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    IL-7 in mucosal Immunity

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    The mucosal-associated immune system is an essential part of the organism's defenses against pathogenic infections. In recent years, the laboratory has identified interleukin-7 (IL-7) as a cytokine produced by mucosae during the first few hours after infection (Ponte et al., 2017). However, we have also demonstrated that this cytokine is able to recruit immune cells to tissues (Beq et al 2009) and thus could play a role in the establishment of mucosal immune responses. The purpose of this part of the laboratory project is to better understand the mechanisms implicated in the mucosal response to infections. We study the mechanisms involved in the production of IL-7 in tissues and its consequences on mucosal physiology. We are also exploring the use of IL-7 as a mucosal vaccine adjuvant to stimulate the development of strong and prolonged mucosal immunity allowing an effective protection at the portals of entry for pathogens in the body.

     

    Mechanisms of action of IL-7 in the digestive mucosa

    Principal investigator: Anne Couëdel-Courteille (MCU Paris Diderot)

    Contact anne.couedel@inserm.fr - tel: +33 1 40 51 65 41

    Aims

    Our previous experiments in acutely SIV-infected rhesus macaques (Ponte et al. 2017) demonstrated the existence in vivo of cells able to produce diverse chemokines in response to IL-7 stimulation in the intestinal mucosa. This mucosa contains cells from the immune system (T-cells and APCs), known to express the IL-7 receptor and capable of producing chemokines. However, other stromal cell types, which participate to the architecture of the intestinal mucosa (epithelial cells and fibroblasts), as well as cells constituting the wall of vascular and lymphatic vessels (endothelial and smooth muscle cells), can also express this receptor under inflammatory conditions and could favor the recruitment of immune cells during early viral infection.

     

    Questions

    The objectives of this project are to identify the cells of the intestinal mucosa capable of responding to IL-7 and to analyze their contribution to the cell migrations observed in the intestinal mucosa following stimulation by IL-7 in vivo.

    Lymphocyte infiltration in the ileal mucosa from SIVmac-infected macaques. T-cells were labeled with anti-CD3 (red), anti-CD4 (red, left panel) or anti-CD8 (red right panel). Cell nuclei were labeled with DAPI (blue)

     

    Signal transduction downstream the IL-7 receptor in stromal cells

    Principal investigator: Magali Mas (MCU Paris Descartes)

    Contact magali.mas@inserm.fr - tel : +33 1 40 51 65

    Aims

    Signal transduction pathway downstream of the IL-7 receptor (IL-7R), well described in T lymphocytes, results, via the activation of the JAK/STAT and PI3K pathways, in the stimulation of cell survival, as well as in the increase of cell metabolism and cell proliferation, thus allowing a fine regulation of the T-cell homeostasis. However, the signal transduction pathway induced by IL-7 in stromal cells (epithelial cells, fibroblasts, endothelial and smooth muscle cells of the walls of the blood and lymphatic vessels ...) tissues remains unknown to be defined.

    Questions

    This part of the project aims at exploring signal transduction pathways in different stromal cell types, including endothelial cells and fibroblasts, in both Human and Macaque. These experiments will be performed by Western blot, immunostaining on tissue and protemomic analyses.

     

    IL-7 as a mucosal vaccine adjuvant

    Principal investigator: Magali Rancez (CR CNRS)

    Contact magali.rancez@inserm.fr - tel : +33 1 40 51 65 14

    Aims

    Like most viral and bacterial infections, HIV transmission principally occurs through mucosal barriers. But HIV viral dissemination is really rapid being detectable from the first hours following viral exposure (Ribeiro Dos Santos et al., 2011). In order to protect against infection through vaccination, developing a strong mucosal immune response is thus essential to block infection at the mucosal site, before dissemination. However, most commercial and experimental vaccines are administered through systemic route and do not specifically trigger mucosal immune responses. It is thus mandatory to develop specific adjuvants able to stimulate this kind of immunity in order to protect human populations against mucosally transmitted pathogens.

     

    Questions

    The aim of this part of the project is to develop an original approach to mucosal vaccination, based on the use of the new property of IL-7 identified in the laboratory (Beq et al., 2009). This project aims to exploit the capacity of IL-7 to induce, by stimulating the local production of chemokines, the massive relocation of the immune cells in the mucosae. This property of IL-7 will be used to enhance the uptake and presentation of mucosally administered antigens, leading to the establishment of a mucosal immune response. Through local production of neutralizing antibodies, such a protocol should block viruses at the portals of entry. These studies are carried out in both mice and PNH models.

     

     

    The team

    This work was performed by Rosalie Ponte and Sandrine Logerot (PhD students, Université Paris Descartes, ANRS), Suzanne Figueiredo-Morgado (engineer INSERM), Bénédicte Charmeteau de-Muylder (technician INSERM), and Master students.

     

    Main publications

     

    Ponte, R., M. Rancez, S. Figueiredo-Morgado, J. Dutrieux, V. Fabre-Mersseman, B. Charmeteau-de-Muylder, T. Guilbert, J.P. Routy, R. Cheynier and A. Couedel-Courteille. (2017) Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing. Front Immunol,. 8: p. 588.

    Rancez M., Couëdel-Courteille A. and Cheynier R. (2012) Chemokines at mucosal barriers, impact on HIV infection. Cytokine & Growth Factor Reviews. 23(4-5):233-43.

    Ribeiro Dos Santos P., Rancez M., Prétet J.L., Michel-Salzat A., Messent V., Bogdanova A., Couëdel-Courteille A., Souil E., Cheynier R. and Butor C. (2011) Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation. PLoS One. 6(5): e19493.

    Parker R., Dutrieux J., BeqS., Lemercier B., Rozlan S., Fabre-Mersseman V., Rancez M., Gommet C., Assouline B., Rancé I., Lim A., Morre M. and Cheynier R. (2010) Interleukin-7 Treatment Counteracts IFNa Therapy-Induced Lymphopenia and Stimulates SIV-specific CTL Responses in SIV-infected Rhesus Macaques. Blood; 116 :5589-99.

    Beq S., Rozlan S., Gautier D., Parker R., Mersseman V., Schilte C., Assouline B., Rancé I., Lavedan P., Morre M. and Cheynier R. (2009) Injection of Glycosylated Recombinant Simian IL-7 Provokes Rapid and Massive T-cell Homing in Rhesus Macaques. Blood, 114 :816-825.

    Beq S., Nugeyre M.T., Ho Tsong Fang R., Gautier D., Legrand R., Schmitt N., Estaquier J., Barré-Sinoussi F., Hurtrel B., Cheynier R. and Israël N. (2006) Interleukin-7 Induces Immunological Improvement in SIV-infected Rhesus Macaques under antiviral therapy. Journal of Immunology. 176: 914-922.

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