) caractérisée par une destruction de la gaine de myéline et une perte axonale à l’origine des symptômes cliniques. L’impact des médiateurs immunitaires dans la destruction et/ou la réparation reste néanmoins à éclaircir. Plusieurs études suggèrent que l’interleukine-27 (IL-27) joue un rôle central dans la SEP : l’IL-27 diminue la sévérité de la maladie dans un modèle murin de la SEP ; la réponse des patients à certaines thérapies corrèle avec des niveaux périphériques élevés d’IL-27. Notre étude avait pour but de déterminer comment l’IL-27 module les LT des patients atteints de SEP. Nous avons observé des niveaux d’IL-27 augmentés à la fois en périphérie et dans le SNC des patients SEP. Nous avons mis en évidence que les effets induits par l’IL-27 sont altérés dans les LT des patients SEP ; notamment l’induction de PD-L1 et la réponse à l’IL-12 sont plus faibles comparées aux LT de sujets sains. La voie de signalisation STAT3 est induite plus fortement en réponse à l’IL 27 dans les cellules de patients SEP en comparaison à celles de sujets sains. Finalement, nous avons démontré que la forme soluble du récepteur à l’IL-27 est présente en plus grande quantité dans le sérum des patients SEP et ces niveaux sont suffisants pour bloquer l’effet de l’IL-27 sur ses cellules cibles. En conclusion, nos résultats permettent de mieux comprendre comment certaines cytokines participent à la régulation des populations lymphocytaires. En condition pathologique, la modulation de ces cytokines pourrait s’avérer efficace dans un but thérapeutique afin de promouvoir et/ou inhiber certaines réponses immunitaires notamment dans la SEP. / Cytokines play an essential role in modulating the immune response. They act on cells from both innate and adaptive immunity by modulating their phenotype and influencing their survival. T cells are highly regulated by a broad spectrum of cytokines. Nevertheless, some subsets of T cells remain ill-defined and a better understanding of cytokine-mediated responses in physiological and pathological conditions requires further investigation. A T cell population characterized by the dual expression of CD4 and CD8 co-receptors has been identified in the periphery of healthy donors and its frequency is notably increased in several pathologies. However, very few studies have determined the phenotype and functions of these cells under physiological conditions. We performed an ex vivo phenotypic characterization of CD4+CD8+ T cells from healthy subjects and analyzed the response of these cells to several important cytokines implicated in homeostasis and activation of immune cells. Our study reveals that CD4+CD8+ T cells are heterogeneous and exhibit many characteristics of memory cells. In addition, our study shows that these cells have an enhanced ability to produce cytokines and lytic enzymes compared to CD4 and CD8 T cells. Finally, we found that a higher proportion of CD4+CD8+ T cells respond to IL-2, IL-15 and IL-7 cytokines compared to CD4 and CD8 counterparts. Numerous studies showed that lymphocyte populations and some cytokines are involved in the development of several autoimmune diseases, including multiple sclerosis (MS). MS is a chronic inflammatory disease of the central nervous system (CNS) characterized by the destruction of the myelin sheath, axonal loss and oligodendrocytic death leading to clinical symptoms. The immune mediators involved in the destruction and/or repair remain to be clarified. Several studies suggest that interleukin-27 (IL-27) plays a central role in MS: IL-27 dampens the severity of the disease in a MS mouse model and in MS patients the response to some therapies correlates with higher levels of peripheral IL-27. The purpose of our study was to determine how IL-27 modulates T cells in MS patients. We observed that IL-27 levels are increased in both periphery and CNS of MS patients. We found that IL-27-mediated effects are impaired in T cells from MS patients in particular PD-L1 induction and IL-12 response that are lower compared to T cells from healthy subjects. IL-27-triggered STAT3 signaling pathway is also enhanced in cells from MS patients compared to healthy subjects. Finally, our study showed that the soluble form of the receptor of IL-27 is present in greater levels in the serum of MS patients and the measured doses are sufficient to block the capacity of IL-27 to act on its target cells. To conclude, our results provide a better understanding of how certain cytokines participate in the regulation of lymphocyte populations. Under pathological conditions, modulation of these cytokines may be effective for therapeutic applications in order to promote and/or inhibit immune responses, particularly in MS.