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1. A lentiviral vector expressing a dendritic cell-targeting multimer induces mucosal anti-mycobacterial CD4+ T-cell immunity

Author: François Anna, Jodie Lopez, Fanny Moncoq, Catherine Blanc, Pierre Authié, Amandine Noirat, Ingrid Fert, Philippe Souque, Fabien Nevo, Alexandre Pawlik, David Hardy, Sophie Goyard, Denis Hudrisier, Roland Brosch, Françoise Guinet, Olivier Neyrolles, Pierre Charneau, Laleh Majlessi, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-Forme d’Histopathologie / Histopathology Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Plateforme d'Innovation et de Développement de Tests Diagnostiques / Diagnostic Test Innovation and Development Core Facility, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was also supported by the Programmes Transversaux de Recherche (PTR # 52-17 from Institut Pasteur to L.M. and P.C.), the EU program TBVAC2020 (contract n°643381 to P.C.), CNRS, University of Toulouse, Agence Nationale de la Recherche/Program d’Investissements d’Avenir (ANR-11-EQUIPEX-0003 to O.N.), the Fondation pour la Recherche Médicale (DEQ20160334902 to O.N.), the Bettencourt Schueller Foundation (Grants Coup d’Élan pour la Recherche Française and Explore-TB to O.N.)., European Project: 643381,H2020,H2020-PHC-2014-single-stage,TBVAC2020(2015), Hardy, David, TBVAC2020, Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development - TBVAC2020 - - H20202015-01-01 - 2018-12-31 - 643381 - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract: International audience; Abstract Most viral vectors, including the potently immunogenic lentiviral vectors (LVs), only poorly direct antigens to the MHC-II endosomal pathway and elicit CD4 + T cells. We developed a new generation of LVs encoding antigen-bearing monomers of collectins substituted at their C-terminal domain with the CD40 ligand ectodomain to target and activate antigen-presenting cells. Host cells transduced with such optimized LVs secreted soluble collectin-antigen polymers with the potential to be endocytosed in vivo and reach the MHC-II pathway. In the murine tuberculosis model, such LVs induced efficient MHC-II antigenic presentation and triggered both CD8 + and CD4 + T cells at the systemic and mucosal levels. They also conferred a significant booster effect, consistent with the importance of CD4 + T cells for protection against Mycobacterium tuberculosis . Given the pivotal role of CD4 + T cells in orchestrating innate and adaptive immunity, this strategy could have a broad range of applications in the vaccinology field.
Published: 2022
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2. Mice Humanized for MHC and hACE2 with High Permissiveness to SARS-CoV-2 Omicron Replication

Author: Fabien Le Chevalier, Pierre Authié, Sébastien Chardenoux, Maryline Bourgine, Benjamin Vesin, Delphine Cussigh, Yohann Sassier, Ingrid Fert, Amandine Noirat, Kirill Nemirov, François Anna, Marion Bérard, Françoise Guinet, David Hardy, Pierre Charneau, François Lemonnier, Francina Langa-Vives, Laleh Majlessi, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Animalerie Centrale (plateforme) - Central Animal Facility (platform) (C2RA), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plate-Forme d’Histopathologie / Histopathology Platform, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur et Theravectys
Subjects: HLA, Infectious Diseases, SARS-CoV-2, [SDV]Life Sciences [q-bio], Immunology, Transgenesis, Omicron variant, Microbiology, COVID-19 animal model
Abstract: International audience; Human Angiotensin-Converting Enzyme 2 (hACE2) is the major receptor enabling host cell invasion by SARS-CoV-2 via interaction with Spike. The murine ACE2 does not interact efficiently with SARS CoV-2 Spike and therefore the laboratory mouse strains are not permissive to SARS-CoV-2 replication. Here, we generated new hACE2 transgenic mice, which harbor the hACE2 gene under the human keratin 18 promoter, in “HHD-DR1” background. HHD-DR1 mice are fully devoid of murine Major Histocompatibility Complex (MHC) molecules of class-I and -II and express only MHC molecules from Human Leukocyte Antigen (HLA) HLA 02.01, DRA01.01, DRB1.01.01 alleles, widely expressed in human populations. We selected three transgenic strains, with various hACE2 mRNA expression levels and distinctive profiles of lung and/or brain permissiveness to SARS-CoV-2 replication. These new hACE2 transgenic strains display high permissiveness to the replication of SARS-CoV-2 Omicron sub-variants, while the previously available B6.K18-ACE22Prlmn/JAX mice have been reported to be poorly susceptible to infection with Omicron. As a first application, one of these MHC- and ACE2-humanized strains was successfully used to show the efficacy of a lentiviral-based COVID-19 vaccine
Published: 2023
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3. Assembling the layers of the hematopoietic system: A window of opportunity for thymopoiesis in the embryo

Author: Francisca Soares‐da‐Silva, Ramy Elsaid, Marcia Mesquita Peixoto, Gonçalo Nogueira, Pablo Pereira, Antonio Bandeira, Ana Cumano, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universidade do Porto = University of Porto, Institut Pasteur, INSERM, ANR (grant Twothyme, grant EPI-DEV and grant DELSTAR), Ligue contre le cancer, and REVIVE Future Investment Program through grants to A.C. FSS is financed by a post-doctoral grant from REVIVE (ANR-10-LABX-73), GN is financed by a PhD grant from REVIVE and MMP is financed by a grant from FCT SFRH/BD/143605/2019., We thank all members from the Lymphocyte and Immunity Unit, Elisa Gomez-Perdiguero and the members from her laboratory for excellent discussions., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-19-CE14-0018,Epi-Dev,Bases moléculaires de la spécification vers le lignage lymphoïde : une approche comparative trans-espèce(2019), ANR-21-CE15-0028,DELSTAR,Développement des cellules lymphoïdes embryonnaires qui organisent l'architecture du thymus(2021), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Vougny, Marie-Christine, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, Bases moléculaires de la spécification vers le lignage lymphoïde : une approche comparative trans-espèce - - Epi-Dev2019 - ANR-19-CE14-0018 - AAPG2019 - VALID, Développement des cellules lymphoïdes embryonnaires qui organisent l'architecture du thymus - - DELSTAR2021 - ANR-21-CE15-0028 - AAPG2021 - VALID, and Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID
Subjects: fetal hematopoiesis, [SDV] Life Sciences [q-bio], thymus, [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy, lymphoid tissue inducer cells, hematopoietic stem cells, thymic seeding progenitors
Abstract: International audience; During embryonic development, several independent generations of hematopoietic cells were identified. They occur in the yolk sac and the intra-embryonic major arteries, in a narrow window of development. They arise sequentially, starting with primitive erythrocytes in the yolk sac blood islands, progressing to less differentiated erythromyeloid progenitors still in the yolk sac, and culminating with multipotent progenitors, some of which will generate the adult hematopoietic stem cell compartment. All these cells contribute to the formation of a layered hematopoietic system that reflects adaptative strategies to the fetal environment and the embryo's needs. It is mostly composed, at these stages, of erythrocytes and tissue-resident macrophages both of yolk sac origin, the latter persisting throughout life. We propose that subsets of lymphocytes of embryonic origin derive from a different intra-embryonic generation of multipotent cells occurring before the emergence of hematopoietic stem cell progenitors. These multipotent cells have a limited lifespan and generate cells that provide basic protection against pathogens before the adaptive immune system is functional, contribute to tissue development and homeostasis, and shape the establishment of a functional thymus. Understanding the properties of these cells will impact the understanding of childhood leukemia and of adult autoimmune pathology and thymic involution.
Published: 2023
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4. Inflammatory-driven NK cell maturation and its impact on pathology

Author: Bourayou, Elsa, Golub, Rachel, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work has been supported by Institut Pasteur, University of Paris Cité, Institut National de la santé et de la recherche Médicale (INSERM) and by grants from INSERM by the French Government (National Research Agency, ANR), ANR project NASHILCCD8 (#18-CE15-0024-01). E.B. is funded by La Ligue Nationale Contre Le Cancer., and ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018)
Subjects: MESH: Killer Cells, Natural, MESH: Cell Differentiation, bone marrow, inflammation, maturation, MESH: Cell Growth Processes, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, NK cells, development
Abstract: NK cells are innate lymphocytes involved in a large variety of contexts and are crucial in the immunity to intracellular pathogens as well as cancer due to their ability to kill infected or malignant cells. Thus, they harbor a strong potential for clinical and therapeutic use. NK cells do not require antigen exposure to get activated; their functional response is rather based on a balance between inhibitory/activating signals and on the diversity of germline-encoded receptors they express. In order to reach optimal functional status, NK cells go through a step-wise development in the bone marrow before their egress, and dissemination into peripheral organs via the circulation. In this review, we summarize bone marrow NK cell developmental stages and list key factors involved in their differentiation before presenting newly discovered and emerging factors that regulate NK cell central and peripheral maturation. Lastly, we focus on the impact inflammatory contexts themselves can have on NK cell development and functional maturation.
Published: 2022
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5. Hypoxia promotes a perinatal-like progenitor state in the adult murine epicardium

Author: David Sassoon, Jean-Sébastien Hulot, Mariana Valente, Szimonetta Turoczi, Francisca Soares-da-Silva, Giovanna Marazzi, Angeliqua Sayed, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by a grant from the Fondation Leducq (13CVD01), Fédération Française de Cardiologie, Era-CVD (ANR-16-ECVD-0011-03), ANR PACIFIC (ANR-18-CE14-0032-02), ANR REVIVE (F.S.S. and M.V. Laboratoire d’Excellence, ANR-10-LABX-73), Le Fonds Marion Elizabeth BRANCHER (A.S.) and GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013)., ANR-18-CE14-0032,PACIFIC,Cellules PW1+ dans la fibrose cardiaque(2018), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), and ANR-16-ECVD-0011,CLARIFY,Communication between cardiomyocytes and innate immune cells in failing hearts(2016)
Subjects: Mammals, Stromal cell, Multidisciplinary, Cell growth, Stem Cells, Lineage markers, [SDV]Life Sciences [q-bio], Cell Differentiation, Biology, Cell cycle, Cell fate determination, Cell biology, Endothelial stem cell, Mice, Animals, Progenitor cell, Hypoxia, Pericardium, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cell Proliferation, Progenitor
Abstract: The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fate. We found that in vivo exposure of mice to physiological hypoxia induced adult epicardial cells to re-enter the cell cycle and to express a subset of developmental genes. Multiplex transcriptional profiling revealed a lineage relationship between epicardial cells and smooth muscle, stromal, and endothelial fates, and that physiological hypoxia promoted an endothelial cell fate. In vitro analyses of purified epicardial cells showed that cell growth and subsequent differentiation is dependent upon hypoxia, and that resident epicardial cells retain progenitor identity in the adult mammalian heart with self-renewal and multilineage differentiation potential. These results point to a source of progenitor cells in the adult heart that can promote heart revascularization, providing an invaluable in vitro model for further studies.
Published: 2022
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6. Synergistic prostaglandin E synthesis by myeloid and endothelial cells promotes fetal hematopoietic stem cell expansion in vertebrates

Author: Pietro Cacialli, Marie‐Pierre Mailhe, Ingrid Wagner, Doron Merkler, Rachel Golub, Julien Y Bertrand, Université de Genève = University of Geneva (UNIGE), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), RG work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8 (#18-CE15-0024-01). JYB is funded by the Swiss National Fund (310030_184814). DM is funded by the Swiss National Fund (310030B_201271). Open access funding provided by Universite de Geneve., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Cacialli P., Mailhe M.-P., Wagner I., Merkler D., Golub R., and Bertrand J.Y.
Subjects: General Immunology and Microbiology, [SDV.IMM] Life Sciences [q-bio]/Immunology, slco2b1, Animal, Hemangioblasts, General Neuroscience, Hematopoietic Stem Cell, HSC, Hemangioblast, Hematopoietic Stem Cells, General Biochemistry, Genetics and Molecular Biology, Dinoprostone, Mice, hematopoietic niche, HSCs, Animals, Prostaglandin H2, [SDV.IMM]Life Sciences [q-bio]/Immunology, PGE2, Molecular Biology, Zebrafish
Abstract: International audience; During development, hematopoietic stem cells (HSCs) are produced from the hemogenic endothelium and will expand in a transient hematopoietic niche. Prostaglandin E2 (PGE2) is essential during vertebrate development and HSC specification, but its precise source in the embryo remains elusive. Here, we show that in the zebrafish embryo, PGE2 synthesis genes are expressed by distinct stromal cell populations, myeloid (neutrophils, macrophages), and endothelial cells of the caudal hematopoietic tissue. Ablation of myeloid cells, which produce the PGE2 precursor prostaglandin H2 (PGH2), results in loss of HSCs in the caudal hematopoietic tissue, which could be rescued by exogeneous PGE2 or PGH2 supplementation. Endothelial cells contribute by expressing the PGH2 import transporter slco2b1 and ptges3, the enzyme converting PGH2 into PGE2. Of note, differential niche cell expression of PGE2 biosynthesis enzymes is also observed in the mouse fetal liver. Taken altogether, our data suggest that the triad composed of neutrophils, macrophages, and endothelial cells sequentially and synergistically contributes to blood stem cell expansion during vertebrate development.
Published: 2022
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7. A lentiviral vector encoding fusion of light invariant chain and mycobacterial antigens induces protective CD4+ T cell immunity

Author: Jodie Lopez, François Anna, Pierre Authié, Alexandre Pawlik, Min-Wen Ku, Catherine Blanc, Philippe Souque, Fanny Moncoq, Amandine Noirat, David Hardy, Wladimir Sougakoff, Roland Brosch, Françoise Guinet, Pierre Charneau, Laleh Majlessi, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-Forme d’Histopathologie / Histopathology Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This project received funding from the European Union's Horizon 2020 research and innovation program (TBVAC2020 643381) and the Marie Sklodowska-Curie grant agreement 665807. The work was also supported by the Programmes Transversaux de Recherche (PTR) 52-17 from the Institut Pasteur and in part by the French National Research Council ANR (ANR-10-LABX-62-IBEID) and the Institut Carnot Pasteur Microbes & Santé. M.-W.K. is a participant of the Pasteur-Paris University (PPU) International PhD Program., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 643381,H2020,H2020-PHC-2014-single-stage,TBVAC2020(2015), Hardy, David, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, TBVAC2020, Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development - TBVAC2020 - - H20202015-01-01 - 2018-12-31 - 643381 - VALID, Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière] (CNR-MyRMA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV] Life Sciences [q-bio], CD4+ T cell response, polyfunctional T cells, tuberculosis, mycobacteria, antigen routing, [SDV]Life Sciences [q-bio], polyantigen, mucosal immunity, lentiviral vectors, intranasal immunization, General Biochemistry, Genetics and Molecular Biology, MHC-II antigenic presentation
Abstract: International audience; Lentiviral vectors (LVs) are highly efficient at inducing CD8+ T cell responses. However, LV-encoded antigens are processed inside the cytosol of antigen-presenting cells, which does not directly communicate with the endosomal major histocompatibility complex class II (MHC-II) presentation pathway. LVs are thus poor at inducing CD4+ T cell response. To overcome this limitation, we devised a strategy whereby LV-encoded antigens are extended at their N-terminal end with the MHC-II-associated light invariant chain (li), which contains an endosome-targeting signal sequence. When evaluated with an LV-encoded polyantigen composed of CD4+ T cell targets from Mycobacterium tuberculosis, intranasal vaccination in mice triggers pulmonary polyfunctional CD4+ and CD8+ T cell responses. Adjuvantation of these LVs extends the mucosal immunity to Th17 and Tc17 responses. A systemic prime and an intranasal boost with one of these LV induces protection against M. tuberculosis. This strategy improves the protective power of LVs against infections and cancers, where CD4+ T cell immunity plays an important role.
Published: 2022
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8. Signaling Pathways Tuning Innate Lymphoid Cell Response to Hepatocellular Carcinoma

Author: Bourayou, Elsa, Golub, Rachel, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work has been supported by Institut Pasteur, Université de Paris, Institut National de la santé et de la recherche Médicale (INSERM) and by grants from the French Government (National Research Agency, ANR), ANR project NASHILCCD8 (#18-CE15-0024-01)., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, and APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID
Subjects: Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, Notch and TGF-β pathways, Immunology, Liver Neoplasms, NASH, NK cells, liver, Immunity, Innate, digestive system diseases, ILC1, Killer Cells, Natural, inflammation, Immunology and Allergy, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, HCC, Signal Transduction
Abstract: International audience; Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and its incidence continues to rise globally. Various causes can lead to its development such as chronic viral infections causing hepatitis, cirrhosis or nonalcoholic steatohepatitis (NASH). The contribution of immune cells to HCC development and progression has been extensively studied when it comes to adaptive lymphocytes or myeloid populations. However, the role of the innate lymphoid cells (ILCs) is still not well defined. ILCs are a family of lymphocytes comprising five subsets including circulating Natural Killer (NK) cells, ILC1s, ILC2s, ILC3s and lymphocytes tissue-inducer cells (LTi). Mostly located at epithelial surfaces, tissue-resident ILCs and NK cells can rapidly react to environmental changes to mount appropriate immune responses. Here, we provide an overview of their roles and actions in HCC with an emphasis on the importance of diverse signaling pathways (Notch, TGF-β, Wnt/β-catenin…) in the tuning of their response to HCC.
Published: 2022
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9. Identification of fetal liver stroma in spectral cytometry using the parameter autofluorescence†

Author: Francisca Soares-da-Silva, Marie-Pierre Mailhé, Ait-Mansour C, Marcia Peixoto, Ana Cumano, Sophie Novault, Sandrine Schmutz, Novault, Sophie, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, Développement des cellules lymphoïdes embryonnaires qui organisent l'architecture du thymus - - DELSTAR2021 - ANR-21-CE15-0028 - AAPG2021 - VALID, Blanc - A comprehensive approach to the study of epigenetic regulation of gene expression during development by the C. elegans HP1 proteins - - EpiDev2007 - ANR-07-BLAN-0081 - BLANC - VALID, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universidade do Porto = University of Porto, Cytométrie (plateforme) - Flow Cytometry (platform), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Sony Corporation, This work was financed by the Institut Pasteur, INSERM, ANR (grant Twothyme, grant DELSTAR and grant EPI-DEV), REVIVE Future Investment Program and Pasteur-Weizmann Foundation through grants to A.C. This work was financed by Portuguese funds through FCT/MCTES in the framework of the project PTDC/MED-OUT/32656/2017 (POCI-01-0145-FEDER-032656). F.S.S is funded by the REVIVE Future investments post-doctoral grant (Investissement d'Avenir, ANR-10-LABX-73). MP is funded by FCT grant SFRH/BD/143605/2019, We thank all members of the flow cytometry core facility, the members of the Institut Pasteur laboratory, Antonio Bandeira, Paulo Vieira, Rachel Golub and Pablo Pereira., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-21-CE15-0028,DELSTAR,Développement des cellules lymphoïdes embryonnaires qui organisent l'architecture du thymus(2021), ANR-07-BLAN-0081,EpiDev,A comprehensive approach to the study of epigenetic regulation of gene expression during development by the C. elegans HP1 proteins(2007), and ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010)
Subjects: Histology, Stromal cell, [SDV]Life Sciences [q-bio], Population, Bone Marrow Cells, Biology, autofluorescence, Pathology and Forensic Medicine, Flow cytometry, Pregnancy, Bone Marrow, medicine, Humans, education, education.field_of_study, hepatoblast-like cells/hepatocytes, medicine.diagnostic_test, Mesenchymal stem cell, Cell Differentiation, Cell Biology, Hematopoietic Stem Cells, Flow Cytometry, Cell biology, Spectral flow cytometry, [SDV] Life Sciences [q-bio], Autofluorescence, medicine.anatomical_structure, Liver, Female, Bone marrow, Stem cell, Cytometry, fetal liver
Abstract: The fetal liver is the main hematopoietic organ during embryonic development. The fetal liver is also the unique anatomical site where hematopoietic stem cells expand before colonizing the bone marrow, where they ensure life-long blood cell production and become mostly resting. The identification of the different cell types that comprise the hematopoietic stroma in the fetal liver is essential to understand the signals required for the expansion and differentiation of the hematopoietic stem cells. We used a panel of monoclonal antibodies to identify fetal liver stromal cells in a 5-laser equipped spectral flow cytometry analyzer. The “Autofluorescence Finder” of SONY ID7000 software identified two distinct autofluorescence emission spectra. Using autofluorescence as a fluorescence parameter we could assign the two autofluorescent signals to three distinct cell types and identified surface markers that characterize these populations. We found that one autofluorescent population corresponds to hepatoblasts and cholangiocytes whereas the other expresses mesenchymal transcripts and was identified as stellate cells. Importantly, after birth, autofluorescence becomes the unique identifying property of hepatoblasts because mature cholangiocytes are no longer autofluorescent.These results show that autofluorescence used as a parameter in spectral flow cytometry is a useful tool to identify new cell subsets that are difficult to analyze in conventional flow cytometry.
Published: 2022
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10. An intranasal lentiviral booster reinforces the waning mRNA vaccine-induced SARS-CoV-2 immunity that it targets to lung mucosa

Author: Benjamin Vesin, Jodie Lopez, Amandine Noirat, Pierre Authié, Ingrid Fert, Fabien Le Chevalier, Fanny Moncoq, Kirill Nemirov, Catherine Blanc, Cyril Planchais, Hugo Mouquet, Françoise Guinet, David Hardy, Francina Langa Vives, Christiane Gerke, François Anna, Maryline Bourgine, Laleh Majlessi, Pierre Charneau, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lymphocytes et Immunité - Lymphocytes and Immunity, Plate-Forme d’Histopathologie / Histopathology Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Service développement de l'innovation - Innovation Office, Direction des Applications de la Recherche et des Relations industrielles - The Technology Transfer and Industrial Partnership Department (DARRI), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), This work was supported by TheraVectys and Institut Pasteur., The authors are grateful to Dr. Marie José Quentin-Millet and Estelle Besson (TheraVectys) for discussion and advice, to Magali Tichit and Sabine Maurin for excellent technical assistance in preparing histological sections, to Sébastien Chardenoux (CIGM, Institut Pasteur) for excellent technical assistance in B6.K18-hACE2IP−THV mouse transgenesis, and to Marie Laure Loriquet and Dr. Paul-Henri Consigny (Institut Pasteur Medical Center) for their gift of the leftover Moderna vaccines, not unusable in humans, so that this study did not deprive any individual of a vaccine dose during the COVID-19 pandemic. The SARS-CoV2 variant Delta/2021/I7.2 200 was supplied by the Virus and Immunity Unit (Institut Pasteur, Paris, France) headed by Olivier Schwartz. The SARS-CoV-2 Omicron BA.1 variant was initially supplied by the Virus and Immunity Unit (Institut Pasteur, Paris, France) headed by Olivier Schwartz, and was provided to our laboratory by Matthieu Prot and Etienne Simon-Lorière (G5 Evolutionary Genomics of RNA Viruses, Institut Pasteur, Paris, France)., and Majlessi, Laleh
Subjects: COVID-19 Vaccines, lentiviral vaccine, Antibodies, Viral, Mice, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Drug Discovery, Genetics, mucosal booster vaccine, Animals, Humans, SARS-CoV-2 emerging variants of concern, Lung, Molecular Biology, Pharmacology, Vaccines, Synthetic, Mucous Membrane, SARS-CoV-2, Vaccination, COVID-19, Viral Vaccines, Antibodies, Neutralizing, intranasal vaccination, Molecular Medicine, mucosal immunity, waning anti-COVID-19 immunity, mRNA Vaccines, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Abstract: International audience; As the coronavirus disease 2019 (COVID-19) pandemic continues and new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern emerge, the adaptive immunity initially induced by the first-generation COVID-19 vaccines starts waning and needs to be strengthened and broadened in specificity. Vaccination by the nasal route induces mucosal, humoral, and cellular immunity at the entry point of SARS-CoV-2 into the host organism and has been shown to be the most effective for reducing viral transmission. The lentiviral vaccination vector (LV) is particularly suitable for this route of immunization owing to its non-cytopathic, non-replicative, and scarcely inflammatory properties. Here, to set up an optimized cross-protective intranasal booster against COVID-19, we generated an LV encoding stabilized spike of SARS-CoV-2 Beta variant (LV::SBeta-2P). mRNA vaccine-primed and -boosted mice, with waning primary humoral immunity at 4 months after vaccination, were boosted intranasally with LV::SBeta-2P. A strong boost effect was detected on cross-sero-neutralizing activity and systemic T cell immunity. In addition, mucosal anti-spike IgG and IgA, lung-resident B cells, and effector memory and resident T cells were efficiently induced, correlating with complete pulmonary protection against the SARS-CoV-2 Delta variant, demonstrating the suitability of the LV::SBeta-2P vaccine candidate as an intranasal booster against COVID-19. LV::SBeta-2P vaccination was also fully protective against Omicron infection of the lungs and central nervous system, in the highly susceptible B6.K18-hACE2IP-THV transgenic mice.
Published: 2022
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11. Brain Cross‐Protection against SARS‐CoV‐2 Variants by a Lentiviral Vaccine in New Transgenic Mice

Author: Ku, Min-Wen, Authié, Pierre, Bourgine, Maryline, Anna, François, Noirat, Amandine, Moncoq, Fanny, Vesin, Benjamin, Nevo, Fabien, Lopez, Jodie, Souque, Philippe, Blanc, Catherine, Fert, Ingrid, Chardenoux, Sébastien, Lafosse, llta, Cussigh, Delphine, Hardy, David, Nemirov, Kirill, Guinet, Françoise, Vives, Francina Langa, Majlessi, Laleh, Charneau, Pierre, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris], Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), This work was supported by the «URGENCE COVID-19» fundraising campaign of Institut Pasteur, TheraVectys and Agence Nationale de la Recherche (ANR) HuMoCID. M.W. Ku is part of the Pasteur - Paris University (PPU) International PhD Program and received funding from the Institut Carnot Pasteur Microbes & Santé, and the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 665807., The authors are grateful to Pr S. van der Werf (National Reference Centre for Respiratory Viruses hosted by Institut Pasteur, Paris, France), F. Guivel-Benhassine and Pr O. Schwartz (Institut Pasteur) for providing the BetaCoV/France/IDF0372/2020 and Gamma (P.1) SARS-CoV-2 clinical isolates. The strain BetaCoV/France/IDF0372/2020 was supplied through the European Virus Archive goes Global (Evag) platform, a project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 653316. The authors thank Pr G. Milon and Dr L.A. Chakrabarti for fruitful advice and discussion, Dr H. Mouquet and Dr C. Planchais for providing recombinant homotrimeric S proteins, Dr N. Escriou and Dr M. Gransagne for providing a plasmid containing the prefusion SCoV-2 sequence,M. Tichit and N. Dominique, for excellent technical assistance, respectively, in preparing histological sections and in animal immunization., ANR-20-COVI-0028,HuMoCID,Développement de modèles murins de COVID-19(2020), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hardy, David, Développement de modèles murins de COVID-19 - - HuMoCID2020 - ANR-20-COVI-0028 - COVID-19 - VALID, and Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 - VALID
Subjects: Central Nervous System, Medicine (General), COVID-19 Vaccines, [SDV]Life Sciences [q-bio], Immunology, Mice, Transgenic, QH426-470, Antibodies, Viral, Article, Mice, R5-920, Genetics, Animals, Humans, SARS-CoV-2, Brain, COVID-19, Articles, hACE2 Transgenic Mice, Antibodies, Neutralizing, Olfactory Bulb, SARS-CoV-2 Emerging Variants of Concern, Microbiology, Virology & Host Pathogen Interaction, [SDV] Life Sciences [q-bio], Intranasal Vaccination, Spike Glycoprotein, Coronavirus, SARS‐CoV‐2 emerging variants of concern
Abstract: COVID‐19 vaccines already in use or in clinical development may have reduced efficacy against emerging SARS‐CoV‐2 variants. In addition, although the neurotropism of SARS‐CoV‐2 is well established, the vaccine strategies currently developed have not taken into account protection of the central nervous system. Here, we generated a transgenic mouse strain expressing the human angiotensin‐converting enzyme 2, and displaying unprecedented brain permissiveness to SARS‐CoV‐2 replication, in addition to high permissiveness levels in the lung. Using this stringent transgenic model, we demonstrated that a non‐integrative lentiviral vector, encoding for the spike glycoprotein of the ancestral SARS‐CoV‐2, used in intramuscular prime and intranasal boost elicits sterilizing protection of lung and brain against both the ancestral virus, and the Gamma (P.1) variant of concern, which carries multiple vaccine escape mutations. Beyond induction of strong neutralizing antibodies, the mechanism underlying this broad protection spectrum involves a robust protective T‐cell immunity, unaffected by the recent mutations accumulated in the emerging SARS‐CoV‐2 variants., A lentiviral vector‐based vaccine, used in prime and intranasal boost, induces strong B‐ and T‐cell immunity. This vaccine candidate protects against both pulmonary and neurological COVID‐19 caused by either ancestral or emerging SARS‐CoV‐2.
Published: 2021
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12. Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis

Author: Ana, Cardoso, Ana Catarina, Martins, Ana Raquel, Maceiras, Wei, Liu, Isabel, Castro, António G, Castro, António, Bandeira, James P, Di Santo, Ana, Cumano, Yan, Li, Paulo, Vieira, Margarida, Saraiva, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal] (IBMC), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Medical School (University of Nanjing), Nanjing University (NJU), University of Minho [Braga], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Immunité Innée - Innate Immunity, A. Cardoso (SFRH/BD/84704/2012) and A.C.M. (SFRH/BD/136800/2018) were supported by the Portuguese Foundation for Science and Technology (FCT) through PhD grants.This study was partially supported by grants from the National Key Research and Development Program of China (2019YFA0802900), National Natural Science Foundation of China (32070942), and Fundamental Research Funds for the Central Universities.The M.S. lab was financed by a FCT-ANR grant (MyeloTEN-FCTANR/ BIM-MEC/0007/2013). We acknowledge the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by FCT.This work was funded by National Funds through FCT, I.P., under the project UIDB/04293/2020, and backed by the COST Action BM1404 European Network of Investigators Triggering Exploratory Research on Myeloid Regulatory Cells (http://www.mye-euniter.eu), which is supported by the Horizon 2020—EU Framework Program Research and Innovation Programme. M.S. is funded by FCT through Estímulo Individual ao Emprego Científico.A. Cumano and P.V. were financed by ANR Twothyme and by REVIVE (Investissement d’Avenir, ANR-10-LABX-73). A.B., A. Cumano, and P.V. were also financed by the Institut Pasteur, INSERM, and ANR (project MYELOTEN, ANR-13-ISV1-0003-01)., We thank Vincent Rouilly for statistical advice and Werner Müller (University of Manchester), Rui Appelberg (i3S), and Bruno Silva-Santos (iMM) for providing the IL-10Rα-, IFN-γ-, and TCRγδ-deficient animals, respectively. We thank Anne O’Garra for helpful discussions and for critical reading of the manuscript. We also thank Delfim Duarte and Maria José Teles for helpful discussions and for helping with the hemogram quantification. We thank Caetano Reis e Sousa for help with the preparation of the graphical abstract. We thank the support of the personnel in the animal facilities, the i3S scientific platforms Translational Cytometry (TraCy), and Histology and Electron Microscopy (HEMS). HEMS is a member of the national infrastructure PPBI (Portuguese Platform of Bioimaging, PPBI-POCI-01-0145-FEDER-022122)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), European Project, Vougny, Marie-Christine, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, Blanc – Accords bilatéraux 2013 - DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES - - MYELOTEN2013 - ANR-13-ISV1-0003 - Blanc – Accords bilatéraux 2013 - VALID, COST Action BM1404 MyeEUNITER - INCOMING, Universidade do Porto, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CD4-Positive T-Lymphocytes, Mice, Knockout, Myelopoiesis, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cells, emergency myelopoiesis, CD8-Positive T-Lymphocytes, Interleukin-10, Interferon-gamma, Mice, IL-10, Animals, [SDV.IMM]Life Sciences [q-bio]/Immunology, IFN-γ, Myeloid Progenitor Cells
Abstract: International audience; In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the pro-inflammatory cytokine interferon gamma (IFN-γ). Interleukin-10 (IL-10) inhibits IFN-γ secretion, but paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work, we use different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also find that IL-10, unexpectedly, reprograms CD4 and CD8 T cells toward an activation state that includes IFN-γ production by these T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening additional perspectives for the design of IL-10-based immunotherapies.
Published: 2021
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13. Full-Lung Prophylaxis against SARS-CoV-2 by One-Shot or Booster Intranasal Lentiviral Vaccination in Syrian Golden Hamsters

Author: Benjamin Vesin, Pierre Authié, Catherine Blanc, Ingrid Fert, Amandine Noirat, Fabien Le Chevalier, Yu Wei, Min-Wen Ku, Kirill Nemirov, François Anna, David Hardy, Cyril Planchais, Hugo Mouquet, Françoise Guinet, Pierre Charneau, Laleh Majlessi, Maryline Bourgine, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Plate-Forme d’Histopathologie / Histopathology Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lymphocytes et Immunité - Lymphocytes and Immunity, and BOURGINE, Maryline
Subjects: Pharmacology, SARS-CoV-2 variants, [SDV]Life Sciences [q-bio], lung inflammation, cross-neutralization, Immunology, lentiviral vectors, intranasal vaccination, [SDV] Life Sciences [q-bio], Infectious Diseases, Drug Discovery, mucosal immunity, Pharmacology (medical)
Abstract: International audience; Following the breakthrough of numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in recent months and the incomplete efficiency of the currently available vaccines, development of more effective vaccines is desirable. Non-integrative, non-cytopathic and non-inflammatory lentiviral vectors elicit sterilizing prophylaxis against SARS-CoV-2 in preclinical animal models and are particularly suitable for mucosal vaccination, which is acknowledged as the most effective in reducing viral transmission. Here, we demonstrate that a single intranasal administration of a vaccinal lentiviral vector encoding a stabilized form of the original SARS-CoV-2 Spike glycoprotein induces full-lung protection of respiratory tracts and strongly reduces pulmonary inflammation in the susceptible Syrian golden hamster model against the prototype SARS-CoV-2. In addition, we show that a lentiviral vector encoding stabilized Spike of SARS-CoV-2 Beta variant (LV::SBeta-2P) prevents pathology and reduces infectious viral loads in lungs and nasal turbinates following inoculation with the SARS-CoV-2 Omicron variant. Importantly, an intranasal boost with LV::SBeta-2P improves cross-seroneutralization much better in LV::SBeta-2P-primed hamsters than in their counterparts primed with an LV-encoding Spike from the ancestral SARS-CoV-2. These results strongly suggest that an immune imprint with the original Spike sequence has a negative impact on cross-protection against new variants. Our results tackle the issue of vaccine effectiveness in people who have already been vaccinated and have vanished immunity and indicate the efficiency of LV-based intranasal vaccination, either as a single dose or as booster.
Published: 2022
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14. The Notch signaling pathway involvement in innate lymphoid cell biology

Author: Rachel Golub, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), RG work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8(#18-CE15-0024-01), Projets ARC 2020 PJA3, Fonds AMGENFrance., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lassailly-Bondaz, Anne, and APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID
Subjects: 0301 basic medicine, Medicine (General), [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Notch pathway, Notch signaling pathway, Stimulation, Biology, Cell fate determination, 03 medical and health sciences, 0302 clinical medicine, Immune system, R5-920, Secretion, Lymphocytes, Biology (General), skin and connective tissue diseases, Development of lymphoid cells, Innate lymphoid cell, Cell Differentiation, General Medicine, Immunity, Innate, Cell biology, Immune functions, body regions, 030104 developmental biology, ILC, Review Article: Special Edition, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Polarization of immune subsets, Signal Transduction
Abstract: International audience; The role of Notch in the immune system was first described in the late 90s. Reports revealed that Notch is one of the most conserved developmental pathways involved in diverse biological processes such as the development, differentiation, survival and functions of many immune populations. Here, we provide an extended view of the pleiotropic effects of the Notch signaling on the innate lymphoid cell (ILC) biology. We review the current knowledge on Notch signaling in the regulation of ILC differentiation, plasticity and functions in diverse tissue types and at both the fetal and adult developmental stages. ILCs are early responder cells that secrete a large panel of cytokines after stimulation. By controlling the abundance of ILCs and the specificity of their release, the Notch pathway is also implicated in the regulation of their functions. The Notch pathway is therefore an important player in both ILC cell fate decision and ILC immune response.
Published: 2021
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15. Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life

Author: Soares-Da-Silva, Francisca, Freyer, Laina, Elsaid, Ramy, Burlen-Defranoux, Odile, Iturri, Lorea, Sismeiro, Odile, Pinto-Do-Ó, Perpétua, Gomez-Perdiguero, Elisa, Cumano, Ana, Gestionnaire, Hal Sorbonne Université, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, Bases moléculaires de la spécification vers le lignage lymphoïde : une approche comparative trans-espèce - - Epi-Dev2019 - ANR-19-CE14-0018 - AAPG2019 - VALID, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universidade do Porto = University of Porto, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Macrophages et Cellules endothéliales / Macrophages and Endothelial Cells, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Sorbonne Université (SU), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Agence Nationale de la Recherche (Twothyme, EPI-DEV)European Research Council (2016-StG-715320)Fundação para a Ciência e a Tecnologia (POCI-01-0145-FEDER-032656, PD/BD/114128/2015, POCI-0100145-FEDER-01638)Institut National de la Santé et de la Recherche Médicale (NO AWARD)Institut Pasteur (NO AWARD), ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-19-CE14-0018,Epi-Dev,Bases moléculaires de la spécification vers le lignage lymphoïde : une approche comparative trans-espèce(2019), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universidade do Porto, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Sorbonne Université (SU), and Institut Pasteur [Paris]-Institut Pasteur [Paris]
Subjects: Mice, Knockout, Erythrocytes, Macrophages, [SDV]Life Sciences [q-bio], Stem Cells & Regeneration, Embryonic Development, Article, Hematopoiesis, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Mice, Proto-Oncogene Proteins c-myb, Pregnancy, embryonic structures, Animals, Cell Lineage, Erythropoiesis, Female, Erythropoietin, Megakaryocyte Progenitor Cells, Yolk Sac
Abstract: Yolk sac erythropoiesis is not replaced by hematopoietic stem cell–derived progeny up until birth. Yolk sac–derived erythroid progenitors require 10-fold lower concentrations of erythropoietin for differentiation, which confers a competitive advantage over progenitors of hematopoietic stem cell origin., In the embryo, the first hematopoietic cells derive from the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. We used three lineage-tracing mouse models to show that, contrary to what was previously assumed, hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac erythromyeloid progenitors, which generate tissue resident macrophages, identified highly proliferative erythroid progenitors that rapidly differentiate after intra-embryonic injection, persisting as the major contributors to the embryonic erythroid compartment. We show that erythrocyte progenitors of yolk sac origin require 10-fold lower concentrations of erythropoietin than their hematopoietic stem cell–derived counterparts for efficient erythrocyte production. We propose that, in a low erythropoietin environment in the fetal liver, yolk sac–derived erythrocyte progenitors efficiently outcompete hematopoietic stem cell progeny, which fails to generate megakaryocyte and erythrocyte progenitors.
Published: 2021
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16. A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner

Author: Ana Cumano, Elisa Gomez Perdiguero, Pablo Pereira, Rachel Golub, Paulo Vieira, Laina Freyer, Ramy Elsaid, Odile Burlen-Defranoux, Francisca Soares-da-Silva, Thibaut Perchet, Antonio Bandeira, Sylvain Meunier, Lorea Iturri, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Macrophages et Cellules endothéliales / Macrophages and Endothelial Cells, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP), This work was financed by the Institut Pasteur, INSERM, Pasteur-Weizmann Foundation and ANR (grant Twothyme and Epi-Dev) through grants to A.C., by REVIVE (Investissement d'Avenir, ANR-10-LABX-73)to A.C. and R.E., by recurrent funding from the Institut Pasteur, the CNRS, Revive (Investissement d'Avenir, ANR-10-LABX-73) and by an ERC investigator award (2016-StG-715320) from the European Research Council to E.G.P., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universidade do Porto, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris], Vougny, Marie-Christine, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, and Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID
Subjects: 0303 health sciences, education.field_of_study, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Population, Hematopoietic stem cell, Cell Biology, Hematology, Biology, Biochemistry, Embryonic stem cell, Cell biology, 03 medical and health sciences, Haematopoiesis, 0302 clinical medicine, Lymphatic system, Immune system, medicine.anatomical_structure, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Lymphopoiesis, Progenitor cell, education, 030304 developmental biology, 030215 immunology
Abstract: During embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave, and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here, we show that the first wave of thymic progenitors comprises a unique population of bipotent T and innatel lymphoid cells (T/ILC), generating a lymphoid tissue inducer cells (LTi's), in addition to invariant Vγ5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and, more precisely, the LTi-associated transcripts were expressed in the first, but not in the second, wave of thymic progenitors. Depletion of early thymic progenitors in a temporally controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator–expressing medullary thymic epithelial cells (mTECs). We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid-associated transcripts in yolk sac (YS) erythromyeloid-restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system.
Published: 2021
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17. Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models

Author: Hugo Mouquet, Benjamin Vesin, Houda Tabbal, Françoise Guinet, Jodie Lopez, Pierre Authié, Laurence Fiette, Marine Le Dudal, Catherine Blanc, François Anna, Maryline Bourgine, Nicolas Escriou, David Hardy, Fanny Moncoq, Kirill Nemirov, Fabien Nevo, Annette Martin, Pierre Charneau, Philippe Souque, Laleh Majlessi, Emeline Simon, Amandine Noirat, Min Wen Ku, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Mutualiste de Montsouris (IMM), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d’innovation : vaccins – Innovation lab : vaccines, The authors are grateful to Prof. Sylvie van der Werf (National Reference Centre for Respiratory Viruses, Institut Pasteur, France) for providing the BetaCoV/France/IDF0372/2020 SARS-CoV-2 clinical isolate, supplied through the European Virus Archive Global (Evag), funded by the European Union’s Horizon 2020 program under grant agreement no. 653316. This work was also supported by grants from Institut Pasteur, TheraVectys, and Agence Nationale de la Recherche HuMoCID. M.W.K. is part of the Pasteur - Paris University PhD program and received funding from Institut Carnot Pasteur Microbes & Santé and the European Union’s Horizon 2020 program under Marie Sklodowska-Curie grant agreement no. 665807., ANR-20-COVI-0028,HuMoCID,Développement de modèles murins de COVID-19(2020), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris]-TheraVectys, Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hardy, David, Développement de modèles murins de COVID-19 - - HuMoCID2020 - ANR-20-COVI-0028 - COVID-19 - VALID, European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID, and Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 - VALID
Subjects: Male, [SDV]Life Sciences [q-bio], Respiratory System, lentiviral vectors, immunoglobulin A, Antibodies, Viral, Mice, Transduction (genetics), 0302 clinical medicine, Cricetinae, respiratory tracts, 0303 health sciences, Viral Load, 3. Good health, Vaccination, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, in vivo Ad5 transduction, Models, Animal, Spike Glycoprotein, Coronavirus, Lentivirus, Female, COVID-19 Vaccines, Genetic Vectors, Immunization, Secondary, Biology, Microbiology, Article, Viral vector, 03 medical and health sciences, Immune system, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Virology, boost-target, medicine, Animals, neutralizing antibodies, Immunity, Mucosal, Administration, Intranasal, 030304 developmental biology, SARS-CoV-2, lung inflammation, COVID-19, beta-coronavirus, Vaccine efficacy, biology.organism_classification, Antibodies, Neutralizing, intranasal vaccination, Immunology, mucosal immunity, Parasitology, Nasal administration, golden hamsters, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, 030217 neurology & neurosurgery, Respiratory tract
Abstract: To develop a vaccine candidate against COVID-19, we generated a Lentiviral Vector (LV), eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, confers only partial protection, despite high levels of serum neutralizing activity. However, eliciting an immune response in the respiratory tract through an intranasal boost results in > 3 log10 decrease in the lung viral loads and reduces local inflammation. Moreover, both integrative and non-integrative LV platforms display strong vaccine efficacy and inhibit lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and closely mirror human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of the LV-based vaccination against SARS-CoV-2 and designate intranasal immunization as a powerful approach against COVID-19., Graphical Abstract, Highlights A lentiviral vector encoding for Spike shows preclinical efficacy as a COVID-19 vaccine. Targeting the immune response to the upper respiratory tract provides critical protection. Intranasal vaccination induces protective mucosal immunity against SARS-CoV-2 in rodents. Lung anti-Spike IgA responses correlate with protection and reduced inflammation., Ku and colleagues present a lentiviral vaccination vector that encodes a full-length, membrane anchored form of SARS-CoV-2 Spike glycoprotein that induces neutralizing antibodies and T-cell responses. An intranasal boost strategy triggers a localized immune response in the upper respiratory tract that provides disease protection in mouse and hamster COVID-19 models.
Published: 2020
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18. The interplay between innate lymphoid cells and T cells

Author: Gayetri Ramachandran, Rachel Golub, Marie Cherrier, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), M.C. is supported by INSERM and Association François Aupetit dedicated to patients suffering from IBD. R.G. work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8 (#18-CE15-0024-01)., We thank Serge van de Pavert for critical discussions and for review of the paper., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Context (language use), Cell Communication, Biology, Gut flora, Adaptive Immunity, Lymphocyte Activation, Substrate Specificity, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, T-Lymphocyte Subsets, Immunology and Allergy, Animals, Humans, skin and connective tissue diseases, Immunity, Cellular, Innate lymphoid cell, Cell Differentiation, Acquired immune system, biology.organism_classification, Immunity, Innate, body regions, 030104 developmental biology, Gene Expression Regulation, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neuroscience, Immunologic Memory, Function (biology), Homeostasis, Biomarkers, 030215 immunology, Signal Transduction
Abstract: International audience; ILCs and T cells are closely related functionally but they significantly differ in their ability to circulate, expand, and renew. Cooperation and reciprocal functional regulation suggest that these cell types are more complementary than simply redundant during immune responses. How ILCs shape T-cell responses is strongly dependent on the tissue and inflammatory context. Likewise, indirect regulation of ILCs by adaptive immunity is induced by environmental cues such as the gut microbiota. Here, we review shared requirements for the development and function of both cell types and divergences in the orchestration of prototypic immune functions. We discuss the diversity of functional interactions between T cells and ILCs during homeostasis and immune responses. Identifying the location and the nature of the tissue microenvironment in which these interactions are taking place may uncover the remaining mysteries of their close encounters.
Published: 2020
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19. Crosstalk Between the Hepatic and Hematopoietic Systems During Embryonic Development

Author: Francisca Soares-da-Silva, Márcia Peixoto, Ana Cumano, Perpetua Pinto-do-Ó, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto = University of Porto, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), FS-d-S funded by FCT grants PD/BD/114128/2015 and POCI-0100145-FEDER-01638. MP funded by FCT grant SFRH/BD/143605/2019. AC financed by the Institut Pasteur, INSERM, ANR (grant Twothyme and EpiDev) and REVIVE Future Investment Program and Pasteur-Weizmann Foundation. PP-d-Ó financed by Portuguese funds through FCT/MCTES in the framework of the projects PTDC/MED-OUT/32656/2017, POCI-01-0145-FEDER-032656, and by – FCT – UIDB/04293/2020., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-07-BLAN-0081,EpiDev,A comprehensive approach to the study of epigenetic regulation of gene expression during development by the C. elegans HP1 proteins(2007), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Universidade do Porto, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Instituto de Investigação e Inovação em Saúde
Subjects: 0301 basic medicine, Cell type, Hematopoietic stem cell niche, Review, Biology, self-renewal, Cell therapy, fetal hematopoiesis, Cell and Developmental Biology, 03 medical and health sciences, 0302 clinical medicine, hematopoietic stem cell expansion, medicine, lcsh:QH301-705.5, Embryo, hematopoietic stem cell niche, Cell Biology, Cell biology, hematopoietic stem cells, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, fetal liver microenvironment, lcsh:Biology (General), 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, cytokine signaling, Stem cell, Ex vivo, Developmental Biology, fetal liver
Abstract: Hematopoietic stem cells (HSCs) generated during embryonic development are able to maintain hematopoiesis for the lifetime, producing all mature blood lineages. HSC transplantation is a widely used cell therapy intervention in the treatment of hematologic, autoimmune and genetic disorders. Its use, however, is hampered by the inability to expand HSCs ex vivo, urging for a better understanding of the mechanisms regulating their physiological expansion. In the adult, HSCs reside in the bone marrow, in specific microenvironments that support stem cell maintenance and differentiation. Conversely, while developing, HSCs are transiently present in the fetal liver, the major hematopoietic site in the embryo, where they expand. Deeper insights on the dynamics of fetal liver composition along development, and on how these different cell types impact hematopoiesis, are needed. Both, the hematopoietic and hepatic fetal systems have been extensively studied, albeit independently. This review aims to explore their concurrent establishment and evaluate to what degree they may cross modulate their respective development. As insights on the molecular networks that govern physiological HSC expansion accumulate, it is foreseeable that strategies to enhance HSC proliferation will be improved. FS-d-S funded by FCT grants PD/BD/114128/2015 and POCI-0100145-FEDER-01638. MP funded by FCT grant SFRH/BD/143605/2019. AC financed by the Institut Pasteur, INSERM, ANR (grant Twothyme and EpiDev) and REVIVE Future Investment Program and Pasteur-Weizmann Foundation. PP-d-Ó financed by Portuguese funds through FCT/MCTES in the framework of the projects PTDC/MEDOUT/32656/2017, POCI-01-0145-FEDER-032656, and by – FCT – UIDB/04293/2020.
Published: 2020
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20. Elevated Fatty Liver Index as a Risk Factor for All‐Cause Mortality in Human Immunodeficiency Virus–Hepatitis C Virus–Coinfected Patients (ANRS CO13 HEPAVIH Cohort Study)

Author: Firouzé Bani-Sadr, Lionel Piroth, Tangui Barré, Linda Wittkop, Marie-Laure Chaix, Teresa Rojas Rojas, Lawrence Serfaty, Fabienne Marcellin, Julie Chas, Camelia Protopopescu, Dominique Salmon-Ceron, Karine Lacombe, Laure Esterle, Olivia Zaegel, Philippe Sogni, Patrick Miailhes, Maria Patrizia Carrieri, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie Médicale et Moléculaire - EA 4684 (CardioVir), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Centre Hospitalier Universitaire Marseille, CHU Marseille, Team MORPH3EUS (INSERM U1219 - UB - ISPED), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Hôpital universitaire Robert Debré [Reims], Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Maladies infectieuses et tropicales [AP-HP Hôpital Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Santé publique [CHU Bordeaux], CHU de bordeaux, Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Tenon [AP-HP], Aix Marseille Université (AMU), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service des maladies infectieuses et tropicales [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Dupuis, Christine, and Service de Maladies infectieuses et tropicales [CHU Tenon]
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Cirrhosis, Hepatitis C virus, medicine.medical_treatment, [SDV]Life Sciences [q-bio], HIV Infections, Liver transplantation, medicine.disease_cause, Gastroenterology, Antiviral Agents, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Cause of Death, medicine, Humans, Risk factor, ComputingMilieux_MISCELLANEOUS, Hepatology, business.industry, Coinfection, Hazard ratio, Fatty liver, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Fatty Liver, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030211 gastroenterology & hepatology, Female, France, Steatosis, Viral hepatitis, business
Abstract: International audience; Background and aims: Human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients are at high risk of metabolic complications and liver-related events, which are both associated with hepatic steatosis and its progressive form, nonalcoholic steatohepatitis, a known risk factor for mortality. The fatty liver index (FLI), a noninvasive steatosis biomarker, has recently drawn attention for its clinical prognostic value, although its capacity to predict mortality risk in HIV-HCV-coinfected patients has never been investigated. Using a Cox proportional hazards model for mortality from all causes, with data from the French National Agency for Research on Aids and Viral Hepatitis CO13 HEPAVIH cohort (983 patients, 4,432 visits), we tested whether elevated FLI (≥60) was associated with all-cause mortality.Approach and results: After multiple adjustment, individuals with FLI ≥ 60 had almost double the risk of all-cause mortality (adjusted hazard ratio [95% confidence interval], 1.91 [1.17-3.12], P = 0.009), independently of the following factors: HCV cure (0.21 [0.07-0.61], P = 0.004), advanced fibrosis (1.77 [1.00-3.14], P = 0.05), history of hepatocellular carcinoma and/or liver transplantation (7.74 [3.82-15.69], P < 10-3 ), history of indirect clinical signs of cirrhosis (2.80 [1.22-6.41], P = 0.015), and HIV Centers for Disease Control and Prevention clinical stage C (2.88 [1.74-4.79], P < 10-3 ).Conclusions: An elevated FLI (≥60) is a risk factor for all-cause mortality in HIV-HCV-coinfected patients independently of liver fibrosis and HCV cure. In the present era of nearly 100% HCV cure rates thanks to direct-acting antivirals, these findings encourage the more systematic use of noninvasive steatosis biomarkers to help identify coinfected patients with higher mortality risk.
Published: 2020
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21. Life after hepatitis C cure in HIV-infected people who inject drugs and men who have sex with men treated with direct-acting antivirals in France: Health perceptions and experiences from qualitative and quantitative findings (ANRS CO13 HEPAVIH)

Author: Trevor Goodyear, Chiara Calzolaio, Fabienne Marcellin, Rod Knight, Dominique Salmon-Ceron, Linda Wittkop, Philippe Sogni, David Zucman, Jeannie Shoveller, Marion Mora, Vincent Di Beo, Isabelle Poizot-Martin, Karine Lacombe, Patrizia Carrieri, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), British Columbia Centre on Substance Use [Vancouver, BC, Canada] (BCCSU), University of British Columbia (UBC), École des hautes études en sciences sociales (EHESS), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Team MORPH3EUS (INSERM U1219 - UB - ISPED), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Santé publique [CHU Bordeaux], CHU de bordeaux, Service de Médecine Interne [Hôpital Foch, Suresnes] (SMI), Hôpital Foch [Suresnes], Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Maladies infectieuses et tropicales [AP-HP Hôpital Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Dupuis, Christine
Subjects: Male, medicine.medical_specialty, mixed methods, [SDV]Life Sciences [q-bio], men who have sex with men, people who inject drugs, Qualitative property, HIV Infections, DIRECT ACTING ANTIVIRALS, Antiviral Agents, Article, Men who have sex with men, 03 medical and health sciences, Sexual and Gender Minorities, 0302 clinical medicine, Mixed approach, Quality of life (healthcare), Virology, Hiv infected, medicine, HIV-HCV co-infection, Humans, 030212 general & internal medicine, Prospective Studies, Homosexuality, Male, Substance Abuse, Intravenous, direct-acting antivirals, Hepatology, business.industry, virus diseases, Hepatitis C, Hepatitis C, Chronic, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Pharmaceutical Preparations, Family medicine, Cohort, Quality of Life, 030211 gastroenterology & hepatology, Perception, business
Abstract: International audience; There remains a substantial gap in our understandings of the life experiences of patients following HCV cure among HIV-HCV-co-infected people who inject drugs (PWID) and men who have sex with men (MSM), two key populations targeted for HCV elimination. We described the experiences and perspectives of HIV-positive PWID and MSM, HCV-cured following treatment with direct-acting antivirals (DAA). We used an exploratory sequential mixed approach using both qualitative data (semi-structured interviews with 27 PWID and 20 MSM) and quantitative data (self-administered questionnaires with 89 PWID) via the prospective ANRS CO13 HEPAVIH cohort. PWID reported improvements in physical health-related quality of life (HRQL) and self-reported symptoms following treatment, but no significant change in mental HRQL. During interviews, several MSM, more recently diagnosed with HCV, expressed less concern regarding HCV than HIV infection and interpreted improvements in their overall well-being after HCV cure to be more related to a closer connection with healthcare providers than with viral elimination. By contrast, PWID, particularly those previously exposed to interferon-based treatments, described major improvements in their physical HRQL. Both MSM and PWID reported improvements in cognitive or psychological wellbeing, and a majority of them reported some degree of concern over potential HCV reinfection. To conclude, though health benefits of HCV cure concern both groups, HIV-infected PWID and MSM may have different representations and experiences following DAA treatment, related to their history with HCV. They are thus likely to benefit from holistic, post-treatment follow-up care that is responsive to their evolving health and social contexts.
Published: 2020
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22. Hematopoiesis: A Layered Organization Across Chordate Species

Author: Ramy Elsaid, Francisca Soares-da-Silva, Marcia Peixoto, Dali Amiri, Nathan Mackowski, Pablo Pereira, Antonio Bandeira, Ana Cumano, Instituto de Investigação e Inovação em Saúde, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), This work was financed by the PPU Pasteur Ph.D. program. This work was financed by the Institut Pasteur, INSERM, Pasteur-Weizmann Foundation and ANR (grant Twothyme and Epi-Dev) through grants to AC, by REVIVE (Investissement d’Avenir, ANR-10-LABX-73) through grants to AC and RE, by FCT through the grants PD/BD/114128/2015 and POCI-0100145-FEDER-01638 to FS, and the grant SFRH/BD/143605/2019 to MP, ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universidade do Porto = University of Porto, Vougny, Marie-Christine, and Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID
Subjects: Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Hematopoieisis, embryo, lymphopoieis, Review, Biology, 03 medical and health sciences, Cell and Developmental Biology, 0302 clinical medicine, Immune system, layered, evo devo biology, Progenitor cell, lcsh:QH301-705.5, Tissue homeostasis, 030304 developmental biology, 0303 health sciences, hematopoieisis, Innate lymphoid cell, Cell Biology, Layered, Cell biology, Haematopoiesis, Lymphopoieis, lcsh:Biology (General), Embryo, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Stem cell, Evo devo biology, Developmental Biology, Homing (hematopoietic)
Abstract: The identification of distinct waves of progenitors during development, each corresponding to a specific time, space, and function, provided the basis for the concept of a “layered” organization in development. The concept of a layered hematopoiesis was established by classical embryology studies in birds and amphibians. Recent progress in generating reliable lineage tracing models together with transcriptional and proteomic analyses in single cells revealed that, also in mammals, the hematopoietic system evolves in successive waves of progenitors with distinct properties and fate. During embryogenesis, sequential waves of hematopoietic progenitors emerge at different anatomic sites, generating specific cell types with distinct functions and tissue homing capacities. The first progenitors originate in the yolk sac before the emergence of hematopoietic stem cells, some giving rise to progenies that persist throughout life. Hematopoietic stem cell-derived cells that protect organisms against environmental pathogens follow the same sequential strategy, with subsets of lymphoid cells being only produced during embryonic development. Growing evidence indicates that fetal immune cells contribute to the proper development of the organs they seed and later ensure life-long tissue homeostasis and immune protection. They include macrophages, mast cells, some ¿d T cells, B-1 B cells, and innate lymphoid cells, which have “non-redundant” functions, and early perturbations in their development or function affect immunity in the adult. These observations challenged the view that all hematopoietic cells found in the adult result from constant and monotonous production from bone marrow-resident hematopoietic stem cells. In this review, we evaluate evidence for a layered hematopoietic system across species. We discuss mechanisms and selective pressures leading to the temporal generation of different cell types. We elaborate on the consequences of disturbing fetal immune cells on tissue homeostasis and immune development later in life. This work was financed by the PPU Pasteur Ph.D. program. This work was financed by the Institut Pasteur, INSERM, Pasteur-Weizmann Foundation and ANR (grant Twothyme and Epi-Dev) through grants to AC; by REVIVE (Investissement d’Avenir; ANR-10-LABX-73) through grants to AC and RE; by FCT through the grants PD/BD/114128/2015 and POCI-0100145-FEDER-01638 to FS; and the grant SFRH/BD/143605/2019 to MP.
Published: 2020
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23. FIB-4 index to rule-out advanced liver fibrosis in NAFLD patients

Author: Emmanuel Tsochatzis, Stanislas Pol, Benoit Terris, Lucia Parlati, Anaïs Vallet-Pichard, Vincent Mallet, Philippe Sogni, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Royal Free Hospital [London, UK], University College of London [London] (UCL), CCSD, Accord Elsevier, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Gynecology, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], Disease progression, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Medicine, 030211 gastroenterology & hepatology, business, 030304 developmental biology
Abstract: Key pointsThe FIB-4 index is a biomarker of advanced hepatic fibrosis in a context of fatty liver disease.The calculation of the FIB-4 index requires of age, serum ALT and AST transaminase levels and platelet count.A FIB-4 index < 1.45 in a context of fatty liver disease excludes clinically significant hepatic fibrosis.Additional explorations are mandatory to excluded hepatic fibrosis for a a FIB-4 index > 1.45 in a context of fatty liver disease.A complete hepatological workup is mandatory for a FIB-4 index > 3.25 in a context of fatty liver disease., Points essentielsL’index FIB-4 est un biomarqueur simple pour diagnostiquer la fibrose hépatique avancée dans un contexte de stéatose.Le calcul de l’index FIB-4 nécessite de connaître l’âge, les transaminases ALT et AST et le taux de plaquettes.Un index FIB-4 < 1,45 dans un contexte de stéatose permet d’exclure une fibrose hépatique cliniquement significative.Un index FIB-4 > 1,45 dans un contexte de stéatose indique des explorations complémentaires, par exemple une élastométrie.Un index FIB-4 > 3,25 dans un contexte de stéatose évoque une fibrose hépatique avancée et indique une évaluation hépatologique complète.
Published: 2019
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24. [FIB-4 index to rule-out advanced liver fibrosis in NAFLD patients]

Author: Mallet, Vincent, Parlati, Lucia, Vallet-Pichard, Anaïs, Terris, Benoit, Tsochatzis, Emmanuel, Sogni, Philippe, Pol, Stanislas, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Royal Free Hospital [London, UK], and University College of London [London] (UCL)
Subjects: Diagnosis, Differential, Liver Cirrhosis, Male, Liver Function Tests, Non-alcoholic Fatty Liver Disease, [SDV]Life Sciences [q-bio], Disease Progression, Health Status Indicators, Humans, Middle Aged, Biomarkers
Abstract: International audience; Key pointsThe FIB-4 index is a biomarker of advanced hepatic fibrosis in a context of fatty liver disease.The calculation of the FIB-4 index requires of age, serum ALT and AST transaminase levels and platelet count.A FIB-4 index < 1.45 in a context of fatty liver disease excludes clinically significant hepatic fibrosis.Additional explorations are mandatory to excluded hepatic fibrosis for a a FIB-4 index > 1.45 in a context of fatty liver disease.A complete hepatological workup is mandatory for a FIB-4 index > 3.25 in a context of fatty liver disease.; Points essentielsL’index FIB-4 est un biomarqueur simple pour diagnostiquer la fibrose hépatique avancée dans un contexte de stéatose.Le calcul de l’index FIB-4 nécessite de connaître l’âge, les transaminases ALT et AST et le taux de plaquettes.Un index FIB-4 < 1,45 dans un contexte de stéatose permet d’exclure une fibrose hépatique cliniquement significative.Un index FIB-4 > 1,45 dans un contexte de stéatose indique des explorations complémentaires, par exemple une élastométrie.Un index FIB-4 > 3,25 dans un contexte de stéatose évoque une fibrose hépatique avancée et indique une évaluation hépatologique complète.
Published: 2019
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25. Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing

Author: Anastasia du Halgouet, Aurélie Darbois, Mansour Alkobtawi, Martin Mestdagh, Aurélia Alphonse, Virginie Premel, Thomas Yvorra, Ludovic Colombeau, Raphaël Rodriguez, Dietmar Zaiss, Yara El Morr, Hélène Bugaut, François Legoux, Laetitia Perrin, Selim Aractingi, Rachel Golub, Olivier Lantz, Marion Salou, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universität Regensburg (UR), University Hospital Regensburg, Leibniz Institute of Immunotherapy - University of Regensburg, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This study received funding from the following institutions: Institut National de la Santé et de la Recherche Médicale (O.L.), Institut Curie (O.L.), Agence Nationale de la Recherche Grant MAITANR-16-CE15-0020-01 (O.L.), Agence Nationale de la Recherche Grant MAIT-repair ANR-20-CE15-0028-01 (O.L.), Agence Nationale de la Recherche ANR-10-IDEX-0001-02 PSL (O.L.), European Research Council ERC-2019-ADG-885435 (O.L.), and Fondation pour la Recherche Médicale FDT202106013036 (A.d.H.)., ANR-16-CE15-0020,MAIT,Biologie des cellules MAIT in vivo en situation normale ou pathologique(2016), ANR-20-CE15-0028,MAIT-repair,Mécanisme de la fonction de réparation tissulaire des lymphocytes MAIT(2020), and ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010)
Subjects: MESH: Minor Histocompatibility Antigens, MESH: Humans, [SDV]Life Sciences [q-bio], Immunology, MAIT cells, MESH: Receptors, Antigen, T-Cell, MESH: Amphiregulin, MESH: Mucosal-Associated Invariant T Cells, CXCR6 chemokine receptor, MESH: Histocompatibility Antigens Class I, TCR signaling, MESH: Wound Healing, Infectious Diseases, scRNA-seq, Immunology and Allergy, MESH: Animals, amphiregulin, tissue repair, skin excision, MESH: Mice
Abstract: International audience; Tissue repair processes maintain proper organ function following mechanical or infection-related damage. In addition to antibacterial properties, mucosal associated invariant T (MAIT) cells express a tissue repair transcriptomic program and promote skin wound healing when expanded. Herein, we use a human-like mouse model of full-thickness skin excision to assess the underlying mechanisms of MAIT cell tissue repair function. Single-cell RNA sequencing analysis suggested that skin MAIT cells already express a repair program at steady state. Following skin excision, MAIT cells promoted keratinocyte proliferation, thereby accelerating healing. Using skin grafts, parabiosis, and adoptive transfer experiments, we show that MAIT cells migrated into the wound in a T cell receptor (TCR)-independent but CXCR6 chemokine receptor-dependent manner. Amphiregulin secreted by MAIT cells following excision promoted wound healing. Expression of the repair function was probably independent of sustained TCR stimulation. Overall, our study provides mechanistic insights into MAIT cell wound healing function in the skin.
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25 results on '"Lymphocytes et Immunité - Lymphocytes and Immunity"'

1. A lentiviral vector expressing a dendritic cell-targeting multimer induces mucosal anti-mycobacterial CD4+ T-cell immunity

2. Mice Humanized for MHC and hACE2 with High Permissiveness to SARS-CoV-2 Omicron Replication

3. Assembling the layers of the hematopoietic system: A window of opportunity for thymopoiesis in the embryo

4. Inflammatory-driven NK cell maturation and its impact on pathology

5. Hypoxia promotes a perinatal-like progenitor state in the adult murine epicardium

6. Synergistic prostaglandin E synthesis by myeloid and endothelial cells promotes fetal hematopoietic stem cell expansion in vertebrates

7. A lentiviral vector encoding fusion of light invariant chain and mycobacterial antigens induces protective CD4+ T cell immunity

8. Signaling Pathways Tuning Innate Lymphoid Cell Response to Hepatocellular Carcinoma

9. Identification of fetal liver stroma in spectral cytometry using the parameter autofluorescence†

10. An intranasal lentiviral booster reinforces the waning mRNA vaccine-induced SARS-CoV-2 immunity that it targets to lung mucosa

11. Brain Cross‐Protection against SARS‐CoV‐2 Variants by a Lentiviral Vaccine in New Transgenic Mice

12. Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis

13. Full-Lung Prophylaxis against SARS-CoV-2 by One-Shot or Booster Intranasal Lentiviral Vaccination in Syrian Golden Hamsters

14. The Notch signaling pathway involvement in innate lymphoid cell biology

15. Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life

16. A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner

17. Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models

18. The interplay between innate lymphoid cells and T cells

19. Crosstalk Between the Hepatic and Hematopoietic Systems During Embryonic Development

20. Elevated Fatty Liver Index as a Risk Factor for All‐Cause Mortality in Human Immunodeficiency Virus–Hepatitis C Virus–Coinfected Patients (ANRS CO13 HEPAVIH Cohort Study)

21. Life after hepatitis C cure in HIV-infected people who inject drugs and men who have sex with men treated with direct-acting antivirals in France: Health perceptions and experiences from qualitative and quantitative findings (ANRS CO13 HEPAVIH)

22. Hematopoiesis: A Layered Organization Across Chordate Species

23. FIB-4 index to rule-out advanced liver fibrosis in NAFLD patients

24. [FIB-4 index to rule-out advanced liver fibrosis in NAFLD patients]

25. Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing

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25 results on '"Lymphocytes et Immunité - Lymphocytes and Immunity"'

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