Dissertations / Theses on the topic 'Lymphocytes innés'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 47 dissertations / theses for your research on the topic 'Lymphocytes innés.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
Grau, Morgan. "Identification de nouveaux biomarqueurs permettant la caractérisation des lymphocytes T CD8 mémoires innés." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1023/document.
The pool of memory CD8 T cells is composed of two major cell classes. On one hand, conventional memory CD8 T cells are generated consequently to the specific recognition of pathogen or tumor derived antigens. On the other hand, innate memory CD8 T cells are generated through several mechanisms involving strong yc cytokine stimulation in the absence of cognate antigen recognition. However, these cell classes harbor a very similar phenotype. As a consequence, innate memory CD8 T cell population remains poorly characterized. This PhD has two main objectives : 1 / Identify new biomarkers that enable the discrimination between memory CD8 T cell classes 2/ Characterize the population of innate memory CD8 T cells in physiological condition Our results show that among the pool of memory CD8 T cells, only the conventional ones express the chemokine CCL5 and the NK receptor NKG2D. These two biomarkers enable for the first time the discrimination of memory CD8 T cell classes in physiological settings, in both mouse and human. Thanks to these new tools, we show that innate memory CD8 T cells hold typical memory features, such as an increased reactivity compared to naïve cells and a genetic program similar to the one of conventional memory cells. Nevertheless, this cell population also retains some features typical of naïve cells. The diversified TCR repertoire of this cell population allows it to participate to primary immune responses against various intracellular pathogens. Moreover, like naïve cells, innate memory CD8 T cells fail to access peripheral tissues upon local inflammation, which correlate with an absence of expression of some integrins. Altogether, these results demonstrate that innate memory CD8 T cells, characterized by the absence of expression of CCL5 and NKG2D, represent a hybrid cell population, at the boundary between naïve cells and conventional memory cells
Cayssials, Émilie. "Les lymphocytes T CD8 innés et immunosurveillance antitumorale : application au modèle de la leucémie myéloïde chronique." Thesis, Poitiers, 2020. http://www.theses.fr/2020POIT1407.
We have recently identified a new subset of innate T cells in humans, which we have termed « innate CD8 T-cells ». These cells express TCRαβ along with the transcription factor Eomesodermine (Eomes) and KIR/NKG2A membrane receptors. Innate CD8 T-cells share functional and phenotypic features with “innate memory” CD8 T-cells discovered in mice in the early 2000s. The development of these cells depends on the secretion of IL-4 by the T cells expressing the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF), and particularly iNKT, also called « invariant Natural Killer T-cells ». We have used the physiopathological model of chronic myeloid leukemia (CML) to study the potential role of innate CD8 T -cells in anticancer immunity in humans. Indeed, CML is considered to be one of the cancers most sensitive to immunological manipulation. CML is a malignant hemopathy that belongs to the family of myeloproliferative neoplasms characterized by the presence of the BCR-ABL1 oncogene. This oncogene is responsible for expression of the oncoprotein BCR-ABL with deregulated tyrosine kinase activity. Tyrosine kinase inhibitors (TKI) represent the standard of care for CML patients, of which the first in class was Imatinib. This targeted therapy has dramatically improved outcomes CML patients' outcomes, but they cannot achieve a cure. We previously reported that iNKT lymphocytes, a sub-population of innate T cells of which the implication into anti-tumoral immunosurveillance has been clearly demonstrated in human and in mouse models, are anergic in CML patients at diagnosis. Although these cells are functionally impaired, particularly in terms of IL-4 secretion, we have shown that their functional deficiencies are totally restored in CML patients in complete cytogenetic remission upon Imatinib therapy. Similarly to the iNKT lymphocytes, we presently show a major defect in the innate CD8 T-cells during the chronic phase in CML patients compared to those of healthy donors (HD) or patients in major molecular remission (MMR). This numerical defect is associated with a loss of NK-like functions (interferon-γ expression after innate stimulation by IL-12+IL-18 cytokines and with a loss of degranulation after stimulation via CD16). Interestingly, we have observed in patients in MMR under Imatinib a numeric and functional restoration that is at least partial, in terms of interferon-γ secretion after innate stimulation, of the innate CD8 T-cells. In analysis of cohorts of HD, CML patients at diagnosis and those in MMR under TKI, we have observed a correlation between Eomes expression by innate T CD8 T-cells and PLZF expression by iNKT cells. This finding underscores a possible dynamic process of generation of innate CD8 T-cells in humans that would depend on iNKT cells, as is the case in mice. To test the hypothesis that innate CD8 T-cells contribute to the control of CML, we have analyzed their status in a cohort of CML patients who, in spite of a persistent minimal residual disease, had maintained remission (MMR) more than two years after TKI discontinuation. In these patients, we demonstrate a dramatic increase of functional active innate CD8 T-cells as compared to HD and patients in MMR under TKI. All in all, these results underscore the major role of innate CD8 T-cells in anti-leukemic immunity during CML disease. We believe and we will test the hypothesis that the numeric and functional restoration of this subset might constitute a potential biomarker of successful TKI cessation in CML. We will also investigate whether innate CD8 T-cells could be a target for immunotherapy-based strategy
Hariss, Fatima. "Etude du rôle des Lymphocytes Intraépithéliaux innés dans la réponse immune protectrice contre Cryptosporidium parvum." Thesis, Université de Lille (2018-2021), 2021. http://www.theses.fr/2021LILUS047.
Intraepithelial lymphocytes (IEL) reside between intestinal epithelial cells and thus are the first immune cells to contact intestinal pathogens. In addition to respond rapidly to infection, they regulate intestinal homeostasis and maintain the epithelial barrier. This wide range of functions is achieved by distinct subsets of T and innate lymphocytes. Innate IEL which share many features with NK/ILC1 cells have been identified recently. These cells dominate the gut epithelium at birth and when the adaptive immunity is compromised. Their role in the immune response against intestinal pathogens remains however poorly studied.During my PhD thesis, I have investigated the role of innate IEL subsets in Crysptosporidium infection. Crysptosporidium is a common parasite that infects the gut epithelium. The infection is self-limiting in immunocompetent individuals, but it can be severe in immunocompromised individuals and children in whom innate IEL dominate.To study the specific role of innate IEL, we have developed an in vitro model that consist to co-culture mice 3D intestinal organoids infected with C parvum with innate IELs from RAG2-/- mice. Thanks to this original model, we demonstrated that innate IELs control parasite proliferation. We further showed that although innate IEL secrete IFN-ƴ in response to C parvum infection, the IFN-ƴ secretion was not sufficient to inhibit parasite proliferation. The protective effect of innate IELs was in fact mediated by a cytotoxic, granzyme-dependent mechanism. Moreover, transcriptomic analysis revealed that infected epithelial cells down regulated serpinb9b, a granzyme inhibitor, and thus may be more sensitive to cytotoxic attack
Daniel, Lauren. "Les lymphocytes T CD8 innés, une nouvelle population T non conventionnelle (re)programmée en transplantation rénale." Thesis, Poitiers, 2021. http://www.theses.fr/2021POIT1403.
Innate CD8 T-cells are a non-conventional αβ-T-cell population recently described in our laboratory. We call them “non-conventional” because of their expression of markers from both adaptive immunity (transcription factor Eomesodermin and memory T-cell phenotype) and innate immunity (Natural Killer cell receptors, response to innate-like cytokine stimulation). The functions of innate CD8 T-cells are not well-known, although there are strong arguments for their involvement in anti-infectious and anti-tumor immunity.It has been reported that immunosenescence and/or chronic antigenic stimulation (induced, for example, by chronic viral cytomegalovirus (CMV) infections) result(s) in NK marker expression by T-cells. This phenotype is therefore similar to that of our cells of interest. To study the influence of chronic antigen stimulation on CD8 T-cells, and especially their innate component, we chose organ transplantation as a model. In this domain, research has been focused on immune cell populations that may play a role in graft tolerance or rejection. Among them, innate CD8 T-cells deserve special attention due to their effector/cytotoxic innate functions. We presumed their being reprogrammed by graft and/or viral chronic stimulation during organ transplantation. This hypothesis was tested in a cohort of patients with kidney-transplants for more than ten years, under minimized immunosuppressive treatment (ciclosporin A (CsA) monotherapy), without any clinical and biological sign of rejection. First, our work revealed a more accentuated senescent phenotype (increased frequency of CD27(-)CD28(-) cells) in innate CD8 T-cells from healthy donors (HD) than in their conventional counterpart. Moreover, the frequency of the innate T-cell population, unlike that of conventional CD8 T-cells, did not correlate with age.In the cohort of transplant patients, we observed an increased frequency of innate CD8 T-cells, accompanied by an exacerbated senescent and terminal effector (CD45RA(+)CCR7(-)) phenotype, compared to HD cells. Patients with positive CMV serology had an increased senescent phenotype compared to patients with negative serology.By altering TCR signaling, CsA immunosuppressive therapy could also facilitate the (re)programming of CD8 T-cells in favor of their innate counterpart. In agreement with this hypothesis, in vitro modeling of CsA effects on CD8 T-cells from HD in the presence of IL-15 and TCR stimulation enabled us to document an increased innate CD8 T-cell pool to the detriment of the naive CD8 T-cell pool, accompanied by an enhancement of their functions (innate production of IFN-γ).Conversely, in transplant patients, innate CD8 T-cells were dysfunctional, with decreased innate IFN-γ production, which may result from their decreased membrane expression of the IL-15 receptor, a cytokine essential for innate CD8 T-cells. This dysfunction, which cannot be attributed to cellular exhaustion or cancer history, raises the question of the role of chronic allo-specific stimulation.All in all, this work suggests that the context of renal allogenic transplantation leads to reprogramming and aging-like phenotype of innate CD8 T-cells, linked (at least partially) to immunosuppressive treatment. This hypothesis requires confirmation by a precise analysis of the direct allo-specificity of innate CD8 T-cells against the graft
Dupraz, Louise. "Régulation des lymphocytes T innés par le microbiote intestinal Enterobacteriaceae are essential for the modulation of colitis severity by fungi Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS598.
From birth, a very large number of commensal microorganisms such as bacteria, yeasts and viruses colonize the human gastrointestinal tract. This gut microbiota is essential to develop the immune defences of the host against the infections, to allow a tissue repair and an adequate nutritional metabolism. Gamma-delta T lymphocytes, or innate T lymphocytes, are resident T cells in tissues, implicated in intestinal inflammation such as inflammatory bowel disease (IBD). Placed between innate and adaptive immunity, this population has activation capacities and functional properties, that give it functions both beneficial and deleterious. Decoding their regulation is crucial to prevent inappropriate immune responses without compromising intrinsic protective mechanisms. During my PhD, we have highlighted that short chain fatty acids (SCFA), metabolites producted by the gut microbiota, inhibit IL-17 and IL-22 productions by innate T cells, in vitro and in vivo by decreasing histone deacetylases (HDACs) (Dupraz et al. submit). These data contribute to a better understanding of the intestinal physiology as well as the environmental mechanisms involved in IBD and thus will open potentially new therapeutic perspectives
Chabab, Ghita. "Caractérisation d'une sous-population de LT γδ régulateurs dans les cancers solides humains." Electronic Thesis or Diss., Université de Montpellier (2022-....), 2022. http://www.theses.fr/2022UMONT067.
Γδ T cells contribute to the anti-tumor immunity within the tumor microenvironment in various cancers. Despite their well-described effector functions, recent studies correlated their presence in the tumor microenvironment with solid tumor progression suggesting that γδ T cells may display pro-tumor activities. My project aimed to characterize those regulatory γδ T cells and decipher their role in cancer.We demonstrated in vitro that inflammatory signals promote the development of a regulatory γδ T cell sub-population characterized by the expression of CD73 and displaying immunosuppressive functions through the production of immunosuppressive molecules such as IL-10, adenosine and the angiogenic and chemotactic factor IL-8. The challenge associated with the characterization of CD73+ γδ T cells resides in assessing their existence in vivo as well as their relevance in human cancers. We showed in human breast cancer that ~20% of tumor infiltrating γδ T lymphocytes (TILs) expressed CD73 and displayed the same immunosuppressive functions as described in vitro, suggesting that they could promote tumor development via these mechanisms. In line with these observations, we showed that the presence of γδ TILs is associated with late tumor grades in breast cancer. We extended such observations to ovarian cancer and showed that the density of CD73+ γδ TILs negatively correlates with patient survival, suggesting that CD73+ γδ TILs density could be used as a prognosis factor. Using Imaging by Mass Cytometry, we investigated the cellular networks of regulatory γδ TILs (CD73+) and their effector counterpart (CD73-) in breast and ovarian tumors to better understand their role in cancer. Our data show different ecosystems for CD73+ compared to CD73- γδ TILs reinforcing the idea that CD73+ and CD73- γδ T cells are functionally different.Altogether, these data improve our knowledge on human γδ T cell biology during cancer development, with the in-depth characterization of the new regulatory γδ T cell subset, their localization and their functions within the tumor microenvironment
Velut, Yoan. "Caractérisation des clusters de lymphocytes T CD8+, T régulateurs FoxP3+ et des neutrophiles CD66b+ dans le cancer broncho-pulmonaire et son impact dans l'immunothérapie." Electronic Thesis or Diss., Sorbonne université, 2022. http://www.theses.fr/2022SORUS457.
Lung cancer is the leading cause of cancer death. Although having benefited from numerous medical advances in the prevention, diagnosis and treatment of cancers, survival of patients suffering from lung cancer remains poor with a 5-year survival of approximately 20%, all stages combined. Nowadays, the immune system influence on tumor control and progression is clearly established. Numerous studies have shown that the immune cell composition of the tumor microenvironment has a strong prognostic and predictive impact on the anti-tumor treatment response. In this context, immunotherapy targeting the PD1/PD-L1 and CTLA4 axis has experienced rapid growth, but only 20% of patients will benefit from this treatment in lung cancer. Beyond the density of immune cells, the mutual influence of immune cells probably affects their anti-tumor functions, thus this factor must be taken into account in the analysis of tumors. This would explain the discrepancies observed between the density of a cell subtype, the expected survival and the observed survival. The team's work has shown the presence of cellular proximities between different immune cells in the tumor stroma. In this work, we determined the impact of these contacts and the cellular mechanisms involved. We quantified, by multiplex immunohistochemistry, the spatial interactions between CD8+ T lymphocytes, FoxP3+ T lymphocytes and CD66b+ neutrophils in the tumor microenvironment of 3 cohorts of patients suffering from non-small cell lung cancer (NSCLC ), treated or not by immunotherapy, radiotherapy and their prognostic and predictive impacts of response to treatment. We completed our study using flow cytometry, gene expression and spatial proteomic and transcriptomic. A Normalized Interaction Index (IND) was calculated to normalize the density of interactions between 2 cell types according to their respective densities. We have shown the prognostic impact of IND, particularly IND CD66b-FoxP3, on overall survival. By flow cytometry, we observed a decrease in the expression of immune checkpoints CTLA-4, TIM-3 and LAG-3 and an increase in the expression of PD-1 on CD8+ T lymphocytes, but not on CD4+ T lymphocytes when IND is high. An analysis of gene expression in the tumor microenvironment showed that IND was related to an immunosuppressive tumor environment, with decreased expression of genes involved in immune cell activation and differentiation, and overexpression of genes from the epithelial side of the epithelial-mesenchymal transition. We confirmed these results by Digital Spatial Profiling by analyzing the expression of immunity proteins at the paucicellular level. We observed an increase in the expression of co-stimulatory and activation proteins on CD8+ T cells in interaction regions, compared to the “free” CD8-enriched regions. The use of an online database of spatial transcriptomic at cellular scale (CosMx) made it possible to confirm the regulation of immune functions in cellular interactions compared to cells “free” of interaction. These cellular interactions influence the response to conventional therapies, notably IND CD66b-FoxP3, but do not seem to modify the efficacy of immunotherapy. Taken together, these results suggest that interactions between neutrophils and FoxP3+ T cells promote CD8+ T cell activation and an effective anti-tumor response, highlighting the complexity of anti-tumor immunity, its organization and the presence of cellular interactions
Ranson, Thomas. "Homéostasie des lymphocytes de l'immunité innée chez la souris." Paris 7, 2004. http://www.theses.fr/2004PA077150.
Deknuydt, Florence. "L'il-17 : polarisation innée et adaptative." Nantes, 2011. http://archive.bu.univ-nantes.fr/pollux/show.action?id=0a95bdaa-9fdf-4d66-bc51-42db3353fd4d.
During my PhD, I characterized the cells producing the pro-inflammatory cytokine: IL-17. These cells seem to be implicated in autoimmune diseases and some bacterial infections. In these pathologies, the immune system plays an important role and particularly two cell subsets: Treg and γδ T cells. During a first period, I investigated these cells in uninfected PBMCs. During this work I demonstrated the capacity of Treg to polarise into Th17. I also demonstrated that Treg could produce IL-17 when they are activated via the TCR combined with IL-1 and IL-2. Moreover when these cells produce IL-17 they loose the expression of Foxp3 and their suppressive capacity. During a second period, I studied this cytokine in a pathologic context: human tuberculosis. To develop this project, I used an in vitro granuloma model developed by F. Altare’s team. During this work, I demonstrated the presence of IL-17 within characteristic structure of human tuberculosis: the granuloma. This cytokine is present in vitro and in sample biopsies of human granuloma. Moreover, within granuloma, γδ T cells have the best capacity to polarise. In Humans, the γδ T cells are composed of two subset: δ1 and δ2. The δ2 cells are mainly found within epithelia, whereas δ1 are mainly circulating. During my study, I could demonstrate that δ1 cells are the only cells to be able to produce IL-17 within human granulomas. This production is only displayed in late stage of granuloma. A relationship seems to exist between IL-17, δ1 and the necrosis present in the middle of granuloma, because these cells are present only in necrotic biopsies thus strongly suggesting a direct role of δ1-induced IL-17 in necrosis induction
Simoni, Yannick. "L’immunité innée dans le diabète sucré." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T074/document.
The type 1 diabetes ( T1D ) is an autoimmune disease characterized by the destruction of β cells in the pancreas by autoreactive T lymphocytes. During my thesis, we are interested in the role of cells of innate immunity in T1D using a mouse model of the disease: NOD mice. In contrast to cells of the adaptive system (T and B lymphocytes ) cells of innate immunity is the first line of defense of the body during infection . This population consists of neutrophils , among other , plasmacytoid dendritic cells ( pDC ) , macrophages , T lymphocytes but not conventional B as iNKT cells and B -1a.Previously, our laboratory has highlighted the role of iNKT cells in the development of T1D . During the first part of my thesis , we demonstrated that iNKT17 cells, a subpopulation of iNKT cells, have a deleterious role in T1D in NOD mice . These cells infiltrate the pancreas and there produce IL -17 , a proinflammatory cytokine. Through transfer experiments , we demonstrated that lymphocytes iNKT17 exacerbate disease through the production of IL-17 . In the second part of my thesis , we investigated the mechanisms that induce the activation of autoreactive T lymphocytes. We observed in NOD mice , the physiological death of β cells leads to activation of innate immunity cells : neutrophils, lymphocytes B- 1a and pDCs . The cooperation between these cells leads to activation of pDC that produce IFNa . This cytokine activates autoreactive T cells which will destroy the β cells of the pancreas. Our results show that innate immunity is an important player in the pathogenesis of diabetes mellitus
Posso, Cécilie. "Développement des cellules lymphoïdes innées RORγt⁺." Paris 7, 2011. http://www.theses.fr/2011PA077147.
RORyt is a transcription factor expressed by several populations of innate lymphoid cells (ILC), like lymphoid tissue inducer cells and NKR+RORyt+ cells that co-express RORyt and the NK cell receptor, NKp46. Here, we propose a model for RORyt+ ILC differentiation from the common lymphoid progenitor (CLP). Based on clonal assays of fetal liver CLP, we hâve shown that B, T, NK and RORyt+ cells are originating from a common progenitor. CLP lose B and T potential as they express a4b7 and CXCR6 respectively. The acquisition of RORyt occurs in the fetal liver. RORyt+precursors are observed in the blood and in the anlagen of peripheral organs. We have identified two distinct RORyt+ precursors that differentiate into RORyt+CCR6+ and NKR+RORyf cells. These precursors develop independently in the fetal liver. They are also observed in the spleen and the anlagen of mesenteric lymph nodes. We have also established the potential of these precursors in vivo by transfer into immunodeficient mice. The analysis of fate-mapping mice has shown that RORyt+-derived NK cells develop and are maintained in the peripheral organs of young adult mice. In adult mice, the bone marrow does not contain RORyt+ and in vitro cultures of bone marrow progenitors do not give rise to RORyt+ cells. Transfer experiments allowed us to identify the CLP as the progenitor of adult RORyt+ ILC. Populations that display a CLP phénotype are observed in the spleen and the lamina propria of adult mice. These peripheral CLP differentiate into RORyt+cells in vitro, indicating that the adult progenitor of RORyt+ ILC has to migrate to the periphery to receive the signal required for its differentiation
Bresler, Priscillia. "Étude de la régulation des cellules lymphoïdes innées par les lymphocytes T chez la souris." Electronic Thesis or Diss., Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB078.
Many articles in the literature report that the composition, the frequency and the activity of ILCs are strongly affected when the adaptive immune system is deficient in mice. However, the mechanisms by which adaptive immunity regulates the homeostasis of ILCs remain largely unknown. The objective of my thesis was to address the role played by T cells in this regulation within lymphoid tissues such as peripheral and mesenteric lymph nodes and in the small intestine. I also characterised some of the regulatory mechanisms involved in this dialogue between ILCs and T cells and determined their tissue specificity. During my thesis, I confirmed that the regulation of gut resident ILC3 by CD4+ T cells is based on their ability to participate in the containment and diversification of bacterial communities colonizing the gut. In addition, I have also highlighted the role of CD4+ T cells in the regulation of the frequency and activity of type 2 ILCs in the mesenteric lymph nodes. The latter does not rely on the activation of CD4+ T cells by the gut microbiota. Indeed, I showed that the expression of the gene encoding IL-33 is increased in the mesenteric lymph nodes of T cell deficient mice and that the short-term neutralization of IL-33 signalling in vivo significantly reduces the frequency of type 2 ILCs in the mLNs of these mice. In collaboration with Lucie Peduto's team, we showed that T lymphocytes indirectly regulate the expression of IL-33 by mesenteric lymph nodes stromal cells. However, the mechanisms underlying these interactions remain to be elucidated. Finally, the role of other T-cell dependent environmental factors remains to be characterised. Indeed, our preliminary results indicate that T-B cooperation may be instrumental in the regulation of mesenteric lymph nodes resident ILC2 while it is redundant in the regulation of gut resident type 3 ILCs by CD4+ T cells
Soulard, Valérie. "Etude des réponses des lymphocytes NKT et NK à l' infection par Plasmodium yoelii 265BY chez la souris C57BI/6." Paris 6, 2005. http://www.theses.fr/2005PA066358.
Mozeleski, Brian Matthew. "The presence of an effector CD4 T cell population at birth." Paris 7, 2014. http://www.theses.fr/2014PA077009.
The immune response in the newbom is characterized by limited protection (<6 mo), low Ab responses (<12-24 mo), and limited T cell responses characterized by a biased towards Th2 responses. Minimal IFN-D producing T cell— responses fail to defend against microbial infection contributing to the WHO estimation that 2M children between 1-6 mo die each year from preventable infections. Human T cell development begins at —10 gestational weeks (g. W. ) where cells then egress from the thymus to colonize the periphery. Around 20 g. W. , terminal deoxynucleotidyl transferase expression is initiated, conferring maximum TCR diversity. Pregnancy requires establishment of a feto¬maternai tolerance state between mother and fetal antigens at the fetal interface. Similarly, the fetus develops regulatory T cells to maternai antigens. Therefore at birth and in the absence of any fetal infection, the T cell compartment putatively contains only naïve and regulatory T cells. Here we characterized the newbom' s peripheral CD4+ T cell compartment in ternis of its maturity and its potential to develop or elicit a diversity of effector functions. CD127hi and CD12710 expression separates conventional CD4+ T cells from Tregs respectively. Apart from CD127hi T cells and CD127lowFoxp3 Tregs, we identified a small population of CD45RO+CD127hi cells devoid of Foxp3 expression in cord blood. These cells represent around 3% of the total CD4+ population and were consistently found in ail cord blond samples (n=10), in the absence of any reported natural infection of the fetus. Following anti-CD3 and anti-CD28 stimulation, and within hours these cells produced Thl and Th2 effector cytokines IFN-y, IL-13, and IL-4, but IL-22 and IL-17a remained undetected. The presence of adult Th subset associated chemokine receptors (CXCR3, CCR4, CCR6) in cord blond promoted the screening conventional putative Th subsets for cytokine response and showed that the 1FNy response could be isolated to CXCR3+ while IL-4 and IL-13 were produced on ail subsets expressing a Th subset associated CCR. Direct microarray analysis comparisons of putative cord blood Th subsets versus defmed adult Th subsets revealed distinct adult-like signatures as well as a degree of plasticity in sharing Th2-like functions such as IL-4 and IL-13 production. The striking evidence that a mature T cell compartment exists at birth raises the question of how conventional T memory develops and winch antigens stimulate a response. Overall, these T memory cells may also influence the development of T cell responses in early life and offer important insight for the design of new and future neonatal vaccines
Simoni, Yannick. "L'immunité innée dans le diabète sucré." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00944309.
Tout, Issam. "Rôle du TLR9 et des lymphocytes B dans l'échappement du virus de l'hépatite B à l'immunité innée." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1308/document.
Chronic HBV infection is a major health problem worldwide. Ineffective T cell and antibody responses have been demonstrated, yet the precise events that may contribute to insufficient B cell responses remain to be determined. Optimal B cell function, expansion and differentiation rely on Toll Like Receptor 9 (TLR9) activity which senses dsDNA and is expressed in human mainly by plasmacytoid dendritic ( pDC) and B cells. The impact of HBV on TLR9 in human B cell subsets remains to be explored.Here, we investigated the effects of HBV on TLR9 function in human B cells. Both primary and B cell lines were used to analyze the effect of HBV on TLR9 expression and function. These results were corroborated in a cohort of chronically infected HBV patients. TLR9 expression was reduced in all peripheral blood B cells subsets exposed to HBV. B cell function mediated by TLR9, such as proliferation and pro-inflammatory cytokines secretion were abrogated in the presence of HBV. Our results show that the viral surface antigen HBsAg inhibited the phosphorylation of the transcription factor CREB which could no longer bind the CRE site located on the TLR9 promoter. Finally, we corroborated our in vitro findings in a cohort of chronic HBV carriers (CHB) and found that TLR9 expression and function were significantly suppressed.Our findings reveal the mechanism that induces an immunosuppressive response by HBV on TLR9 function in human B cells, which may contribute to HBV persistence in the host
Thierry, Antoine. "Implication de l'immunité innée au cours des phénomènes d'ischémie-reperfusion : rôle de l'axe IL-33/lymphocytes iNKT." Thesis, Poitiers, 2013. http://www.theses.fr/2013POIT1409.
Ischemia reperfusion injury (IRI) is inherent to the transplantation process and its severity is correlated with graft outcome. The pathophysiological mechanisms of these lesions are still poorly understood. The endogenous molecules high mobility group box 1 (HMGB1) and interleukin (IL)-33 have been identified as alarmins, capable of initiating the inflammatory response and thereby to be potentially useful biomarkers in IRI. The pig is a relevant preclinical model to investigate IRI. Because iNKT cells are a component of innate immunity implicated in IRI, we first identified and characterized these cells in pig peripheral blood and showed that they are targeted by IL-33. We then addressed the role of alarmins as innate immune mediators in IRI following human kidney transplantation. Urinary HMGB1 and IL-33 levels were increased early after reperfusion, whereas increased serum and urinary IL-33 were positively correlated with cold ischemia time. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Moreover we showed that peripheral leukocytes from recipients are potentially targeted by both HMGB1 and IL-33, as attested by increased transcription of their respective receptors. Consistent with this view, we found that iNKT cells that are targeted by IL-33 but not by HMGB1 were activated as soon as 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans
Lisbonne, Mariette. "Rôle des lymphocytes iNKT dans les réponses immunes innée et acquise : application à l' asthme allergique expérimental." Paris 7, 2005. http://www.theses.fr/2005PA077037.
Lafarge, Sandrine. "Signalisation dans le lymphocyte B humain au décours de son activation in vitro via les molécules de l'immunité innée." Saint-Etienne, 2008. http://www.theses.fr/2008STET007T.
Lim, Ai Ing. "Cytokine control of human innate lymphoid cell development and function." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC272/document.
Innate lymphoid cells (ILC) represent a novel family of hematopoietic effectors that serve essential roles in early immune response by rapid cytokines production. Three distinct groups of ILC subsets have been described. Group 1 ILC include cytotoxic natural killer (NK) cells and other type-1 cytokines (IFN-? and TNF-?) producing cells that regulated by T-BET. Group 2 ILC (ILC2) express GATA-3 and ROR?, secrete type-2 cytokines, IL-5 and IL-13. Group 3 ILC (ILC3) utilize ROR?t to drive production of the TH17-associated cytokines, IL-17 and/or IL-22. In this thesis, I have performed series of experiments to uncover the developmental pathway and function of human ILC that may allow us to harness ILC in diverse clinical settings. First, I analyzed the phenotypic and functional heterogeneity of human peripheral blood ILC2. I found human IL-13+ ILC2 can acquire the capacity to produce IFN-?, thereby generating ÔplasticÕ ILC2. ILC2 cultures demonstrated that IFN-?+ ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12/IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease (MSMD) due to IL-12R?1 deficiencies that failed to generate plastic ILC2. This IL-13+IFN-?+ ILC2 are detected ex vivo in gut tissues from CrohnÕs patients. Second, I identified and isolated ILC precursors (ILCP) in peripheral blood of healthy donors. This circulating ILCP can give rise to four lineages of mature ILC including cytotoxic NK cells and helper ILC1, 2 and 3 in vitro and in vivo. Transcirptomic and epigenetic analysis showed ILCP have ILC-committed transcription factor profiles but have mature ILC signature locus at the epigenetics poised states. We further identified ILCP in various tissues including fetal liver, cord blood, postnatal lung and tonsil. Our result proposed a new model of ÒILC-poiesisÓ where circulating ILCP serve as cellular substrates to generate mature ILC subsets in tissues. Understanding the role of IL-12 on driving ILC2 to ILC1 plasticity may allow us to target plastic ILC2 in various diseases. The identification and isolation of ILCP from circulating blood allow further transfer into clinical setting for cellular therapy, especially for various diseases that ILC has been shown to be importance including infection, allergy, cancer and metabolic diseases
Vourc'h, Mickaël. "Immunosubversion du Lymphocyte Natural Killer par Pseudomonas aeruginosa." Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1042/document.
Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes lung infections in immunosuppressed patients. Among its virulence factor PA expresses the type III secretion system (T3SS) and effector Exoenzymes (ExoS, T and Y). Natural killer (NK) cell plays a key role in anti-bacterial immunity especially after PA infection. Their activation is highly dependent on their microenvironment especially on myeloid cells. NK cell exhibits two main functions: Cytokines production and cytotoxicity toward stressed or abnormal cells. We studied PA influence on these two main functions. We used peripheral blood mononuclear cells (PBMC), sorted human NK cells and two human NK cell lines (NK92, NK3.3) for in vitro experiments and a PA-pneumonia mouse model to validate our hypothesis in vivo. Degranulation was assessed by cytotoxicity assay, exposing NK cells to 721.221 targets lacking HLA-A, B and C class I antigens. NK cells required IL-12 priming to produce IFN-g in response to the infection and PA increased IFN-g activity as compared to IL-12 stimulation in noninfected conditions. The modulation of IFN-g production after PA infection required bacteria-to-cell contact. Among T3SS and its effector, ExoT is the key regulator of IFN-g activity through a ERK dependant signalisation. Our hypotheses were confirmed in vivo. Alongside with cytokine function, CD107a activity, a surrogate marker of degranulation (Cytotoxic function), dramatically decreased after NK cells infection with PA. Cytotoxicity impairment could be explained by the modification of NK cells receptor expression after infection (notably NKG2D) or accessory cells, especially T cells
Brest, Patrick. "Interaction entre les Escherichia coli pathogènes et la muqueuse intestinale : mécanismes cellulaires et moléculaires de la réponse immunitaire innée induite par les facteurs de virulence bactériens." Nice, 2003. http://www.theses.fr/2003NICE4038.
Pallandre, Jean-René. "Régulation de l'activation des cellules NK par les cellules dendritiques et étude des interactions entre le système immunitaire inné et adaptatif." Besançon, 2008. http://www.theses.fr/2008BESA3009.
The cross-talk between a natural killer lymphocyte (NK) and an antigen presenting dendritic cell (DC) is a central event in the initiation and development of the adaptive immune response. - Contact between the cells (IS, immunological synapse) is a dynamic process involving many molecular changes with consequential biological implications. For example, the interaction allows the NK cell to initiate the production of IFN-γ which initiate specifically an immunological adaptative Th1 response. - Regulatory T lymphocytes (CD4+CD25+FoxP3+ also play an essential role in peripheral tolerance. Their absence in the body leads to auto-immune disease. Equally they are complicated in response to infections or tumoural challenge. - This study has centered on the regulatory initiation steps of the immune response. We have identified the chemokine CX3CL1 (fractalkine) as a key molecule in the formation of SI and the production of lFN-γ by NK cells. This secretion favours Th1 polarisation and peripheral conversion of FoxP3 (Forkhead transcription factor 3) expressing regulatory T cells (Treg). - ln the ongoing second part of our study we show that STAT3 is a critical transcription factor in the generation and function of Tregs. - These results may help to appreciate the possibility of modulating the immune response by manipulation of Treg populations
Fichou, Nolwenn. "Implication des récepteurs de l'immunité innée dans l'activation des lymphocytes T CD8+ et dans la fonction immunostimulante des miARNs. Application au diabète auto-immun." Nantes, Ecole nationale vétérinaire, 2012. https://doc-veto.oniris-nantes.fr/GED_CHN/197444691562/Fichou_Nolwenn.pdf.
Gigante, Marc. "Mise au point d'un modèle ex-vivo d'étude de l'immunité innée des anticorps naturels lors de l'ischémie-reperfusion rénale." Nice, 2008. http://www.theses.fr/2008NICE4076.
Mise au point d’un modèle ex-vivo d’étude de l’immunité innée des anticorps naturels lors de l’ischémie reperfusion rénale. Les développements récents des études sur le syndrome d’ischémie-reperfusion tendent à mettre en évidence le rôle de l’immunité innée avec une participation d’anticorps naturels autoréactifs et polyréactifs de type IgM. Afin d’étayer cette hypothèse il nous fallait mettre au point un modèle associant un système ex vivo d’ischémie perfusion normothermique d’une part et d’un moyen de production d’anticorps de type IgM autoréactifs et polyréactifs. Les lignées cellulaires lymphoblastiques B (LCLs) obtenues par transformation par le virus d’Epstein-Barr (EBV) sont largement utilisées en pratique courante. En utilisant l’infection par virus EBV associée à une stimulation du Toll like receptor 9 (TLR9), le but de ce travail était d’établir des lignées cellulaires lymphoblastiques B issues de différentes sous population lymphocytaire B sanguines (lymphocytes B transitionnels, lymphocytes B naïfs, lymphocytes B mémoires) et d’étudier l’effet de cette transformation sur l’expression des marqueurs phénotypiques ainsi que sur la capacité de production d’immunoglobulines, et ce, pour chacune des sous-populations étudiées. Après sélection des différentes sous-populations, chacune était immortalisée. L’expression des marqueurs phénotypiques des LCLs obtenues (12 marqueurs CD et 4 Ig membranaires) était étudiée. Par une méthode ELISA, la présence d’Ig dans le surnageant était mesurée et leur poly-réactivité était estimée. Le caractère autoréactif de ces anticorps était apprécié par un test ana HEP-2. Parallèlement, un système de perfusion de rénal normothermique était construit à partir d’une machine à perfusion pulsatile modifiée (MOX100 ou RM3), notamment pour ses variables d’oxygénation et de contrôle de température. Obtention de lignées lymphoblastiques produisant des anticorps autoréactifs semblables aux anticorps IgM naturels : Les quatre sous-populations lymphocytaires B peuvent être immortalisées par le virus EBV associé au Cpg. Ce résultat n’avait jamais été rapporté. Parmi tous les marqueurs phénotypiques étudiés, les effets de l’immortalisation sont pertinents pour 8 d’entre eux : CD5, CD10, CD23, CD24, CD27, CD38, IgD, IgM. Concernant la sécrétion d’immunoglobuline : Des IgM, IgA ou IgG peuvent être secrété mais pas des IgD. Les classes d’immunoglobulines sécrétées diffèrent selon la sous-population lymphocytaire B à l’origine de la transformation. Il existe une forte corrélation entre l’expression des Ig membranaires et la sécrétion d’immunoglobulines. Certaines LCL secrètent des anticorps autoréactifs de type IgM ; il n’a pas été mis en évidence d’autoanticorps de type IgA ou IgG. Certaines LCL secrètent des anticorps poly-réactifs de type IgM. Les résultats obtenus concernant les caractères phénotypiques. Les tentatives d’immortalisation de la sous-population lymphocytaire B1 furent un échec. Le système de perfusion rénal normothermique, utilisant des reins porcins entiers permettait d’obtenir une diurèse efficace pendant 6 heures avec un pic à la deuxième heure de 140ml/h
Jacomet, Florence. "Étude d'une nouvelle population de lymphocytes T « innate-memory » : implication dans l'immunité anti-leucémique au cours de la leucémie myéloïde chronique." Thesis, Poitiers, 2015. http://www.theses.fr/2015POIT1406/document.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL, which is sufficient to induce malignant transformation. A critical role of the immune system in the control of CML is supported by several reports. Invariant Natural Killer T (iNKT) lymphocytes are a population of non-conventional T cells that are believed to play a key role in cancer immunosurveillance. Here, we showed that CML in chronic phase is associated with anergy of iNKT cells that is restored upon complete cytogenetic remission (CCyR) following Imatinib Mesylate (IM) or IFN-α therapy. In mouse, iNKT cells are involved in the generation of a recently characterized subset of innate CD8 T cells. Importantly, we provided definitive evidence of the existence of an equivalent of these innate CD8 T cells in humans, harboring innate and memory phenotype with high Eomesodermin expression. These cells also exhibited innate functions such as prompt IFN-γ expression in response to innate stimulation by interleukin (IL)-12 and IL-18 and cytolytic activity in a TCR independent manner.Size and functions of this innate-like CD8 T cell subset were severely impaired in CML patients at chronic phase. These defects were partially reversed in patients who achieved CCyR following IM treatment.Altogether, these results reveal a possible contribution of innate CD8 T lymphocytes in anti-leukemic immunity and should contribute to development of immunotherapeutic strategies against CML
Boeglin, Emmanuelle. "Contrôle de la prolifération et de la différenciation des lymphocytes B murins par des signaux de l'immunité innée et de l'immunité adaptative." Strasbourg, 2010. http://www.theses.fr/2010STRA6260.
Terminal differentiation of B cells requires two signals: a signal deriving from the recognition of the antigen by the specific B cell receptor (BCR) and a signal provided by the interaction between the CD40 molecule expressed on B cells and its ligand CD40L expressed by activated T cells. Nevertheless, it has been recently shown that a third signal deriving from the pathogen recognition by Toll-Like Receptors (TLR) could be important and even necessary for the development of a humoral immune response. Thus the role of TLRs, but also of two NLR (NOD-Like Receptor), alone or combined with a signal of adaptive immunity (CD40L + BCR) on the activation and differentiation of B cells have been investigated. We have demonstrated that all TLR agonists, with the exception of TLR3 and 9, induce proliferation, activation and differentiation of B cells. Moreover, the addition of a signal from adaptive immunity to TLR agonists can increase B cell activation and proliferation (TLR3, 4, 9), differentiation of these cells into antibody secreting cells (TLR1/2, 2/6, 4, 7), and the development of memory B cells. Furthermore, we showed that the Nod1 ligand does not induce B cell differentiation but its association with a CD40 signal can enhance it. Thus, we have shown that pathogens alone or combined with signals of adaptive immunity can trigger and control the B cell response. These different stimuli can induce the development of either plasma cells or memory B cells, this could be an important asset for the development of new vaccines
Ronet, Catherine. "Lymphocytes T utilisant la chaîne V & 14 invariante du TCR (cellules NKT) : rôle et fonction lors de la réponse immunitaire innée." Paris 6, 2003. http://www.theses.fr/2003PA066290.
Gérart, Stéphane. "Identification d'un nouveau mécanisme de contrôle de l'homéostasie des lymphocytes T iNKT et MAIT." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00754934.
De, Wilde Virginie. "Dialogue entre l'immunité innée et acquise en réponse au lipopolysaccharide." Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210371.
Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished
Duban, Livine Annie Alice. "Les cellules M. A. I. T. (Mucosal-associated Invariant T) : une nouvelle sous-population de lymphocytes Tαß conservée entre espèces." Paris 5, 2006. http://www.theses.fr/2006PA05D052.
Mucosal-Associated Invariant T (MAIT) cells display unique T cell feature : they are phylogenetically conserved (human, mouse and cattle) and used an invariant TCRα chain, iVα7. 2/19-Jα33. These cells localized in the mesenteric lymph nodes (MLN) and the gut lamina propria (LP). They recognize the phylogenetically conserved class Ib MHC molecule MR1 and it expression on B cells is sufficient for selection/expansion of MAIT cells. The study of iVα19-Jα33 transgenic mice showed that the characteristic Vß6/8 biais of repertoire is loss in the thymus, the MLN and LP in the absence of MR1. Expression of a MAIT cells specific TCRß chain induces an increased selection/expansion of these cells in the thymus, MLN and LP. Finally, there selection/expansion is dependant upon the presence of commensal flora in the gut, as they are absent in germfree mice and both Gram+ and Gram- bacteria can induce MAIT selection/expansion
Raffray, Loïc. "Immunopathologie de la leptospirose humaine : exploration de la réponse immunitaire innée." Thesis, La Réunion, 2017. http://www.theses.fr/2017LARE0006/document.
Leptospirosis is a bacterial zoonosis caused by Leptospira and affecting 1 million people each year worldwide and mainly in tropical areas such as Reunion Island. Usual presentations encompass flu-like syndrome to multiorgan failure with mortality rate between 5 to 10%. To date, pathophysiology in humans is poorly understood, notably the capacity of innateimmunity to mount a robust response to clear pathogen or to induce tissue damages and contributing to disease severity. Our study aimed at assessing the role of innate immune cells and molecules within the first days of leptospiral infection.Using blood samples, we performed quantitative and qualitative assessment of circulating innate immune cells from leptospirosis cases and healthy controls. The first study explored the levels of gamma-delta T-cells (γδT-cells), a subset of unconventional T cells with innate immune functions. Gamma-delta T cells were found deeply decreased and levels wereinversely correlated to bacterial burden and liver damage. The second study focused on membrane bound receptors indicative of activation and tissue migration ability of neutrophil polymorphonuclear cells: CD15, CD11b, and CD182. Although neutrophil rates were high in leptospirosis cases, the levels of studied receptors were either lower (CD15) or identical to healthy controls (CD11b, CD182). In addition, only low levels of interleukin-8, a key chemokine for neutrophils, was detected in patients. Lastly, we ascertained the plasmatic levels of several shed cell adhesion molecules notably expressed by endothelial cells. The levels of soluble E-selectin and ICAM-1 were significantly increased compared to controls, while P-selectin level was lower. We did not find any correlation with disease severity or organ failure. This finding indicates that endothelial cell may be activated but further experiments are warranted to explain the functional impact of our findings. Altogether, our results add to the field of knowledge of leptospirosis pathophysiology, and in particular the implication of key innate immune cells at the stage of plasmatic bacterial dissemination. Our findings will support the view that there is an inappropriate immune response to Leptospira
Fernandez, Nadine. "Modulation de l'immunité antitumorale innée et acquise par transfert de gènes codant pour des immunomodulateurs ou par flt3 ligand." Paris 11, 1998. http://www.theses.fr/1998PA11T052.
Gérart, Stéphane. "Identification d’un nouveau mécanisme de contrôle de l’homéostasie des lymphocytes T iNKT et MAIT." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05TO22/document.
Invariant natural killer T (iNKT) lymphocytes represent a peculiar T cell-lineage that differs from conventional T cells by its development, function, and ligands it recognizes. In humans, iNKT cells express an invariant TCR made of the V?24-J?18/V?11 rearrangement, which recognizes glycosphingolipids presented by the MHC class I monomorphic molecule CD1d. Moreover, they rapidly produce high amounts of cytokines when stimulated and are thus considered as innate-like T cells. The molecular mechanisms that control the homeostasis of iNKT are poorly understood. XIAP (X-linked Inhibitor of Apoptosis) is a physiological inhibitor of caspases 3, 7 and 9 and is mutated in the X-linked lymphoproliferation syndrome 2 (XLP-2), a rare primary immunodeficiency (PID) characterized by a peculiar susceptibility to Epstein-Barr virus (EBV) infection. Patients with a XIAP deficiency exhibit a strong reduction of their iNKT cells in blood. Here, I report that XIAP is required for the survival of iNKT cells in humans. The requirement of XIAP correlates with a pro-apoptotic phenotype of iNKT cells that is not observed in conventional T cells. The increased susceptibility to apoptosis of iNKT cells was observed upon stimuli that trigger either extrinsic or intrinsic apoptosis pathways. iNKT cells by contrast to conventional T cells express elevated amounts of pro-apoptotic molecules including caspases 3 or 7 and Bid. The pro-apoptotic phenotype of iNKT cells is early acquired since iNKT cells from cord blood and thymus display a similar pro-apoptotic phenotype. Knock-down of XIAP in iNKT cells and analysis of XIAP-deficient humans indicate that XIAP is a potent inhibitor of apoptosis in iNKT cells while it has only a moderate effect in conventional T cells. I also show that this pro-apoptotic phenotype of iNKT cells is dependent of the expression of the transcription factor PLZF. This factor is already known to be necessary for the acquisition of the effector functions of these cells. Conversely, over expression of PLZF in conventional T cells leads to a pro-apoptotic phenotype and to an increased expression of caspase 3. Recently, a second invariant T cell subpopulation, the mucosal associated invariant T (MAIT) cells was identified both in humans and mice. These cells express a semi-invariant TCR made of V?7.2-J?33 rearrangements and share with iNKT cells a number of developmental, functional and phenotypical features that lead to consider MAIT cells as innate-like T cells like iNKT cells. Similarly, MAIT cells also exhibit a pro-apoptotic phenotype and are decreased in XIAP-deficient humans. The pro-apoptotic phenotype of MAIT cells is also dependent on PLZF. Interestingly, one XIAP-deficient patient with normal iNKT cell number was identified. This patient has not yet encountered EBV, suggesting that reduction of iNKT cells in XIAP-deficient patients is likely due to increased apoptosis in the context of EBV infection. I also show that EBV might have an escape mechanism from iNKT cells by down-regulating the expression of CD1d on the surface of B cells. My thesis works identify a previously unknown pathway controlling innate T cell homeostasis depending on XIAP and PLZF. PLZF is thus a key factor involved in the differentiation and the homeostasis of innate T cells by regulating the acquisition of their effector functions and their survival. I also identified the first PID associated with a defect in MAIT cells. Finally, these results provide evidences that iNKT cells might play a role against EBV infection
Thiriot, Aude. "Identification et caractérisation, grâce aux lignées de souris dérivées d'individus sauvages, d'une nouvelle population de lymphocytes B conservée dans le genre Mus : les cellules Bw." Paris 6, 2008. http://www.theses.fr/2008PA066673.
Grimaldi, David. "Mécanismes cellulaires et moléculaires de l’immunodépression post-infectieuse." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T049/document.
Severe sepsis leads to a dysregulated inflammatory response followed by a complex immunosuppressive state that can favor the emergence of nosocomial infections. The cellular and molecular mechanisms that drive the post-infective immunosuppression remain poorly understood. They may involve immune cells that link innate and adaptive immunity such as dendritic cells or innate-like lymphocytes. Furthermore, Toll-like receptors (TLR) are critical determinants of the inflammatory response but their role to the development of sepsis-induced immune dysfunction are unknown. The aim of this research project was to investigate the role of dendritic cells, innatelike T cells and TLR-dependent signalling pathways in the sepsis-induced immunosuppression process. For this purpose, we combined a translational and experimental approach. We assessed dendritic cells blood count in septic patients and showed that the depletion of dendritic cells was associated with the advent of nosocomial infections. We studied 3 populations of innate-like T-cells (γδ lymphocytes, NKT- and MAIT-cells) in septic patients and demonstrated that only the MAIT-cells presented a significant depletion following severe sepsis, the persistence of which was correlated with the advent of nosocomial infection. Last, using knockout mice, we analyzed the relative contribution of TLR2, TLR4 and TLR5 to the host response in a model of late-onset secondary Pseudomonas aeruginosa pneumonia following a sublethal polymicrobial sepsis. We observed that TLR2 deficient mice were specifically protected against the secondary pneumonia through a better bacterial clearance. Our results provide new insights in the pathophysiology of post-infective immunosuppression and suggest potential therapeutic applications
Dubois, Natasha. "Caractérisation de la réponse immune induite par un adjuvant comprenant un agoniste du TLR4 dans des modèles murins." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS131/document.
In 2014 tuberculosis (TB) surpassed HIV as the leading cause of death by an infectious disease worldwide emphasizing the urgent need to develop a more effective vaccine against this airborne disease. The Infectious Disease Research Institute (IDRI) TB candidate vaccine ID93/GLA-SE is currently undergoing a Phase IIa clinical trial and has shown promising preclinical and clinical results. In murine models of TB this vaccine drives a strong CD4 TH1 response, which is thought to be important for protection against TB, and an IgG2c skewed B cell response. However, little is known about the cellular and molecular events that drive GLA-SE adjuvanticity.To that end, the main objective of my thesis was to elucidate the key mechanisms that connect innate and adaptive immune responses elicited by this adjuvant in the murine model. A secondary objective was to evaluate the possibility of using ID93/GLA-SE as adjunct therapy to existing antibiotic treatments to reduce relapse rates after TB treatment.Collectively the results obtained during this research project and thesis broaden our knowledge and our current understanding of the mechanisms involved in the adaptive immune response induced by GLA-SE and show the capacity of ID93/GLA-SE to be used as a therapeutic vaccine against TB to reduce post-therapeutic relapse rates
Alyanakian, Marie-Alexandra. "Rôles de l'immunorégulation et de l'environnement dans la physiopathologie du diabète auto-immun." Paris 5, 2006. http://www.theses.fr/2006PA05D030.
The major focus of our studies was the analysis the role of immunoregulation in the development of autoimmune diseases and more particularly of autoimmune insulindependent diabetes. To that aim we have used the experimental model of the NOD (non obese diabetic) mouse. We have developed our work around two essential themes. First, the detailed analysis of the phenotypic and functional characteristics of the main T cell subsets that control autoimmune responses. We have also attempted to study more in depth their antigen specificity using an adoptive transfer model. Secondly, we have described original models showing the protective effect on the development of autoimmune diabetes of certain components of infectious agents. The analysis of the immune mechanisms affording this protection revealed that regulatory T lymphocytes play a central role in the induction and/or the maintenance of the protective effect
Kiaf, Badr. "Les lymphocytes MAIT induisent l'inflammation, la dysbiose et le diabète de type 2 au cours de l'obésité." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC314/document.
Obesity and type 2 diabetes are associated with low-grade chronic inflammation. Immune cells are recruited and activated in several tissues, including adipose tissue, thereby contributing to insulin-resistance and diabetes. Recent studies described gut microbiota dysbiosis as a consequence as well as a driver of obesity and type 2 diabetes. Mucosaassociated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T-cell receptor restricted by the non-classical MHC class I molecule MR1 presenting bacterial ligands. In obese/T2D patients MAIT cells in blood and adipose tissue exhibit a pro-inflammatory profile. In the present study, we show that during high fat diet-induced obesity MAIT cells produce inflammatory cytokines in adipose tissue and the ileum and induce inflammation in these tissues by modifying other immune cell populations (i.e. macrophages, CD8 Taß cells, NK cells, LTreg, eosinophils and ILC2 in the adipose tissue and ILC2, ILC3 and LTreg in the ileum). These changes impair the function of both tissues leading to insulin resistance, glucose intolerance, impaired lipid metabolism and increased gut permeability. MAIT cells also impact gut microbiota dysbiosis during obesity and microbiota transfer experiments highlight a bidirectional crosstalk between MAIT cells and the gut microbiota leading to inflammation and gut leakage. Altogether these results reveal the major role of MAIT cells in promoting the development of type 2 diabetes during obesity
Ebbo, Mikaël. "Rôle des cellules lymphoïdes innées chez l'homme : analyse au cours de déficits immunitaires, pathologies auto-immunes et inflammatoires." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0398.
Innate lymphoid cells (ILCs) are recently identified components of the immune system, but their functions in vivo in humans are still elusive. In a first study, we show in patients with common variable immunodeficiency that non-infectious inflammatory complications and severe bacterial infections were more frequent in patients with severe NK cell lymphopenia, indicating potential non-redundant immune functions of NK cells when the adaptive immune response is not optimal. In a second study, we observe that in patients with ɣc and JAK3 severe combined immunodeficiencies, all ILC subsets are absent. After hematopoietic stem cell transplantation, ILCs remain indetectable with no susceptibility to disease, suggesting that ILCs might be redundant and dispensable in humans, if T and B cells functions are preserved. In the second part of this thesis, we study phenotypic and functional modifications of NK cell compartment in primary immune thrombocytopenia. Interferon gamma production by the peripheral blood NK cells of ITP patients is decreased. In contrast, splenic NK cells of ITP patients tend to be more efficient in antibody-dependent cell cytotoxicity. Intravenous polyvalent immunoglobulins lead to the inhibition of blood NK cell activation. Finally, we present the preliminary results of a study investigating the modifications of circulating ILCs in IgG4-related disease, and present an extensive litterature review concerning the role of ILCs in inflammatory diseases. In conclusion, the apparent redundancy of ILCs for protective immunity and their pathogenic role in inflammatory diseases make their targeting in humans for therapeutic purposes particularly promising
Pham, Van Linh. "Modulation de la réponse immunitaire par des agonistes de la voie de signalisation TLR/IL - 1R dans le modèle d'asthme." Paris 5, 2010. http://www.theses.fr/2010PA05T013.
In our experimental work focusing on the immunoregulation response in a model of asthma, we showed firstly that the basophils were activated by double-stranded RNA poly(A:U) and that this stimulation exacerbated asthmatic responses in vivo. We then investigated the modulation of asthmatic responses using natural and synthetic ligands of TLR/il1r signaling pathway. The results showed that R848, a synthetic TLR7 agonist which promotes Th1 antiviral responses, and IL-33, which is known to favor Th2 responses, activated NKT cells whose rapid and modulated production of cytokines suggested that these cells might have a modulatory effect in asthma. We demonstrated that NKT cells have a regulatory function on development and activity of newly identified Th17 cells. Finally we described the protective and suppressive effects by R848 in the model of asthma and showed that suppression effects were dependent on regulatory T cells and the TGF-β
Grimaldi, David. "Mécanismes cellulaires et moléculaires de l'immunodépression post-infectieuse." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00924659.
Lopez-Lastra, Silvia. "Humanized Mice as Models to study Human Innate Immunity and Immunotherapies." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS039/document.
Animal models have extensively contributed to our understanding of human immunobiology and to uncover the underlying pathological mechanisms occurring in the development of the disease. However, mouse models do not always reproduce the genetic complexity inherent in human disease conditions. Human immune system (HIS) mouse models that are susceptible to human pathogens and can recapitulate human hematopoiesis provide one means to bridge the interspecies gap. Severely immunodeficient host mice support life-long, high level human hematolymphoid development after engraftment with human hematopoietic stem cells (HSC). However, the differentiation and function of some blood cell types, including innate lymphoid cells (ILCs), is poorly characterized in current HIS mice. Here we describe the development of a novel HIS mouse model, named BRGSF, which demonstrate enhanced maturation, function and homeostasis of human natural killer (NK) cells and other ILCs. Furthermore, the BRGSF-based HIS mouse model recapitulated the developmental stages of human ILCs. We could identify for the first time an ILC precursor (ILCP) population that is present both in HIS mice and in human peripheral blood as well as in several lymphoid and non-lymphoid human tissues. This circulating human ILCP population may provide a substrate to generate mature ILCs in tissues in response to environmental stressors, inflammation and infection. In a second part of the thesis we used BRGS immunodeficient mice to assess two innate lymphocyte-based immunotherapeutic approaches for treating EGFR-expressing KRAS-mutated colorectal carcinoma in vivo. The first model used a combination of umbilical cord blood (UCB)-derived NK cells and the monoclonal antibody cetuximab to promote antibody dependent cell cytotoxicity (ADCC) against the tumors. In a second model, we evaluated the therapeutic suitability of novel bispecific VHH constructs that combine inhibition of the EGFR with the target-specific activation of effector Vγ9Vδ2-T cells. These studies highlight the utility for HIS-based mouse models to understand human innate lymphocyte development and to harness these potent effectors for anti-tumor therapies
Fathallah, Ikbal. "Characterization of the molecular mechanisms of Epstein-Barr Virus-mediated inhibition of the innate sensor TLR9." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10323.
Chronic infection causes about 15-20% of cancer worldwide. In most cases, infections are cleared by the immune system with no dramatic consequence for the infected hosts. However, oncoviruses can escape the immune system and induce cellular transformation, two key events in cancer mediated by viruses. EBV is a ubiquitous double-stranded DNA herpesvirus, which infects more than 90% of the population with a specific tropism to B-cells. Upon primo-infection the virus persists in the host for lifetime. EBV is responsible of the benign infectious mononucleosis and is associated to several malignancies such as the Burkitt lymphoma, Hodgkin’s lymphoma and some forms of gastric cancers. Mammalian Toll-like receptors (TLRs) play a key role in host defense during pathogen infection by regulating and linking the innate and adaptive immune responses. TLRs belong to a family of receptors that recognize pathogen-associated molecular patterns and are expressed on immune and non-immune cells, endowing them with the capacity to sense pathogen-derived products and to alert the immune system . In this study we show that EBV can alter the regulation and expression of TLR9, one of the key effector molecules of the innate immune response. EBV infection of human primary B cells resulted in the inhibition of TLR9 functionality. Stimulation of TLR9 on primary B cells led to the production of IL-6, TNFα and IgG, which was inhibited in cells infected with EBV. We observed that EBV exerts its inhibitory function by decreasing TLR9 mRNA and protein levels. This event was observed twelve hours post EBV infection of primary cells as well as in an immortalized B cell line, demonstrating the specific role of the virus to turn down TLR9 levels. In addition, we determined that the EBV oncoprotein LMP1 is a strong inhibitor of TLR9 transcription. Over expression of LMP1 by transient transfection or transduction of B cells, reduced TLR9 promoter activity, mRNA and protein levels. Blocking the NF-κB pathway induced by LMP1 signaling, recovered TLR9 promoter activity and protein expression. Moreover LMP1 mutants deficient in activating the NF-κB pathway inversely restored TLR9 transcription. Taken together, our study reveals a novel mechanism used by EBV to suppress the host immune response by deregulating the TLR9 transcript through LMP1-mediated NF-κB activation
Massot, Bérangère. "ETUDES DE POPULATIONS LYMPHOCYTAIRES T NATURELLES : iNKT17 et Th17." Phd thesis, Paris 5, 2012. http://tel.archives-ouvertes.fr/tel-00738051.
Sanchez, Carole. "Analyse des sous populations lymphocytaires, et plus particulièrement les cellules NK, dans la polyglobulie primitive." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5059/document.
Characterized by the presence of the JAK2 V617F mutation, polycythemia vera's development is content by phlebotomy but is associated with a higher incidence of cancer. A global exploration of the immunity of patients was performed by quantification of lymphocyte subpopulations of innate and adaptive immunity. This allowed the detection of a decrease in B cells and an increase in NK cells. NK cells are known for their antitumor properties but they are not yet able to eradicate PV, raising the question of their functional abilities. If NK cells of patients have a lower basal cytotoxic activity than healthy donors, they do not show abnormal expression of their receptors, the production of cytolytic molecules or proliferation. On the contrary, NK cells from a patient who developed erythroleukemia or NK cells from elderly healthy donors compared with younger healthy donors exhibit abnormalities of receptors expression. The increase in NK cells could be related to the JAK2 V617F mutation. If the mutation is present in cells of all patients, there are arguments for its presence in the NK cells of some patients. Finally, transcriptome analysis has identified an expression profile specific to NK cells of patients
Verrier, Thomas. "Function and plasticity of NKp46 expressing innate lymphoid cells." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC173/document.
Group 3 Innate Lymphoid cells (ILC3) actively maintain mucosal homeostasis through the production of Interleukin-22 (IL-22). ILC3 encompass 2 major populations, LTi (« Lymphoid Tissue inducer »), characterized by the expression of the chemokine receptor CCR6, and ILC3 that express the transcription factor T-bet, which include a population expressing the surface marker NKp46, a receptor originally used to identify group 1 ILC (ILC1). ILC1 plays a major role in the defense against intracellular pathogens and anti-tumoral responses. Three major ILC1 populations have been identified: the cytotoxic lymphocytes « Natural Killer » (NK or ILC1b), which largely rely for on the transcription factor Eomes their generation and express the integrin CD49b; hepatic and intestinal ILC1 that depends on the T-bet transcription factor and express CD49a (ILC1a); and a population that expresses CD49a and CD49b (ILC1ab) and populates the salivary gland and the uterus, which is independent of the transcription factor Nfil3. My work aimed to understand the biology of NKp46 expressing ILC, as well as factor involved in their development, maturation and function. The major part of my work focuses on NKp46+ ILC3. First, we demonstrate a major role for the chemokine receptor CXCR6 in their localisation in the lamina propria villi (Satoh-Takayama et al. 2014). Second, I showed that NKp46+ ILC3 could lose NKp46 expression (Verrier et al. 2016). Induced by TGFβ, this loss of expression was associated with higher IL-22 production and by the acquisition of markers identifying LTi (CCR6, MHC-II), demonstrating NKp46+ ILC3 plasticity. Finally, in collaboration with Rachel Golub’s group, we confirmed a putative role for Notch-signaling in this plasticity (Chea et al. 2016). In this manuscript, I will discuss the development and the heterogeneity of ILC3, ILC1a, ILC1b and ILC1ab. All the results I generated support a dynamic vision of ILC biology, which reflects how they adapt in response to environmental cues. By characterizing the different actors involved in this dynamic process, my work could be used to design therapies aiming at controlling the equilibrium between these different populations in diverse pathologies such as cancer, viral infection, or intestinal diseases