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OLDENHOVE Guillaume
Units
Person in charge of the Unit : Oui
Projetcs
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.
The innate immune response in infection and cancer (starting in 2014)
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.
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.
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.
