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Immunobiologie (anciennement Physiologie animale) [Immunobiology (formerly Animal Physiology)]
Faculté des Sciences / faculty of Sciences - Biologie moléculaire (unité ULB139)

Cette unité de recherche s'intéresse à l'immunologie fondamentale, une discipline au coeur de plusieurs techniques de biologie moléculaire de pointe et de nombreux problèmes médicaux: vaccination, transplantation d'organes, traitement du cancer, maladies auto-immunes, inflammation et allergie.L'équipe cherche à mettre en évidence des facteurs susceptibles d'induire, de renforcer, de limiter ou d'inhiber la réponse immunitaire. L'objectif est de parvenir à adapter la réponse immunitaire aux exigences de situations médicales spécifiques: maladies auto-immunes, transplantation d'organes, immunothérapie du cancer.



coordonnées / contact details


Immunobiologie (anciennement Physiologie animale) [Immunobiology (formerly Animal Physiology)]
tel +32-2-650.98.61, fax +32-2-650.98.60, idecot@ulb.ac.be
http://www.ulb.ac.be/ibmm/immunologie.html
Campus de Charleroi - Gosselies (Biopark), IBMM - niveau 3 - AW.3.101
CP300, rue des Professeurs Jeener et Brachet 12, 6041 Charleroi (Gosselies)

Pour en savoir plus, consultez le site web de l'unité.



responsables / head


Prof. Muriel MOSER Prof. Oberdan LEO Fabienne ANDRIS Guillaume OLDENHOVE


composition / members


Valérie ACOLTY Charlotte BISILLIAT DONNET Delphine DEBUISSON Jean DE CLERCQ Isabelle DECOT Sébastien DENANGLAIRE Maxime DHAINAUT Véronique DISSY Adrien GALUPPO Aurélie HANOTEAU Coralie HENIN Mélanie HERCOR David HUTIN Tiphène PIRNAY Nicolas PREYAT Hussein SHEHADE Martina STEFKOVA


projets / projects


Développement et fonction des cellules ''T helper'' dans la production d'anticorps in vivo [Development and function of helper T cells for antibody production in vivo]
voir version anglaise [Humoral immune protection against pathogens relies on the development of high affinity antibodies produced by activated B cells that differentiated further in memory B cells or long-lived plasma cells. This process takes place in the germinal centers and depends on a subset of CD4+ T cells called T follicular helper (Tfh). Although many studies are devoted to this novel T helper cell population, the molecular mechanisms governing Tfh cell differentiation have yet to be characterized and better understanding of this crucial immune process would have major implications in immune disease treatment and vaccine formulation. In particular modulating Tfh cell activation in vivo may help to develop long term humoral responses that lack allergic, IgE-mediated side effects. Our research group has demonstrated IL-6 promotes the differentiation of naïve T cells into follicular helper T cells. IL-6 appears to control Tfh differentiation in a STAT3 dependent fashion, suggesting an important role for this transcription factor in the control of humoral responses. STAT3 activation also allowed the conversion of Th2 cells into Tfh cells, suggesting that some 'plasticity' exist between T helper cells and highlighting a possible role for the IL-6 / STAT3 signaling pathway in the conversion of pathogenic allergic (IgE) Th2 responses into protective (IgG) humoral Tfh responses.Our current research objective is to identify the molecular mechanism by which STAT3 controls T cells differentiation. In particular, our project aims at understanding the functional relationship between STAT3 and other transcription factors (such as BCL6 and cMAF) known to play a role in T follicular helper differentiation and function. Finally, based on recent finding indicating a role for cell metabolism in the control of T cell differentiation, we plan to explore the possible relationship between intracellular levels of important metabolites (such as NAD and ATP) and STAT3 activation. This novel avenue of research may shed light on a possible link between the nutritional status and the development of humoral immune responses, a finding of potential clinical relevance in the field of vaccination. ]

Lymphocytes T régulateurs [Regulatory T cells]
voir version anglaise [Interest in regulatory T cells (Treg) has exploded since the discovery by Sakaguchi and colleagues of a minor population of CD4+ T cells which expresses Foxp3 and plays a central role in the prevention of autoimmune reactions in vivo.'Natural Treg cells' develop in the thymus, are present in naïve animals and their depletion causes the development of a spectrum of autoimmune disorders. By contrast, 'adaptive or induced' Treg cells develop in peripheral lymphoid tissues. TGF-beta and IL-10 may be involved in the conversion of T cells into CD4+ Foxp3+ displaying suppressive activity. Our laboratory has undertaken studies to evaluate the role of natural Treg cells in the control of humoral and cellular responses.Our results show that thymicTreg cells exert a feedback mechanism on antibody secretion by selectively dampening the T cell help for B cell activation, and downregulate activation of Th1-type responses.The biological basis of Treg cell suppression is still elusive.Using various in vivo and in vitro models, we will investigate the molecular mechanisms underlying their function, and in particular:' Their capacity to inhibit dendritic cell function. We recently found that Treg selectively inhibit thepro-Th1 CD70/CD27 pathway, while sparing interleukin 12 production. We will analyze how the CD27 receptor inhibits CD70 expression on the plasma membrane of dendritic cells. Our data suggest that the CD27 receptor inhibits its own ligand, possibly by inducing its endocytosis in DCs, resulting in impaired Th1-prone CD70 costimulation.' The role of CD27 on the development/function in vivoof Tregs (which express higher levels of CD27 than naïve T cells)in steady state and inflammatory conditions' The roleof the CD39-CD73 axis on the function of Tregswhich overexpress CD73, an ecto-5'-nucleotidase acting in tandem with CD39 (an ecto-ATPase) to produce extracellular adenosine. This purine nucleoside has been shown to inhibit T cell activation. We will analyze the function of the CD39 and CD73 receptors in the homeostasis of the intestinal tract.' The role of the negative receptor PD-1 on the function of Tregsin vivo, and in particular on their capacity to inhibit the migration/function of effector T cells into the tumor bed, using the P815 mastocytoma of DBA/2 mice.]

NAD Métabolisme cellulaire et régulation des réponses immunes [NAD metabolism and regulation of immune responses]
voir version anglaise [During a study aiming at the identification of genes selectively expressed by immune cells, our laboratory has identified over a decade ago the gene coding for a nicotinamidephosphoribosyltransferase (Nampt), an enzyme involved in NAD biosynthesis. Of interest, expression of this gene was found upregulated following antigen stimulation of both innate and adaptive cells. These observations, independently confirmed by others, led us to further explore the possible relationship between NAD metabolism and the control of immune responses. Nicotinamide adenine dinucleotide (NAD) has been known for several decades to play a major role as a coenzyme in numerous oxidation-reduction reactions. Recently however, the distinct role of NAD as a precursor for molecules involved in regulatory processes has also been recognized. Numerous enzymesinvolved in post-translational modification of target proteins and using NAD as a substrate have been identified in mammals and include mono and poly (ADP-ribosyl) transferases (respectively mARTs and PARPs) and deacylases such as Sirtuins. This later family comprises seven members (SIRT1 to SIRT7), whosedeacylase activity appears as strictly linked to intracellular NAD levels. Though the modulation of intracellular NAD levels, Nampt appears therefore to play an important role in the regulation of sirtuin activity. Notably, sirtuins have recently attracted great interest following the demonstration that they may play a role in cell longevity and responses to stress. Based on these considerations, we have undertaken a series of research projects to evaluate the role of the Nampt-NAD-sirtuin axis in the regulation of an immune response. These studies have led to the discovery of the important role of Nampt in lymphocyte development and in the control of TNF (an important pro-inflammatory factor) secretion. Our current studies aim at identifying the role of sirtuins in other aspects of immune regulation including T lymphocyte activation and differentiation. ]

Réponse immunitaire innée dans l'infection et cancer (débuté en 2014) [The innate immune response in infection and cancer (starting in 2014)]
voir version anglaise [The innate immune response is the first line of defense against infections. The innate immune system recognizes pathogens and contributes to their elimination by a diversity of mechanisms. However, an excessive or dysregulated innate response can result in tissue damage and cause pathology. Therefore, a delicate balance needs to be established between the activation and regulation of the immune response in the context of infection.The innate immune system also plays critical roles in cancer initiation, development and metastasis. Depending on the tumor microenvironment, the immune system can either contribute to the elimination of the tumor, or support tumor growth. The molecular mechanisms that determine the anti-tumoralvs. tumor-supporting properties of the immune system are still poorly understood.We use two complementary approaches to address these questions:1) We use mouse models, which can be easily manipulated genetically and experimentally in the laboratory, in order to understand the general principles that govern the mammalian innate immune responsein vivo.2) Mice and humans are separated by ~180 million years of divergent evolution. As a consequence,major differences exist between the immune systems of these two species and frequently, knowledge gained from animal studies cannot be directly translated in the human species. Furthermore, obvious practical and ethical barriers restrict experimentation on human subjects in vivo. To circumvent these limitations, we developed novel models of mice repopulated with a functional human immune system (so-called 'humanized mice'), which combine the advantage of a small animal model with the specificities of the human species. Our work consists in (a) developing and characterizing improved models of humanized mice; and (b) using these models to understand the cellular and molecular mechanisms of the human immune response to infection and cancer in vivo.]

Immunité intestinale [Intestinal Immunity]
voir version anglaise [In microenvironments such as the gastrointestinal tract, in which immune reactivity against intestinal flora or dietary antigen poses a significant risk to the host, immunosuppressive, regulatory elements predominate to suppress local inflammation. Nevertheless, even in highly regulated sites, immune responses need to occur to allow proper control of microbial expansion. How mucosal immune responses inside this tolerance-prone environment are regulated remains largely elusive.ATP is one of the universal cell energy metabolite and functions also as extracellular signaling molecules. In the immune system, extracellular ATP works as a 'danger' signal. The ATP sources are multiple: in particular, cell damage leads to a marked increase in the ATP concentration in the immediate extracellular milieu and intestinal bacteria are able to generate and secrete large amounts of ATP. These observations suggest that, inside the intestine, where T cells are chronically activated and in close contact with intestinal flora, the extracellular ATP generation needs to be tightly regulated to avoid excessive immune activation leading eventually to immunopathology.There is evidence that intestinal T cells are able to mediate extracellular ATP catabolism via the expression of two ectonucleotidase: CD39 and CD73. This capacity to remove ATP from the extracellular space and to generate adenosine seems to negatively regulate the intestinal immune response.Ourfirst objective is therefore to study the role of adenosine in the regulation of mucosal immune responses, including the differentiation and effector function of helper T cells and regulatory T cells.Secondly, inflamed tissue can become hypoxic. T cells are able to sense hypoxia by the Hypoxia inducible transcription factor (HIF-1), a heterodimeric protein composed of two subunits: HIF-1α and HIF-1β.Our second objective is to test whether specialized T helper subsets are differentially adapted to hypoxia and how these inflammatory effector cells can operate in a hypoxic tissue. Understanding the immunomodulatory role of adenosine and the mechanisms underlying immune cell adaptation to hypoxia would help to identify the cellular and molecular pathways involved in immunoregulation in normal, inflamed or cancerous tissues.]

Immunothérapie du cancer [Cancer immunotherapy]
voir version anglaise [There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of our study is to better understand how the host immune system is involved in the success of chemotherapy. We use the P815 mastocytoma of DBA/2 mice, as this tumor is poorly immunogenic, expresses well defined antigens and can elicit the differentiation of T cells specific to tumor-associated and/or tumor-specific antigens in some conditions. We have shown recently that treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long-term protection in a CD4- and CD8-dependent manner. A population of inflammatory-type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4-dependent infiltration, in tumor bed, of tumor-specific CD8+ T lymphocytes. Our data point to a major role of CD4+ T cells in inducing chemokine expression in the tumor, provoking migration of tumor-specific CXCR3+ CD8+ T lymphocytes.Importantly, the analysis of CD8+ T cells specific to P1A/H-2Ld and P1E/H-2Kd revealed that cyclophosphamide altered the P815-specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen. This question is of major importance for immunotherapy to define the role of tumor-associated (encoded by cancer-germline gene) versus tumor-specific (encoded by a mutated gene) antigens as tumor rejection antigens.Collectively our observation reinforce the concept that chemotherapy relies on the immune response to achieve full remission in an experimental tumor model and suggest that that in some instances, chemotherapy may achieve long term effects by favoring the establishment of an immune, memory-like anti-tumor response. Future experiments will attempts to better understand the mechanism whereby chemotherapeutic agents such as cyclophosphamide allow the establishment of an effective immune response to tumor antigens. ]



publications





theses


PREYAT Nicolas -Tumor necrosis factor-induced necroptosis is regulated by nicotinamide adenine dinucleotide in a sirtuin-dependent manner 2013, 2013

HESPEL CINDY - Régulation de la réponse immunitaire adaptative par les cellules dendritiques conventionnelles et inflammatoires - 2012, 2012

WATHELET NATHALIE - Etude de l'effet du cyclophosphamide sur la réponse immunitaire spécifique du mastocytome P815 - 2012, 2012

RAHIR GWENDOLINE - Étude des mécanismes cellulaires et moléculaires impliqués dans la résistance anti-tumorale in vivo induite par le cyclophosphamide - 2012, 2012

WELSBY IAIN - PARP12, a novel interferon stimulated gene potentially involved in the control of protein translation and innate immunity - 2012, 2012

DENOEUD JULIE - Etude des mécanismes cellulaires et moléculaires impliqués dans la fonction suppressive des lymphocytes T régulateurs - 2010, 2010

MAYER ALICE - Rôle de l'interleukine-6 et de l'AMP-activated protein kinase dans la régulation des réponses immunes - 2010, 2010

GALLI MARA - Rôle du métabolisme du NAD dans la réponse immune - 2010, 2010

DE FAUDEUR GEOFFROY - L'indoléamine 2, 3-dioxygénase et la différenciation et maturation des cellules dendritiques - 2009, 2009

BAUP DELPHINE - Identification de gènes préférentiellement exprimés par les cellules dendritiques et évaluation critique d'une approche de transgenèse lentivirale afin d'en étudier la fonction biologique in vivo - 2009, 2009

COQUERELLE Caroline - Contrôle des réponses immunitaires de type Th1 par les lymphocytes T régulateurs naturels et induits - 2008, 2008

VAN GOOL Frédéric - Métabolisme du NAD et contrôle de la réponse inflammatoire 2008, 2008

LANAYA Hanane ''Rôle des cellules lyéloïdes immatures GR1 + CD11b+ dans le rejet du mastocytome P815'' 2008, 2008



collaborations


Thierry Boon, Pierre Coulie, Benoit Vanden Eynde, Ludwig Institute for Cancer Research/UCL, Woluwe, Belgique

Kris Thielemans, VUB, Bruxelles, Belgique

Fabrice Bureau, Université de Liège/ULg, Liège, Belgique

Dr. Benoît Viollet, Institut Cochin, Paris, France

Jeffrey A. Bluestone, University of California/UCSF, San Francisco, Etats-Unis (USA)

Andrew Mellor, Medical College of Georgia, Augusta, Etats-Unis (USA)

Dr Marcelle Van Mechelen, GlaxoSmithKline Biologicals, Rixensart, Belgique

Yasmine Belkaid, NIH, Mucosal Immunology Section, Bethesda, Etats-Unis (USA)

Jeff Bluestone, UCSF, San Fransisco, Etats-Unis (USA)

Jannie Borst, The Netherlands Cancer Institute, Department of Immunology, Amsterdam, Pays-Bas

Georges Kassiotis, Medical Research Council National Institute for Medical Research, London, Grande-Bretagne

Warren J Leonard, N.I.H., Bethesda, Etats-Unis (USA)

Roberto Maldonado, Harvard Medical School, Selectabio, Boston, Etats-Unis (USA)

Andrew Mellor, Georgia Health Sciences University, Augusta, Etats-Unis (USA)

Pedro Romero, Université de Lausanne, Lausanne, Suisse

Anthony Rongvaux, Yale University, New Haven, Etats-Unis (USA)

Tim Sparwasser, Institute of Infection Immunology, Hannover, Allemagne

Hideo Yagita, Juntendo University School of Medicine, Department of Immunology, Tokyo 113-8421, Japon



savoir-faire/équipements / know-how, equipment


Analyse des réponses immunitaires in vitro et in vivo

Analyse et tri cellulaire par cytométrie de flux.

Immunohistochimie.

Modèles inflammatoires in vivo : colites, diabète, tumeurs.

Production d'anticorps polyclonaux et monoclonaux.

Transfert de gènes dans des cellules du système immunitaire.



mots clés pour non-spécialistes / keywords for non-specialists


cellules présentatrices d'antigène contrôle des réponses inflammatoires immunothérapie du cancer lymphocytes b et t réponses immunitaires innées


disciplines et mots clés / disciplines and keywords


Biologie cellulaire Immunologie

anticorps atp cancer cellules t régulatrices centres germinatifs flore intestinale hif immunologie immunothérapie inflammation intestin régulation réponse innée sirtuine souris humanisées tfh


codes technologiques DGTRE


Cancérologie, oncologie Hématologie, fluides extracellulaires Immunologie, sérologie, transplantation Infections