Orientador: José Maurício Sforcin / Banca: Marjorie de Assis Golim / Banca: Maria Angélica Ehara Waranabe / Banca: Ângela M. V. Campos Soares / Banca: Robson Francisco Carvalho / Resumo: Células dendríticas (DCs) são essenciais para o reconhecimento de patógenos e apresentação de seus antígenos aos linfócitos T, desempenhando papel fundamental no elo entre as respostas imunes inata e adaptativa. A própolis é um produto resinoso, elaborado pelas abelhas a partir de diversas partes das plantas, e tem despertado a atenção dos pesquisadores em virtude de suas inúmeras propriedades biológicas, destacando sua ação imunomoduladora. Assim, o presente projeto de pesquisa teve como objetivo investigar o efeito da própolis sobre a maturação e função de DCs humanas. Foi analisado o efeito da própolis na ativação do NF-кB, expressão de micro-RNAs e marcadores de superfície celular (TLR-4, MHC-II, CD80, CD86 e CD40), produção de citocinas (TNF-, IL-6, IL-10 e IL-12), e atividade bactericida das DCs humanas contra Streptococcus mutans. Tomados em conjunto, os dados sugerem o perfil ativador da própolis em DCs, visto que este produto apícola manteve a ação induzida por LPS tanto na ativação do fator de transcrição NF-кB como na produção de TNF-α, IL-6 e IL-10. Ademais, a inibição na expressão de hsa-miR-148a e hsa-miR-148b aboliu o efeito inibitório dos mesmos sobre a expressão de HLA-DR e também pode ter favorecido a produção de citocinas pró-inflamatórias. O aumento na expressão de hsa-miR-155 pode estar correlacionado ao aumento na expressão de TLR-4 e CD86, além de manter a ativação induzida pelo LPS de HLA-DR e CD40. Estes parâmetros podem estar envolvidos com o aumento na atividade bactericida de DCs contra Streptococcus mutans. Estes dados sugerem que a própolis pode modular positivamente a maturação e função de DCs / Abstract: Dendritic cells (DCs) represent a heterogeneous population of professional antigen presenting cells (APCs) and are essential for recognition and presentation of pathogens to T cells. Propolis, a resinous material produced by bees from various plant sources, exhibits numerous biological properties, highlighting its immunomodulatory action. Here, we assayed the effects of propolis on the maturation and fuction of human DCs, assessing the activation of the transcription factor NF-kB, micro-RNAs and cell markers expression (TLR-4, HLA-DR, CD80, CD86, CD40), cytokines production (TNF-α, IL-6, IL-10, IL-12), and the bactericidal activity against Streptococcus mutans. DCs were generated from monocytes treated with IL-4 and GM-CSF and incubated with propolis and LPS. NF-κB in nuclear extract and cytokines were determined by ELISA. microRNAs expression was analysed by RT-qPCR and cell markers by flow cytometry. Colony-forming units were counted to assess the bactericidal activity of propolis-treated DCs. Propolis activated human DCs, inducing the NF-kB signaling pathway and TNF-, IL-6 and IL-10 production. The inhibition of hsa-miR-148a and hsa-miR-148b abolished the inhibitory effects on HLA-DR and pro-inflammatory cytokines. The increased expression of hsa-miR-155 may be correlated to the increase in TLR-4 e CD86 expression, maintaining LPS-induced expression of HLA-DR and CD40. Such parameters may be involved in the increased bactericidal activity of DCs against Streptococcus mutans. These studies are particularly important to develop DC-based modulation strategies for the identification of promising sources for drug discovery / Doutor

INTRODUÇÃO: O papilomavírus humano (HPV) é o agente mais frequentemente encontrado em doenças sexualmente transmissíveis e é responsável por cerca de 40% dos cânceres vulvo-vaginais. Esse trabalho abordou a resposta imune em lesões vulvares, considerando-se as células dendríticas CD1a+, FXIIIa+ e S-100+, citocinas TNF-, IFN- e IL-10 e a molécula de adesão E-caderina. MÉTODOS: Foram utilizadas 49 lesões de vulva pelo HPV (condiloma acuminado, NIV-I, NIV-II e NIV-III) e 11 bióspias com diagnóstico de vulvite crônica inespecífica. Foram constituídos quatro grupos: lesões de baixo grau (condiloma e NIV I), lesões de alto grau (NIV II e III), vulvites inespecíficas e pele normal. A detecção das células, citocinas e E-caderina foi feita através de método imuno-histoquímico. RESULTADOS: As células de Langerhans (CD1a+) estavam distribuídas em todo o epitélio, sobretudo nas camadas suprabasal e espinhosa. Não diferiram entre os grupos de lesões HPV+, mas estavam diminuídas em número e tamanho quando comparadas à pele normal (p<0.0001). As células S-100+ ou FXIIIa+ estavam localizadas em toda a extensão do estroma, sem diferença estatística entre as lesões pelo HPV. Embora os DDFXIIIa+ estivessem aumentados em tamanho nas lesões de vulva, seu número não diferiu da pele normal. Não se observou diferenças numéricas das células S-100+ entre os grupos de lesão e pele normal. Foi possível detectar maior número de DDFXIIIa+ sobre as células S-100+ no grupo de lesões de baixo grau (p = 0,0008) e de alto grau (p = 0,0031). As citocinas foram detectadas em pequenas quantidades nos grupos de lesões, porém sem diferença estatística. Para a análise da expressão de e-caderina, o grupo de vulvites crônicas inespecíficas foi utilizado como controle. Em 91.0% das vulvites inespecíficas foi observado padrão homogêneo e difuso da expressão de e-caderina na camada espinhosa baixa e média. Ambos os grupos de lesões HPV+ exibiram padrões semelhantes de expressão de e-caderina, com marcação difusa ou focal na camada espinhosa baixa e média. Não houve imuno-reatividade nas áreas de displasias. Como resultado da reação de dupla-marcação, feita através da utilização da hibridização in situ para detecção do DNA do HPV e imunohistoquímica para DDFXIIIa+, foi possível identificar antígenos virais no citoplasma dessas células. CONCLUSÕES: o HPV interfere na expressão das células de Langerhans, pois estas estavam diminuídas, com morfologia alterada em relação à pele normal; os DDFXIIIa+ apresentam-se aumentados em número sobre as células S-100+, o que poderia refletir um mecanismo local compensatório contra o HPV; as lesões de baixo e alto grau não apresentam diferenças significativas quanto à densidade de células expressando TNF-, IFN- e IL-10, embora TNF- predomine entre as três citocinas; há uma correlação positiva entre os DDFXIIIa+ e a expressão de TNF-, o que poderia ser explicado por sua capacidade em produzir tal citocina a partir de um provável estímulo desencadeado pelo HPV; o HPV influencia na expressão de E-caderina na vulva, com destaque para a ausência de expressão nas áreas de displasia; o DNA do HPV encontrado no interior dos DDFXIIIa+ aliado às alterações na morfologia celular, a sobreposição destas sobre as células S-100+ e a relação encontrada com a citocina TNF-, nos permitem sugerir que os DDFXIIIa+ têm um papel importante como células apresentadoras de antígeno frente à infecção pelo HPV. / INTRODUCTION: The human papillomavirus (HPV) is the most frequent agent in sexually transmitted diseases and is responsible for almost 40% of vulvovaginal cancer. We studied the immune response in vulvar lesions, considering the CD1a+, FXIIIa+ and S-100+ dendritic cells, TNF-, IFN- and IL-10 cytokines and the adhesion molecule E-cadherin. METHODS: We used 49 vulvar lesions mediated by HPV (condylomata acuminata, VIN-I, VIN-II e VIN-III) and 11 biopsies diagnosed as chronic non-specific vulvitis. Four groups were formed: low-grade lesions (condylomata and VIN-I), high-grade lesions (VIN-II and III), non-specific vulvitis and normal skin. The detection of cells, cytokines and e-cadherin was performed by immunohistochemistry reaction. RESULTS: Langerhans cells (CD1a+) were distributed through epithelia, mainly in suprabasal and spinous layer. They did not differ between HPV groups, but were decreased in number and size when compared to normal skin (p<0.0001). The S-100+ ou FXIIIa+ cells were distributed through stroma and did not differ between HPV lesions. Although the FXIIIa+DD were increased in size in vulvar lesions, their number did not differ from normal skin. The S-100+ cells did not differ in number between the groups of lesions and normal skin. We detected an increased number of FXIIIa+DD over S-100+ cells in the group of low-grade (p = 0.0008) and high-grade lesions (p = 0.0031). The cytokines were detected in small quantities in both the lesions groups, with no statistical difference. The group of chronic non-specific vulvitis was used as control group to analyse the expression of e-cadherin. 91.0% of non-specific vulvitis presented a homogeneous and diffuse pattern of expression in spinous layer Both the HPV+ groups of lesions presented similar patterns of e-cadherin expression, with a focal or diffuse localization in spinous layer. The dysplastic epithelium did not present immunoreactivity. As a result of the double-staining, using in situ hibridization to detect DNA of HPV and immunohistochemistry to FXIIIa+DD, it was possible to observe viral antigens in the cytoplasm of such cells. CONCLUSIONS: The HPV interfere with the expression of Langerhans cells, since they were decreased when compared to the normal skin; the FXIIIa+DD were increased in number over S-100+ cells, suggesting a local compensatory mechanism against the HPV; the low and high grade lesions did not differ in the number of cells expressing TNF-, IFN- and IL-10, although TNF- predominate among the three cytokines; there is a positive correlation between the FXIIIa+DD and the expression of TNF- that could be explained by their role as TNF-producing cells following a stimulus of HPV; the HPV changes the expression of E-cadherin in vulvar lesions, mainly in dysplastic epithelium; HPV DNA visualized in the cytoplasm of FXIIIa+DD and the cellular morphological changes, the increased number over S-100+ cells and the correlation with TNF-, allow us to suggest that FXIIIa+DD play an important role as antigen presenting cells in the infection by HPV.

Os cães são afetados por doenças inflamatórias e neoplásicas que compartilham diversas similaridades com as desordens em humanos, assim seu estudo representa um importante modelo animal para as condições humanas. As células dendríticas (DCs) representam a população mais potente de células apresentadoras de antígenos. As DCs representam também um novo alvo promissor de imunoterapia em cães; no entanto o uso terapêutico de DC caninas é restrito, dentre outros fatores, devido a falta de padronização nas técnicas de isolamento e limitado numero de informações específicas da espécie a esse respeito. Este projeto tem por finalidade avaliar a geração de células dendríticas caninas geradas in vitro e ativadas por diferentes estímulos biológicos na presença e ausência de extrato tumoral de melanoma canino. Os resultados demonstraram que as DCs caninas geradas na presença de extrato tumoral em grandes concentrações apresentavam atividade funcional semelhante as DCs maduras / Dogs are affected by inflammatory and neoplastic diseases that share many similarities with the disorders in humans, so their study is an important animal model for the human condition. Dendritic cells (DCs) are the most potent population of antigen presenting cells. DCs also represent a promising new target for immunotherapy in dogs; However, the therapeutic use of canine DC is restricted among others factors due to lack of standardization in isolation techniques and limited number of species-specific information in this regard. This project aims to assess the generation of canine dendritic cells generated in vitro and activated by different biological stimuli in the presence and absence of tumor extract of canine melanoma. The results showed that the canine DCs generated in the presence of high concentrations tumor extract showed similar functional activity of mature DCs

Introdução: Doenças pulmonares ou infecções que ocorrem no início da vida podem ter permanente impacto na vida adulta. Pouco se sabe sobre o perfil de células do sistema imunológico em pulmões de crianças lactentes. Objetivo: Descrever o perfil de células do sistema imunológico no pulmão de lactentes sem doença pulmonar. Métodos: Amostras de pulmões histologicamente normais, obtidas através de autópsia de dez crianças que morreram de causas acidentais ou de doenças não pulmonares, foram marcadas por anticorpos contra linfócitos B e T, macrófagos, células NK (natural Killer), células citotóxicas, células dendríticas e mastócitos. As células foram quantificadas no epitélio, na camada interna, na camada externa das vias aéreas e nos septos alveolares. Membrana basal e septos alveolares foram medidos através de análise de imagem. Resultados expressos em células/mm de membrana basal epitelial brônquica ou alveolar. Resultados: A mediana das idades foi 2,5 meses (1-730 dias). Os resultados mostraram que a camada interna apresentou pequena densidade celular. No epitélio da via aérea e no parênquima houve predominância de células que estão relacionadas com a imunidade inata, tais como: CD56+, Granzyme + e CD68+. A camada externa e o parênquima alveolar apresentaram a maior densidade celular. Poucas células T CD4+ e células dendríticas foram encontradas na maioria dos compartimentos do pulmão. Conclusão: Há uma compartimentalização de células relacionadas com o sistema imunológico ao longo da via aérea e parênquima dos pulmões das crianças estudadas. Esta configuração pode estar relacionada com o desenvolvimento dos mecanismos de defesa da imunidade inata e da imunidade adquirida. Este conhecimento é importante para entender os mecanismos da imunocompetência pós-natal dos pulmões / Introduction: Pulmonary diseases or infections occurring early in life may have a permanent impact in adulthood. Little is known about the normal immune cell profile in the lungs of infants. Objective: To describe the immune cell profile of infants without lung disease. Methods: Histologically normal lung samples obtained at autopsy of ten infants that died either due to incidental or inflicted causes or non-pulmonary diseases were stained for antibodies against B and T lymphocytes, macrophages, NK cells, cytotoxic cells, dendritic cells and mast cells. Cells were quantified in the airway epithelial layer, inner layer, outer layer and alveolar septa. Basement membrane or alveolar septa lengths were assessed by image analysis. Results are expressed as cells/mm. Results: The median age of patients was 2.5 months and ranged from 1- 730 days. The inner layer of the airways was the region with the smallest density of cells. There was a predominance of cells related to the innate immunity such as CD56+, Granzyme B+ and CD68+ cells in the epithelial layer and alveolar parenchyma. The outer layer and the lung parenchyma presented the highest cellular density. There were very few CD4+ T cells or dendritic cells in most of the lung compartments. Conclusions: There was a compartmentalization of immune cells along airways and parenchyma in infants, which may be related to the development of innate and acquired lung defense mechanisms. This knowledge is important to understand mechanisms of postnatal immune competence of the lungs

A melatonina (MLT) é um hormônio responsável pela regulação dos ritmos circadianos, com ampla atuação na fisiologia animal, incluindo os seres humanos. Sua ação moduladora sobre o sistema imune possibilitou estudar seu efeito sobre a estimulação de monócitos na diferenciação em células dendríticas (DCs). Monócitos estimulados com MLT, durante a etapa de adesão de duas horas, apresentaram aumentada presença dos receptores para citocinas GM-CSF, IL-4 e TNF-a, necessários à geração de DCs in vitro. DCs geradas sob estímulo de MLT mostraram um aumento nas moléculas de membrana como CD40, CD80 e CD83. Foram detectadas as citocinas IL-6, IL-8 e IL-10 nos sobrenadantes de DCs imaturas, bem como IL-6, IL-8 e TNF-a para as DCs maduras. Lys estimulados por estas DCs mostraram um elevado índice de proliferação e detectou-se variação nas concentrações das citocinas IL-2, IL-4, IL-6, IL-10, TNF-a e IFN-g, dos sobrenadantes das co-culturas. O uso do inibidor da MLT, Luzindol mostrou tendência a inibição dos efeitos desse hormônio. / Melatonin (MLT) is a hormone responsible for the circadian rhythm regulation, with wide range of actions in animal physiology, including the human beings. Its modulatory action on immune system permited to study its effects on monocyte stimulation to differentiate into dendritic cells (DCs). Monocytes stimulated with MLT, kept for two hours adhesion time, presented enhanced cytokine membrane receptors for GM-CSF, IL-4, TNF-a, needed to in vitro DCs generation. DCs obtained by MLT stimuli show an enhanced presence of membrane molecules, as CD40, CD80 and CD83. The cytokines IL-6, IL-8 e IL-10 were present in the supernatants of imature DCs, as well the IL-6, IL-8 e TNF-a in mature DCs supernatants. Lymphocytes supernatants from DCs co-culture showed an enhanced proliferation index and, were detected a variation for IL-2, IL-4, IL-6, IL-10, TNF-a e IFN-g cytokines. The MLT inhibitor Luzindole show a tendency to inhibition of this hormone.

Introdução: Doenças pulmonares ou infecções que ocorrem no início da vida podem ter permanente impacto na vida adulta. Pouco se sabe sobre o perfil de células do sistema imunológico em pulmões de crianças lactentes. Objetivo: Descrever o perfil de células do sistema imunológico no pulmão de lactentes sem doença pulmonar. Métodos: Amostras de pulmões histologicamente normais, obtidas através de autópsia de dez crianças que morreram de causas acidentais ou de doenças não pulmonares, foram marcadas por anticorpos contra linfócitos B e T, macrófagos, células NK (natural Killer), células citotóxicas, células dendríticas e mastócitos. As células foram quantificadas no epitélio, na camada interna, na camada externa das vias aéreas e nos septos alveolares. Membrana basal e septos alveolares foram medidos através de análise de imagem. Resultados expressos em células/mm de membrana basal epitelial brônquica ou alveolar. Resultados: A mediana das idades foi 2,5 meses (1-730 dias). Os resultados mostraram que a camada interna apresentou pequena densidade celular. No epitélio da via aérea e no parênquima houve predominância de células que estão relacionadas com a imunidade inata, tais como: CD56+, Granzyme + e CD68+. A camada externa e o parênquima alveolar apresentaram a maior densidade celular. Poucas células T CD4+ e células dendríticas foram encontradas na maioria dos compartimentos do pulmão. Conclusão: Há uma compartimentalização de células relacionadas com o sistema imunológico ao longo da via aérea e parênquima dos pulmões das crianças estudadas. Esta configuração pode estar relacionada com o desenvolvimento dos mecanismos de defesa da imunidade inata e da imunidade adquirida. Este conhecimento é importante para entender os mecanismos da imunocompetência pós-natal dos pulmões / Introduction: Pulmonary diseases or infections occurring early in life may have a permanent impact in adulthood. Little is known about the normal immune cell profile in the lungs of infants. Objective: To describe the immune cell profile of infants without lung disease. Methods: Histologically normal lung samples obtained at autopsy of ten infants that died either due to incidental or inflicted causes or non-pulmonary diseases were stained for antibodies against B and T lymphocytes, macrophages, NK cells, cytotoxic cells, dendritic cells and mast cells. Cells were quantified in the airway epithelial layer, inner layer, outer layer and alveolar septa. Basement membrane or alveolar septa lengths were assessed by image analysis. Results are expressed as cells/mm. Results: The median age of patients was 2.5 months and ranged from 1- 730 days. The inner layer of the airways was the region with the smallest density of cells. There was a predominance of cells related to the innate immunity such as CD56+, Granzyme B+ and CD68+ cells in the epithelial layer and alveolar parenchyma. The outer layer and the lung parenchyma presented the highest cellular density. There were very few CD4+ T cells or dendritic cells in most of the lung compartments. Conclusions: There was a compartmentalization of immune cells along airways and parenchyma in infants, which may be related to the development of innate and acquired lung defense mechanisms. This knowledge is important to understand mechanisms of postnatal immune competence of the lungs

Despite Human Leukocyte Antigen (HLA) matching and use of immunosuppressive drugs, graft-versus-host disease (GVHD) following hematopoietic stem cell transplant (HSCT) is prevalent and often fatal. Additionally, older HSCT recipients experience increased morbidity and mortality. Prophylactic treatment with age-matched syngeneic (recipient strain-derived) cultured regulatory DC (DCreg) has been shown to decrease GVHD-associated mortality in young bone marrow transplanted (BMT) mice. The purpose of this study was to investigate: 1) the potential to generate DCreg from older mice and their subsequent ability to ameliorate GVHD in older BMT mice, 2) the mechanism(s) by which DCreg mitigate GVHD in vivo, 3) the ability of DCreg-treated BMT mice to respond to infectious pathogens, and 4) whether DCreg can be generated under clinically relevant conditions from healthy donor and HSCT recipient PBMCs. To evaluate the efficacy of DCreg treatment in older mice, complete MHC-mismatched BMT mice were treated with DCreg (hereafter referred to as DCreg-treated BMT mice). Although DCreg treatment ameliorated GVHD in older BMT mice, these mice had increased morbidity and decreased survival compared to their young counterparts. Following transfer into BMT mice, older DCreg failed to increase inhibitory molecule (PD-L1 and PIR B) expression while significantly upregulating co-stimulatory molecule (CD40 and CD80) expression, conversely young DCreg upregulated inhibitory molecules as well as co-stimulatory molecules. These phenotypic differences between young and older DCreg in vivo provide a potential mechanism for modestly increased morbidity and mortality in older DCreg-treated BMT mice relative to their young counterparts. Indeed, BMT mice treated with DCreg deficient in PD-L1 or PIR B had significantly reduced overall survival, thus both molecules are required for optimal GVHD mitigation. A murine H1N1 influenza (IAV) infection model was used to assess the donor immune system's capacity to respond to relevant antigens other than those responsible for GVHD. Surprisingly, sub-lethally IAV-infected DCreg-treated BMT mice began to die after d. +21 and all were deceased by d. +25. Virus-specific CD8+ T cell and antibody (Ab) responses were undetectable following primary infection. Interestingly, following a prime-boost infection strategy, DCreg-treated BMT mice survived lethal IAV challenge with no signs of morbidity and had demonstrable IAV-specific Ab and CD8+ T cell responses. Thus a prime-boost IAV infection strategy establishes a protective immune response in the DCreg-treated BMT mice and underscores the potential role vaccination may play in establishing immune competence in DCreg-treated BMT mice. We investigated whether human DCreg can be generated under clinically relevant conditions: 1) following peripheral blood mononuclear cell (PBMC) cryopreservation, 2) in bovine serum-free media, and 3) from older individuals and HSCT recipients. DCreg were generated from healthy donor and HSCT patient PBMCs isolated from young (old) and older (> 50 years old) individuals by culturing cells in X-vivo serum-free. Human DCreg generated from both young and older healthy donor PBMCs had comparable numbers, surface molecule phenotype, cytokine production, and able to induce Treg. Cryopreserved and fresh PBMCs generated DCreg with similar phenotypes and cytokine production. DCreg generated from HSCT recipients maintained low co-stimulatory molecule and high inhibitory molecule expression as well as immunosuppressive cytokine production. These studies confirm DCreg can be generated under clinically relevant conditions.

The discovery that cationic lipids can independently stimulate the immune system has generated interest in their potential as vaccine adjuvants. Here, we show that the cationic lipid R-DOTAP can independently stimulate type 1 interferon production in dendritic cells in both primary culture and immortalized cell culture. Levels of type 1 interferon production are cell line-dependent and limited in vitro by lipid-induced cell death. We show that cationic lipids can independently activate TLR-7 and TLR-9, suggesting a mechanism for type 1 interferon induction. This TLR-stimulatory activity is not restricted to R-DOTAP and can be extended to other similar cationic lipids in a lipid-specific and TLR-specific manner.

Sphingoid bases (sphingosine, dihydrosphingosine and phytosphingosine) have been recently found in the oral cavity where they may serve to fortify innate immunity against commensals and periodontal pathogens. In fact, sphingoid bases have potent antimicrobial activity against Gram- positive and Gram- negative bacteria including oral pathogens like Porphyromonas gingivalis. It is not known whether these lipids are cytotoxic or alter the chemokine and cytokine responses of human dendritic cells, a finding important to their future potential as a therapeutic for treatment of periodontal disease. Objectives: The objective of this study was to determine the effects of sphingoid bases on the cytotoxicity and cytokine responses of human myeloid dendritic cells. Methods: Dendritic cells were treated with sphingoid bases (0.2-80.0 μM) for 16 hours in the presence or absence of 0.02 μM hemagglutinin B, a nonfimbrial adhesin of P. gingivalis used as a pro-inflammatory stimulus. The cytotoxicity of the inocula and its ability to induce the production of chemokines and pro-inflammatory cytokines was determined after 16 hours. Results: Higher concentrations of sphingoid bases were cytotoxic (e.g., 40.0-80.0 μM), but physiologic concentrations of sphingoid bases (e.g., 0.2-20.0 μM) were not. At 5, 10, or 20 μM, sphingosine did not enhance or attenuate any HagB-induced IL-8, GM-CSF, MIP-1α, MIP-1β, or TNFα response of human myeloid dendritic cells. At 5 or 10 μM, neither phytosphingosine nor dihydrosphingosine enhanced or attenuated any HagB- induced IL-8, GM-CSF, MIP-1α, MIP-1β, or TNFα response of human myeloid dendritic cells. Conclusion: Sphingoid bases exhibit dose-dependent cytotoxicity and cytokine responses against human myeloid dendritic cells. But at physiologic concentrations sphingoid bases appear to be safe and efficacious at the doses needed to prevent or treat microbial infections in the oral cavity.

L'athérosclérose est une maladie cardio-vasculaire immuno-inflammatoire se développant sur un terrain de dyslipidémie. De nombreuses composantes de la réponse immunitaire sont capables de moduler le développement des plaques d'athérome. Notamment, les lymphocytes T (LTs) CD4+ dont le rôle dans le processus athérogène dépend de la voie de polarisation. Le mécanisme de polarisation des LTs CD4+ est sous le contrôle des cellules dendritiques conventionnelles (cDCs) CD11b+. Ainsi, moduler ces cDCs et orienter la réponse adaptative vers une polarisation anti-athérogène pourraient représenter une potentielle cible thérapeutique dans la pathologie. Dans cette perspective, nous avons évalué le rôle des cDCs CD11b+ dans le développement de l'athérosclérose qui à ce jour reste totalement inexploré. Nous avons montré que la baisse du nombre des cDCs CD11b+ n'a pas d'impact sur le développement des lésions d'athérome. Cependant, nous montrons que l'absence du facteur de transcription IRF4 nécessaire au développement des cDCs CD11b+ altère le rôle anti-athérogène reconnu de l'adjuvant vaccinal à base d'aluminium (Alum). Nos données suggèrent que les cDCs CD11b+ n'ont pas d'impact direct sur le développement de l'athérosclérose, cependant, elles contrôlent l'effet athéroprotecteur de l'Alum. / Atherosclerosis is a disease characterized by arterial blood vessel thickening due to the accumulation of inflammatory cells in the arterial intima in response to cholesterol deposition. Several components of the immune response are able to modulate the development of atheromatous plaques. In particular, the role of conventional of CD4+ lymphocytes in the atherogenic process depends on their polarization pathway. The polarization mechanism of CD4+ T cells is under the control of conventional CD11b+ dendritic cells (cDCs). Thus, modulating these cDCs and orienting the adaptive response towards anti-atherogenic polarization could represent a potential therapeutic target in pathology. In this context, we evaluated the role of CD11b+ cDCs in the development of atherosclerosis which still remains totally unexplored. We have demonstrated that the decrease of the number of CD11b+ cDCs has no impact on the development of atheroma lesions. However, we show that the deletion of IRF4, the transcription factor necessary for the development of CD11b+ cDCs alters the recognized anti-atherogenic role of the aluminum-based vaccine adjuvant (Alum). However our data suggest that CD11b+ cDCs have no direct impact on the development of atherosclerosis but can control the atheroprotective effect of Alum adjuvant.