Uterine regulatory T cells and dendritic cells cross-talk to ensure a tolerogenic environment during mouse early pregnancy

Event Abstract Back to Event Uterine regulatory T cells and dendritic cells cross-talk to ensure a tolerogenic environment during mouse early pregnancy Laura M. Florez1*, Maria Grazia Ruocco1, Tristan Courau1, Gwladys Fourcade1, Djamel Nehar1 and David Klatzmann1, 2 1 Université Pierre et Marie Curie Paris VI, Sorbonne Universités, UMR 7211 UPMC- FRE3632 CNRS – U 959 INSERM, France 2 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Biotherapies and the Clinical Investigation Center in Biotherapy, France Understanding the evolutionary adaptation of the immune system to the developing fetus and placenta represents one of the most fascinating and physiological models to study immune tolerance. Indeed, the maternal-fetal interface (i.e. the decidua, the place where the maternal immune system first encounters the fetal antigens) is populated by several types of maternal leukocytes during pregnancy. Among them, the role of T lymphocytes remains particularly poorly understood. Specially, Foxp3+CD4+CD25high regulatory T (Tregs) cell subset is thought to play a crucial role during gestation. In fact, depletion of Tregs leads to fetus rejection in mice, while in humans, deficient Treg numbers have been observed in pregnancies with immune-related complications. Moreover, numerous studies have reported increased numbers of Tregs during pregnancy in lymph nodes and blood. However, the activation and function of Tregs at the maternal-fetal interface remains unknown. Critically, the activation of maternal T cells with fetal/placental specificity is thought to be mediated by a potent type of antigen-presenting cells (APCs), known as dendritic cells (DCs). Prior to pregnancy, these cells provide protection to the uterus from infection. In this context, the uterine DC population present at the time of implantation might be expected to pose the greatest immunological threat to fetus survival. In mouse, DCs have been shown to be entrapped within the decidua, minimizing immunogenic T cell exposure to fetal antigens in the draining lymph nodes. Understanding how uterine DCs fail to initiate immunogenic T-cell responses to placental antigens will provide a significant new perspective into the long-standing immunological paradox of feto-maternal tolerance. We hypothesize that uterine DCs will privilege the priming of Tregs rather than the activation of effector T cells, thus, providing a tolerogenic environment to the growing fetus. In this work, we use transgenic mouse models, transcriptome analysis, flow cytometry, confocal and intravital two-photon microscopy to characterize the uterine Treg and DC populations and their interactions at the maternal-fetal interface and in the uterine draining lymph nodes. We study when, where and how Tregs and DCs are activated during the early phases of embryonic development, and how they contribute to establish and maintain tolerance throughout gestation. In order to investigate when priming occurs we first analysed by flow cytometry the DC and Treg populations in the uterus and lymph nodes of mice from day 0 to 12 of pregnancy. Interestingly, we found that only in the uterus Tregs up-regulate CTLA-4 as soon as embryo implantation occurs compared to the draining lymph nodes, suggesting the existence of distinct activation pathways between uterine and lymphatic Tregs. Moreover, activation of Tregs correlated with the acquisition of a tolerogenic phenotype by uterine DCs characterized by down-regulation of their co-stimulatory and antigen presenting molecules CD80, CD86 and MHCII in the uterus. Next we analysed the dynamic behavior of GFP+Tregs and YFP+DCs in the uterus and lymph nodes of pregnant mice by intravital two-photon microscopy. We observed that DCs became activated and established strong interactions with Tregs in the uterine draining lymph nodes, as early as day 7 of pregnancy, i.e. 2.5 days after embryo implantation. These results are in line with the previous published work from our laboratory showing that CD44highCD62low activated memory Tregs appear as early as three days post implantation of the embryo in the uterine draining lymph nodes. Interestingly, this work has also opened up new avenues of investigation concerning the potential non-immunological and trophic function of DCs in the uterine response to implantation itself. In conclusion, we identify a Treg/DC crosstalk both at the maternal-fetal interface and in the lymph nodes that contributes minimizing the pathological activation of effector T cells during pregnancy. Our findings provide a better understanding of the mechanisms necessary for the establishment of maternal-fetal tolerance and have important therapeutic implications for immune-mediated pregnancy complications. Acknowledgements We thank Gerard Chaouat for discussions. The Institut de la Moelle et du Cerveau (ICM) and The College de France for their Imaging facility. This work was supported by a Marie-Sklodowska Curie grant and a Dim Biotherapies and Ile-de-France Region grant. Keywords: regulatory T cells, Dendritic Cells, Maternal-fetal tolerance, Pregnancy, priming, Reproduction Immunology, tolerance mechanisms Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Oral Presentation Topic: Immunology of reproduction Citation: Florez LM, Ruocco M, Courau T, Fourcade G, Nehar D and Klatzmann D (2015). Uterine regulatory T cells and dendritic cells cross-talk to ensure a tolerogenic environment during mouse early pregnancy. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00336 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Apr 2015; Published Online: 15 Sep 2015. * Correspondence: Miss. Laura M Florez, Université Pierre et Marie Curie Paris VI, Sorbonne Universités, UMR 7211 UPMC- FRE3632 CNRS – U 959 INSERM, Paris, 75651 Paris CEDEX 13, France, lauraflorezco@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Laura M Florez Maria Grazia Ruocco Tristan Courau Gwladys Fourcade Djamel Nehar David Klatzmann Google Laura M Florez Maria Grazia Ruocco Tristan Courau Gwladys Fourcade Djamel Nehar David Klatzmann Google Scholar Laura M Florez Maria Grazia Ruocco Tristan Courau Gwladys Fourcade Djamel Nehar David Klatzmann PubMed Laura M Florez Maria Grazia Ruocco Tristan Courau Gwladys Fourcade Djamel Nehar David Klatzmann Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.