Made available in DSpace on 2016-05-11T12:56:38Z (GMT). No. of bitstreams: 2 leonardo_ruivo_ioc_mest_2016.pdf: 2337878 bytes, checksum: 69b7ee821ee7eed53dca00b82150fc69 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2016 / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Alterações no perfil de glicosilação de proteínas, células e tecidos têm sido utilizadas como marcadores biológicos para processos fisiológicos e patológicos. Glicoconjugados contendo o ácido siálico (Neu5Ac) estão envolvidas em interações celulares e parasito-hospedeiro, tráfego de linfócitos e regulação do sistema imune. O Trypanosoma cruzi, agente etiológico da doença de Chagas (DC), expressa em sua superfície e libera no plasma do hospedeiro, uma enzima restrita ao gênero Trypanosoma, a trans-sialidase (TS). Esta é capaz de transferir Neu5Ac de moléculas doadoras e realocá-las em moléculas na superfície do parasito ou sialilar glicoproteínas de células do hospedeiro. A molécula CD43 é um importante aceptor de Neu5Ac em células T e um provável sítio de ação da TS. Na infecção experimental pelo T. cruzi, as células T CD8+ apresentam, majoritariamente, perfis segregados (i) perforina+ (Pfn+), com ação citotóxica, ou (ii) interferon-gama+ (IFN\03B3+), com perfil inflamatório. Estas células estão diferencialmente compartimentalizadas e atuam de forma antagônica, enquanto as Pfn+ se acumulam na inflamação cardíaca e contribuem para a injúria tecidual, as IFN\03B3+ estão majoritariamente na periferia (sangue e baço) e atuam de forma benéfica. Neste trabalho, propomos que na infecção pelo T. cruzi há alterações de glicofenótipos em proteínas séricas e subpopulações de linfócitos T CD8+ funcionalmente segregadas. Camundongos C57BL/6 foram infectados pela cepa Colombiana do T. cruzi e analisados clinicamente. O glicofenótipo de proteínas séricas foi analisado por espectrometria de massas (MALDI-TOF) e o glicofenótipo de tecido cardíaco e de células do baço foi analisado usando lectinas por histoquímica e citometria de fluxo, respectivamente Não detectamos modificação no perfil glicosídico em proteínas séricas em animais infectados. Observamos, no tecido cardíaco, reduzida marcação para a lectina Peanut agglutinin (PNA), aumento para Sambucus nigra (SNA) e não alteração para Maackia amurensis (MAL) em células musculares e inflamatórias. Notamos nas fases aguda (42 dpi) e crônica (120 dpi) aumento na frequência de células PNA+ nas células T CD8+CD43+ e CD4+CD43+, redução no percentual de células SNA+ nas células T CD8+ e CD4+ e diminuição na proporção de células MAL+ nas células T CD4+ e CD8+CD4+. Células T CD8+ totais ou CD8+PNA+ apresentaram perfis semelhantes de ativação (CD44+CD62L-), migração (LFA-1+CCR5+ ou LFA-1+CCR1+) e funcionalidade (Pfn+, Pfn+IFN\03B3+ ou IFN\03B3+). Em 120 dpi, detectou-se enriquecimento de células CD8+PNA+IFN\03B3+ no baço. Assim, durante a DC experimental, células T CD8+PNA+ apresentam-se ativadas e com potencial de migrar e exercer atividade inflamatória (IFN\03B3+), contudo estas não foram detectadas em tecido cardíaco. Resta-nos esclarecer se estas células não migram para este tecido, acumulando-se na periferia, ou se ao entrarem no tecido cardíaco têm seu glicofenótipo alterado ou morrem de modo seletivo. Embora nossos achados não permitam a identificação de biomarcadores de natureza glicosídica de progressão e/ou gravidade da DC, abrem perspectivas para explorar outros modelos experimentais de infecção e para estudos sobre a compartimentalização de células fenotipicamente distintas e funcionalmente relacionadas à proteção contra a injúria cardíaca na infecção pelo T. cruzi / Changes in glycosylation profile of proteins, cells and tissues have been used as biological markers of physiological and pathological processes. Glicoconjugates containing sialic acid (Neu5Ac) are involved in cell and host-parasite interactions, lymphocyte traffic and regulation of the immune system. Trypanosoma cruzi, the causative agent of Chagas disease (CD), expresses on the surface and releases in the host plasma, a restricted enzyme to the genus Trypanosoma, the trans-sialidase (TS). This enzyme transfers Neu5Ac from donor molecules and relocates them on parasite surface molecules or sialylates glycoproteins of the host cells. The CD43 molecule is a major acceptor of Neu5Ac on T cells and a target site for TS. In experimental T. cruzi infection, CD8+ T cells have, mostly, segregated profiles (i) perforin+ (Pfn+) with cytotoxic action, or (ii) interferon-gamma+ (IFN\03B3+), with inflammatory profile. These cells are differentially compartmentalized and play antagonistic roles, while the Pfn+ cells accumulate in cardiac inflammation and contribute to tissue injury, the IFN\03B3+ are, mostly, at the periphery (blood and spleen) and play a beneficial role. In the present study, we propose that in T. cruzi infection there are glycophenotype changes in serum proteins and subpopulations of functionally segregated CD8+ T lymphocytes. C57BL/6 mice were infected with the Colombian strain of T. cruzi and analyzed for clinical changes. The glycophenotype of serum proteins was analyzed by mass spectrometry (MALDI-TOF) and glycophenotypes of the cardiac tissue and splenic cells were analyzed using a lectin-based immunohistochemistry and flow cytometry, respectively In infected mice, we did not detect changes in glycoside profile of serum proteins. In the cardiac tissue, we observed reduced staining for the lectin Peanut agglutinin (PNA), increased for Sambucus nigra (SNA) and no alterations for Maackia amurensis (MAL) in muscle and inflammatory cells. In the acute (42 dpi) and chronic (120 dpi) phases, we noticed increased frequency of PNA+ cells among CD8+CD43+ and CD4+CD43+ T cells, reduced percentage of SNA+ cells among CD8+ and CD4+ T cells and decreased proportion of MAL+ cells among CD4+ and CD8+CD4+ T cells. Total and PNA+ CD8+ T cells showed similar profiles of activation (CD44+CD62L-), migration (LFA-1+CCR5+ cells or LFA-1+CCR1+) and functionality (Pfn+, Pfn+IFN\03B3+ or IFN\03B3+). At 120 dpi, there is an enrichment in IFN\03B3+ cells among splenic CD8+PNA+. Thus, in experimental CD PNA+ CD8+T cells are activated and potentially able to migrate towards heart tissue and show inflammatory profile (IFN\03B3+); however, PNA+ cells were not detected in this tissue. It remains to be clarified whether these cells do not migrate to this tissue, accumulating in peripheral tissues, or whether they enter the cardiac tissue but have their glycophenotype modified or selectively dye. Although, our finds do not allow identifying glycosidic biomarkers of progression and/or severity of CD, they open new pathways to be explored using other experimental models of infection and studying the compartmentalizationof phenotypically and functionally distinct cells associated with detrimental or protective role in heart injury in T. cruzi infection

Submitted by Hiolanda Rêgo (hiolandarego@gmail.com) on 2015-03-27T15:45:24Z No. of bitstreams: 1 Tese_ICS_Thiago Marconi de Souza Cardoso.pdf: 2610900 bytes, checksum: 39ec1903c01809723208857851e6be48 (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2015-03-30T12:07:56Z (GMT) No. of bitstreams: 1 Tese_ICS_Thiago Marconi de Souza Cardoso.pdf: 2610900 bytes, checksum: 39ec1903c01809723208857851e6be48 (MD5) / Made available in DSpace on 2015-03-30T12:07:56Z (GMT). No. of bitstreams: 1 Tese_ICS_Thiago Marconi de Souza Cardoso.pdf: 2610900 bytes, checksum: 39ec1903c01809723208857851e6be48 (MD5) / CNPq / Introdução: A leishmaniose cutânea (LC) causada por Leishmania braziliensis é caracterizada por uma forte resposta tipo Th1, que está envolvida no desenvolvimento das lesões. Em áreas endêmicas de transmissão de L.braziliensis, indivíduos que apresentam reação de hipersensibilidade tardia positiva para antígeno de leishmania (SLA) e sem história atual ou passada de doença são considerados como tendo uma infecção subclínica (SC). Esses indivíduos produzem menos IFN- e TNF-α em comparação com pacientes com LC e os mecanismos pelos quais os indivíduos SC controlam a infecção ainda não são compreendidos Objetivo: O objetivo deste estudo é caracterizar o papel de células T CD8+ na infecção SC e em pacientes com LC. Materiais e Métodos: Os monócitos isolados a partir de células mononucleares do sangue periférico (CMSP) de indivíduos LC e SC foram infectados com L.braziliensis e co-cultivadas com células T CD8+. A avaliação da infecção de monócitos, marcadores citotóxicos e a apoptose de células alvo foi realizada por citometria de fluxo (FACS). A frequência de células T e a produção intracelular de IFN- após estimulação com SLA foi avaliada por FACS. A avaliação da granzima B (GrB) nos sobrenadantes de co-cultura foi realizada por ELISA Resultados: Apesar de não haver diferença na frequência de células T CD4+ e CD8+ entre indivíduos SC e pacientes com LC, após estimulo com SLA observou-se que células T CD8+ são a principal fonte de IFN- em indivíduos SC. Os monócitos de indivíduos SC foram menos susceptíveis à infecção do que os monócitos de LC. As células T CD8+ de pacientes com LC apresentaram um maior efeito citotóxico sobre monócitos infectados em comparação com células T CD8+ de indivíduos SC. Além disso, a produção de GrB por células T CD8+ foi superior em LC do que em indivíduos SC Conclusão: Esses resultados sugerem que enquanto em indivíduos SC as células T CD8+ apresentam funções inflamatórias associadas a bom prognóstico, nos pacientes com LC estas células parecem estar mais envolvidas na patologia.

Early growth response (Egr) gene 2 and 3 are genes encoding transcription factors important for maintaining immune homeostasis. Here we define a fundamental role of Egr2 and 3 to control T cell proliferation and differentiation of effector T cells. Egr2 and Egr3 deficiency in T cells resulted in impaired T cell proliferation, but hyper-activation and excessive differentiation of T cells in response to viral infection, while, conversely, sustained Egr2 expression enhanced proliferation, but severely impaired effector differentiation in to T helper (Th) subsets, such as, Th1 and Th17 subtypes. T-bet is important for differentiation of effector T cells in response to pathogen and in particular it is a master regulator for modulating the T helper 1 lineage specific differentiation programme. Although T-bet has been extensively studied in T cells, the regulation of T-bet function is less well known. We have now discovered that Egr2 and 3 are potent inhibitors for Tbet function in CD4 and CD8 effector T cells. Together with Egr2 and 3, T-bet is induced in naïve T cells by antigen stimulation, but the expression was reciprocally regulated by IFNγ, which inhibited Egr2 and 3, but promoted Tbet expression. The expression of Egr2 and 3 in CD4 T cells under TH2 and TH17 condition was essential to suppress TH1 differentiation in vitro. In response to viral infection, sustained Egr2 expression in T cells profoundly inhibited differentiation of effector cells, while Egr2 and 3 deficient T cells produced excessive levels of IFNγ. We found that both Egr2 and 3 can directly interact with the Tbox domain of T-bet, block its DNA binding and inhibit T-bet mediated production of IFNγ. Thus, Egr2 and 3 are antagonists for T-bet function in effector T cells and essential for the control of T cell differentiation and immune pathology.

Made available in DSpace on 2014-06-12T15:05:22Z (GMT). No. of bitstreams: 2 arquivo4544_1.pdf: 743719 bytes, checksum: 0d1678ceac5de3e304fce7b8f9370d3d (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2005 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Para averiguar a ocorrência de fungemia, foram analisadas no período de janeiro de 2004 a julho de 2004, amostras de sangue de 530 pacientes portadores do HIV, sendo 159 (30%) sem AIDS e 371 (70%) com AIDS, destes 468 pacientes atendidos em ambulatório e 62 pacientes internos, todos procedentes do Hospital Correia Picanço, Recife-PE. Foi detectada fungemia no sangue de quatro pacientes com HIV sem AIDS e em 20 com AIDS. Em quatro pacientes HIV sem AIDS, fungemia foi detectada através da cultura; nos pacientes com AIDS fungemia foi detectada em sete através do exame direto, em oito através da cultura e em cinco através do exame direto e cultura. Do sangue de pacientes com HIV sem AIDS, foram isoladas as espécies Candida humicola, C. pelliculosa e Fusarium lateritium; do sangue de pacientes com AIDS foram isoladas as espécies C. curvata, C. humicula, C. parapsilosis, Cryptococcus albidus, C. neoformans e Histoplasma capsulatum. Segundo a literatura disponível, esta é a primeira citação de F. lateritium, C. curvata e C. humicula relacionando estas espécies a fungemia em pacientes infectados com HIV. A cada episódio de fungemia correspondeu apenas uma espécie de fungo. No sangue dos pacientes HIV sem AIDS a contagem de CD4 variou de 373 a 573 células/mm3 e de CD8 de 807 a 1445 células/mm3; no sangue dos pacientes com AIDS a contagem de CD4 variou de 12 a 346 células/mm3 e de CD8 de 261 a 1375 células/mm3. Baseado no modelo de Regressão logístico há 152,57 mais chances de ocorrer fungemia em pacientes com lesão de pele e níveis de CD4 ≤ 200 mm3, e que não existe relação entre a espécie isolada e níveis de CD4 e CD8. Todos os fungos isolados cresceram a 37ºC. Atividade proteásica foi observada nos isolados utilizando-se como substrato caseína do leite e gelatina. Atividade fosfolipásica foi evidenciada com lecitina de soja, entretanto não foi evidenciada com gema de ovo como substrato

À ce jour, il est connu que le succès des traitements chimiothérapeutiques, outre l’effet cytotoxique direct sur les cellules tumorales, repose sur la contribution du système immunitaire. Nos travaux de recherche montrent que le traitement au cyclophosphamide de souris DBA/2 porteuses du mastocytome P815 induit le rejet de la tumeur, ainsi qu’une protection à long terme, de façon dépendante de la présence des lymphocytes T CD4+ et CD8+. De plus, le rejet du mastocytome P815 corrèle avec une augmentation de l’infiltration au sein de la tumeur de lymphocytes T CD8+ spécifiques d’un antigène muté. Lors de ce travail, nous avons tenté d’identifier les mécanismes moléculaires et cellulaires impliqués dans le rejet du mastocytome P815 induit suite à un traitement au cyclophosphamide. Dans ce but, les lymphocytes T CD8+ spécifiques de l’antigène muté, infiltrant un mastocytome P815 en progression ou en régression (suite à un traitement au cyclophosphamide), ont été analysés afin de mettre en évidence des caractéristiques phénotypiques et/ou fonctionnelles associées à ces populations de cellules T CD8+. Le traitement au cyclophosphamide conduit à l’infiltration de lymphocytes T CD8+ effecteurs en phase terminale de différenciation (KLRG1+ CD27- Eomes+ Perforin+) au sein de la tumeur, alors que les lymphocytes T CD8+ présents dans le microenvironnement tumoral du mastocytome P815 en progression possèdent un phénotype de cellules dysfonctionnelles (PD-1+ LAG-3+ Ki67-). Les IFN-I sont impliqués, au moins partiellement, dans l’acquisition du phénotype effecteur des cellules puisque leur inhibition entraine une augmentation de l’expression du récepteur PD-1.Ces résultats amènent à une meilleure compréhension des mécanismes par lesquels le cyclophosphamide régule l’amplitude et la qualité des réponses immunes spécifiques de la tumeur. Outre un effet quantitatif qui se traduit par l’expansion et l’infiltration dans la tumeur de lymphocytes T CD8+ spécifiques de l’antigène muté, cet agent chimiothérapeutique contribue au rejet du mastocytome P815 en favorisant le développement de lymphocytes T CD8+ effecteurs. La compréhension des effets immunomodulateurs d’un traitement chimiothérapeutique présente un intérêt majeur pour l’amélioration des thérapies en oncologie, tant en ce qui concerne l’immunothérapie que les combinaisons de traitement. / An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8+ T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re-engagement of T lymphocytes into the effector program since most T cells are dysfunctional in the tumor microenvironment before cyclophosphamide treatment. IFN-I appears involved in this remodelling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

The infrequency of known T cell targets in high grade serous ovarian carcinoma (HSGC) is a substantial barrier to the development of targeted immunotherapies. Due to their infrequency, antigen discovery is a crucial component of immunotherapeutic design. In our cohort of HGSC cases, the cancer testis (CT) antigen lactate dehydrogenase C (LDHC) is expressed in 76% of tumours (22/29). As LDHC presents with tumour specificity in women, I hypothesize that LDHC is an immunogenic target in HGSC patients, and that LDHC-specific T cells can be activated and expanded for therapeutic purposes. As such, I sought to examine whether endogenous LDHC-specific T cells were present in the ascites of HGSC patients. A standard Rapid Expansion Protocol was used to expand CD8 T cell cultures from patient ascites. These cultures were screened for reactivity to a peptide library encompassing all possible epitopes of the LDHC protein by interferon-γ ELISpot. With this approach, T cell clones from one of five patients were identified that were reactive to minimal peptides contained within LDHC. In this patient, the antigenic LDHC peptide differentiated from LDHA by a single amino acid at its C-terminus (YTSWAIGLSVM versus YTSWAIGLSVA). In recognition assays, tumour cell lines expressing endogenous LDHC, autologous ascites, or autologous B cells transfected with LDHC were unable to elicit T cell responses. Although this study suggests that LDHC is not immunogenic, continued screening of LDHC and other CT proteins will likely provide additional immunotherapeutic targets. / Graduate

Les lymphocytes T CD8 jouent un rôle central dans l'immunité protectrice contre les pathogènes intracellulaires tels que le parasite Toxoplasma gondii (T. gondii). T. gondii réside à l'intérieur d'une cellule hôte et dans une vacuole parasitophore. L'interface entre l'hôte et le parasite comprend une membrane limitant la vacuole ainsi qu'un réseau intravacuolaire (IVN) composé de tubules membranaires fortement incurvés et dont la fonction reste incertaine. Beaucoup d'effecteurs parasitaires, incluant des sources potentielles d'antigènes pour les lymphocytes T CD8, sont sécrétés par T. gondii dans la vacuole et adressés à différents endroits dans la vacuole ou au-delà, dans la cellule hôte. A l'heure actuelle, les mécanismes contrôlant l'adressage des antigènes parasitaires dans la cellule hôte demeurent mal compris et nous ne savons pas comment le transport intracellulaire des protéines de T. gondii influence leur disponibilité par la voie de présentation CMH I et leur capacité à induire l'immunité T CD8. En utilisant une approche multidisciplinaire combinant la génétique inverse de T. gondii, la microscopie, la présentation antigénique in vitro et l'expérimentation animale, mes travaux de thèse ont montré que l'insertion d'un antigène immunodominant à la membrane limitante de la vacuole constitue une des clés de l'immunogénicité. J'ai également montré que l'association de cet antigène à l'IVN limite sa présentation par les molécules du CMH I et réduit les réponses T CD8 spécifiques de cet antigène chez la souris. L'IVN pourrait jouer un rôle immuno-modulateur dans lequel il limiterait l'accès de protéines parasitaires sécrétées au cytosol de la cellule hôte et à la voie CMH I. / CD8 T cells play a key role in protective immunity against intracellular pathogens such as Toxoplasma gondii (T. gondii) parasite. T. gondii resides inside host cell in parasitophorous vacuole. The host-T. gondii interface comprises a vacuole limiting membrane and a highly curved membraneous IntraVacuolar Network (IVN) of uncertain function. Many parasite effectors, including potential epitopes for CD8 T cells, are secreted by T. gondii to and across the boundary of their parasitophorous vacuole. Currently, the mechanisms controlling the targeting of parasite antigens to host cell are misunderstood et we don't kwnow how the intracellular transport of T. gondii proteins impacts on their access to MCH I pathway and their ability to induce CD8 T cell immunity. Using a multidisciplinary approach which combined reverse genetics in T. gondii, microscopy, antigen presentation measurements and in vivo experiments, I showed that insertion of a T. gondii dominant antigen at the vacuole limiting membrane is key for immunogenicity, yet that association of this antigen to high curvature IVN limits its presentation and curtails specific CD8 responses in mice. The IVN may play a role in immune modulation by limiting the access of parasite proteins to host cytosol and thus to MHC I pathway.

Antigen-specific CD8 T cells provide an important protective role in response to infection by viruses, intracellular bacteria, and parasites. Pathogen-specific CD8 T cells render this protection by undergoing robust expansion in numbers while gaining the ability to produce cytokines and cytolytic machinery. Following expansion and effector differentiation, pathogen-specific CD8 T cells will contract in number while further differentiating into a highly functional population of memory CD8 T cells. These antigen-experienced cells persist in secondary lymphoid organs and the periphery in order to rapidly respond to repeated infection. Creating optimal CD8 T cell responses to infection can be critical for raising sufficient armament to provide protection against invading intracellular pathogens. Although CD8 T cells have protective value, many vaccine strategies tend to focus on creating productive B cell antibody responses to promote immunological protection. Even though antibody responses can be highly protective, coupling optimal CD8 T cell responses with B cell responses could provide higher orders of protection than either one on their own. Therefore, a deeper understanding of the pathways that ultimately guide the magnitude of CD8 T cell responses is required to achieve this potential therapeutic benefit. My studies evaluate the role of receptor signaling events in guiding the expansion of activated CD8 T cells during primary and secondary responses. Specifically, the first portion of my studies dissect the mechanism by which direct IL-12 and Type I IFN stimulation can substantially bolster primary CD8 T cell responses in vivo. Within this context, I demonstrate that direct IL-12 and Type I IFN signaling increases CD8 T cell accumulation during primary expansion by prolonging division without altering survival. IL-12/Type I IFN signaling promoted prolonged division of activated CD8 T cells by maintaining high-affinity IL-2 receptor subunit (CD25) expression and IL-2 signaling. The other portion of my work was dedicated to understanding the expression and role of the inhibitory FcgR (FcgRIIB) during primary and secondary CD8 T cell responses. FcgRIIB expression could be detected as early as the peak of the CD8 T cell response and marked activated CD8 T cells that were highly sensitive to antigen stimulation. Although FcgRIIB did not appear to play a substantial role in regulating the magnitude of primary CD8 T cell responses, it played an important role in inhibiting the expansion and cytotoxicity of memory CD8 T cells during homologous challenge. Collectively, these data highlight potential avenues that could be exploited by future therapies that aim to achieve appropriately sized CD8 T cell responses.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21957号 / 医博第4499号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 濵﨑 洋子, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation to be uncoupled. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished