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1. Cutaneous Squamous Cell Carcinoma Development Is Associated with a Temporal Infiltration of ILC1 and NK Cells with Immune Dysfunctions

Author

Roger Rezzonico, Veronique M. Braud, Ophelie Vermeulen, Sokchea Khou, Gilles Poissonnet, Bernard Mari, Alexandra Popa, Roxane Elaldi, Aida Meghraoui-Kheddar, Fabienne Anjuère, Carmelo Luci, Pierre Bourdely, Anne Sudaka, Alexandre Bozec, Franck Bihl, Julie Cazareth, Gilles Ponzio, Pascal Barbry, Selma Bekri, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Centre Antoine Lacassagne, Nice, France

Subjects
0301 basic medicine, Adoptive cell transfer, Skin Neoplasms, [SDV]Life Sciences [q-bio], Population, Dermatology, Biology, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Immunophenotyping, Immune system, TIGIT, Animals, Humans, Lymphocytes, education, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Neoplasm Staging, Tumor microenvironment, education.field_of_study, Natural Cytotoxicity Triggering Receptor 1, Innate lymphoid cell, Cell Biology, Adoptive Transfer, Immunity, Innate, 3. Good health, Killer Cells, Natural, 030104 developmental biology, Basic-Leucine Zipper Transcription Factors, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, Carcinoma, Squamous Cell
Abstract

NK cells and tissue-resident innate lymphoid cells (ILCs) are innate effectors found in the skin. To investigate their temporal dynamics and specific functions throughout the development of cutaneous squamous cell carcinoma (cSCC), we combined transcriptomic and immunophenotyping analyses in mouse and human cSCCs. We identified an infiltration of NK cells and ILC1s as well as the presence of a few ILC3s. Adoptive transfer of NK cells in NK cell‒ and ILC-deficient Nfil3−/− mice revealed a role for NK cells in early control of cSCC. During tumor progression, we identified a population skewing with the infiltration of atypical ILC1 secreting inflammatory cytokines but reduced levels of IFN-γ at the papilloma stage. NK cells and ILC1s were functionally impaired, with reduced cytotoxicity and IFN-γ secretion associated with the downregulation of activating receptors. They also showed a high degree of heterogeneity in mouse and human cSCCs with the expression of several markers of exhaustion, including TIGIT on NK cells and PD-1 and TIM-3 on ILC1s. Our data show an enrichment in inflammatory ILC1 at the precancerous stage together with impaired antitumor functions in NK cells and ILC1 that could contribute to the development of cSCC and thus suggest that future immunotherapies should take both ILC populations into account.

Published
2021
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2. MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice

Author

Aline Gréchez-Cassiau, Stéphanie Patouraux, Sophie Guerin, Franck Delaunay, Philippe Gual, Anthony A Ruberto, Carmelo Luci, Déborah Rousseau, Malayannan Subramaniam, Albert Tran, Stéphanie Bonnafous, Michèle Teboul, Pierre S. Leclere, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Department of Biochemistry and Molecular Biology, and Mayo Clinic

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Physiology, [SDV]Life Sciences [q-bio], Circadian clock, Kruppel-Like Transcription Factors, lcsh:Medicine, Apoptosis, Caspase 3, Biology, Article, Choline, Mice, 03 medical and health sciences, Methionine, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, medicine, Animals, Gene silencing, Circadian rhythm, lcsh:Science, Cells, Cultured, Mice, Knockout, Liver injury, Multidisciplinary, Tumor Necrosis Factor-alpha, lcsh:R, medicine.disease, Fibrosis, Circadian Rhythm, Diet, Mice, Inbred C57BL, CLOCK, Disease Models, Animal, Metabolism, 030104 developmental biology, Endocrinology, Liver, 030220 oncology & carcinogenesis, Early Growth Response Transcription Factors, Hepatocytes, lcsh:Q, Steatosis, Steatohepatitis, Biomarkers
Abstract

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor.

Published
2020
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3. Hepatic FNDC5 is a potential local protective factor against Non-Alcoholic Fatty Liver

Author

Antonio Iannelli, Philippe Gual, Stéphanie Bonnafous, Stéphanie Patouraux, Béatrice Bailly-Maitre, Sandra Lacas-Gervais, Pierre S. Leclere, Arnaud Sans, Clémence M. Canivet, Rodolphe Anty, Carmelo Luci, Albert Tran, Déborah Rousseau, CCMA - Centre Commun de Microscopie Appliquée, and Université Nice Côte D'Azur

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Biopsy, [SDV]Life Sciences [q-bio], Primary Cell Culture, Bariatric Surgery, Adipose tissue, Apoptosis, Diet, High-Fat, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Downregulation and upregulation, Non-alcoholic Fatty Liver Disease, Internal medicine, medicine, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Liver injury, Chemistry, Gene Expression Profiling, Lipogenesis, Fatty liver, Hep G2 Cells, Middle Aged, Protective Factors, medicine.disease, FNDC5, Fibronectins, Obesity, Morbid, Up-Regulation, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Liver, 030220 oncology & carcinogenesis, Hepatocyte, Hepatocytes, Molecular Medicine, Female, Insulin Resistance, Steatosis, Phosphoenolpyruvate Carboxykinase (ATP)
Abstract

The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK, a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5-silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N-acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death.

Published
2020
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4. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice

Author

Rodolphe Anty, Guido Kroemer, Cynthia Lebeaupin, Philippe Gual, Gilbert Adam, Albert Tran, Carmelo Luci, Stéphanie Patouraux, Déborah Rousseau, Frederic Luciano, Antonio Iannelli, Sandra Lacas-Gervais, Sandrine Marchetti, Déborah Vallée, Stéphanie Bonnafous, Béatrice Bailly-Maitre, CCMA - Centre Commun de Microscopie Appliquée, and Université Nice Côte D'Azur

Subjects
0301 basic medicine, Male, medicine.medical_specialty, XBP1, Inflammasomes, [SDV]Life Sciences [q-bio], Endoribonuclease, Immunoblotting, Cell Culture Techniques, Aspartate transaminase, Protein Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, Mice, Non-alcoholic Fatty Liver Disease, Internal medicine, Nonalcoholic fatty liver disease, Endoribonucleases, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Hepatology, biology, Cell Death, Chemistry, Membrane Proteins, Inflammasome, medicine.disease, Endoplasmic Reticulum Stress, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Alanine transaminase, Liver, Unfolded protein response, biology.protein, Cytokines, Steatohepatitis, Apoptosis Regulatory Proteins, medicine.drug, Signal Transduction
Abstract

Endoplasmic reticulum (ER) stress is activated in nonalcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation, and cell death underlie the transition from steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH). B-cell lymphoma 2 (BCL2)-associated X protein (Bax) inhibitor-1 (BI-1), a negative regulator of the ER stress sensor, inositol-requiring enzyme 1 alpha (IRE1α), has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI-1 would render the liver vulnerable to NASH because of unrestrained IRE1α signaling. ER stress was induced in wild-type and BI-1-/- mice acutely by tunicamycin (TM) injection (1 mg/kg) or chronically by high-fat diet (HFD) feeding to determine NAFLD phenotype. Livers of TM-treated BI-1-/- mice showed IRE1α-dependent NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, hepatocyte death, fibrosis, and dysregulated lipid homeostasis that led to liver failure within a week. The analysis of human NAFLD liver biopsies revealed BI-1 down-regulation parallel to the up-regulation of IRE1α endoribonuclease (RNase) signaling. In HFD-fed BI-1-/- mice that presented NASH and type 2 diabetes, exaggerated hepatic IRE1α, X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP) expression was linked to activated NLRP3 inflammasome and caspase-1/-11. Rises in interleukin (IL)-1β, IL-6, monocyte chemoattractant protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1), and alanine transaminase (ALT)/aspartate transaminase (AST) levels revealed significant inflammation and injury, respectively. Pharmacological inhibition of IRE1α RNase activity with the small molecules, STF-083010 or 4μ8c, was evaluated in HFD-induced NAFLD. In BI-1-/- mice, either treatment effectively counteracted IRE1α RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1α RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1α axis knockdown or its inhibition with STF-083010 or 4μ8c. Conclusion Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or by BI-1 may represent a tangible therapeutic strategy for NASH. (Hepatology 2018).

Published
2018
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5. CD8 + T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity

Author

Nicolas Glaichenhaus, Kevin Lebrigand, Sarah Nicolas, Marie-Jeanne Arguel, Carmelo Luci, Joëlle Chabry, Maud Maillaut, Mélanie Guyot, Anne Lazzari, Douglas Daoudlarian, Hadi Zarif, Valentine Golzné, Alice Guyon, Frédéric Brau, Catherine Heurteaux, Julie Cazareth, Elisa Dourneau, Agnès Paquet, Salma Hosseiny, Agnès Petit-Paitel, María Magdalena Canali, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Immunologie des muqueuses et inflammation, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Immunité muqueuse et vaccination, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Guyon, Alice, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)

Subjects
0301 basic medicine, mice, hippocampus, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Immunology, Hippocampus, Hippocampal formation, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Cytotoxic T cell, ComputingMilieux_MISCELLANEOUS, mice, brain plasticity, hippocampus, CD4 + T cells, enriched environment, Endocrine and Autonomic Systems, Chemistry, Neurogenesis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, CD28, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell biology, 030104 developmental biology, MRNA Sequencing, CD4 + T cells, Synaptic plasticity, Neuroscience, brain plasticity, 030217 neurology & neurosurgery, CD8, enriched environment
Abstract

International audience; Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4 + T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8 + T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hip-pocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8 + T cells. In addition, we show that spleen CD8 + T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFa release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8 + CD44 + CD62L low and CD62L hi T cells repartition 4) transcrip-tomic signature as revealed by RNA sequencing. CD8 + T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8 + T cells are essential mediators of beneficial EE effects on brain plasticity and cogni-tion. Additionally, we propose that EE differentially primes CD8 + T cells leading to behavioral improvement.

Published
2018
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6. Escherichia coli α-Hemolysin Counteracts the Anti-Virulence Innate Immune Response Triggered by the Rho GTPase Activating Toxin CNF1 during Bacteremia

Author

Mamady Diabate, Patrick Munro, Elsa Garcia, Arnaud Jacquel, Gregory Michel, Sandrine Obba, Diogo Goncalves, Carmelo Luci, Sandrine Marchetti, Dieter Demon, Clara Degos, Yassina Bechah, Jean-Louis Mege, Mohamed Lamkanfi, Patrick Auberger, Jean-Pierre Gorvel, Lynda Maria Stuart, Luce Landraud, Emmanuel Lemichez, Laurent Boyer, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Bactériologie, CHU de Nice, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Department of Medical Protein Research, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Benaroya Research Institute at Virginia Mason, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Universiteit Gent = Ghent University (UGENT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), and HAL AMU, Administrateur

Subjects
BACTERIAL, INTERLEUKIN-1-BETA CONVERTING-ENZYME, QH301-705.5, Virulence Factors, Bacterial Toxins, Interleukin-1beta, PROTEIN, Bacteremia, Hemolysin Proteins, Mice, Escherichia coli, Animals, Biology (General), Escherichia coli Infections, CASPASE-1, Mice, Knockout, Mice, Inbred BALB C, PATHOGENS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Virulence, Escherichia coli Proteins, Biology and Life Sciences, RC581-607, Immunity, Innate, Mice, Inbred C57BL, Disease Models, Animal, INFLAMMASOME, Host-Pathogen Interactions, PROTEASOMAL DEGRADATION, Female, Immunologic diseases. Allergy, E.-COLI, BLADDER INFECTION, SYSTEM, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Research Article
Abstract

The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1β signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1β antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1β and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the α-hemolysin toxin inhibits IL-1β secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia., Author Summary The pathogenic potentials of most microbes depend on a repertoire of virulence factors. Despite major progress in the understanding of the molecular mechanisms underlying the activities of bacterial effectors, little is known about how they cooperate during infection to overcome host immune defenses and promote microbial persistence. Here, we investigated the roles of two uropathogenic Escherichia coli (UPEC) effectors that are co-ordinately expressed, α-hemolysin (HlyA) and cytotoxic necrotizing factor 1 (CNF1). We demonstrated that the HlyA toxin is critical for bacterial stability in the blood and showed that one important role of HlyA is to inhibit the CNF1-induced host response. Collectively, these findings reveal why the coordinated activities of HlyA and CNF1 are necessary for the full virulence of UPEC. Moreover, they unravel a HlyA-driven counter-defense mechanism used by bacteria to facilitate their survival.

Published
2015
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7. Antigen-bearing dendritic cells from the sublingual mucosa recirculate to distant systemic lymphoid organs to prime mucosal CD8 T cells

Author

Selma Bekri, T Juhel, Carmelo Luci, Catherine Hervouet, Veronique M. Braud, Cecil Czerkinsky, Franck Bihl, Fabienne Anjuère, Department of Immunobiology, King‘s College London, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), International Vaccine Institute (IVI), Immunité muqueuse et vaccination, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Time Factors, Lymphoid Tissue, [SDV]Life Sciences [q-bio], Immunology, chemical and pharmacologic phenomena, Spleen, Cell Communication, CD8-Positive T-Lymphocytes, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigen, Cell Movement, Immunology and Allergy, Medicine, Cytotoxic T cell, Animals, Antigens, Mouth Floor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Effector, Mouth Mucosa, Dendritic Cells, Lymphatic system, medicine.anatomical_structure, Immunization, Lymph, Lymph Nodes, business, CD8, 030215 immunology
Abstract

Effector T cells are described to be primed in the lymph nodes draining the site of immunization and to recirculate to effector sites. Sublingual immunization generates effector T cells able to disseminate to the genital tract. Herein, we report an alternative mechanism that involves the recirculation of antigen-bearing dendritic cells (DCs) in remote lymphoid organs to prime T cells. Sublingual immunization with a muco-adhesive model antigen unable to diffuse through lymphatic or blood vessels induced genital CD8 T cells. The sublingual draining lymph nodes were not mandatory to generate these lymphocytes, and antigen-bearing DCs from distant lymph nodes and spleen were able to prime specific CD8 T cells in a time- and dose-dependent manner. This study demonstrates, for the first time, that antigen-bearing DCs originating from the site of immunization recirculate to distant lymphoid organs and provides insights into the mechanism of distant CD8 T-cell generation by sublingual immunization.

Published
2014
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8. Sublingual immunization with an HIV subunit vaccine induces antibodies and cytotoxic T cells in the mouse female genital tract

Author

Fabienne Anjuère, Carmelo Luci, Concepción Marañón, Nicolas Çuburu, Catherine Hervouet, Anne Hosmalin, Cecil Czerkinsky, Lene Vimeux, Selma Bekri, Magali Cremel, Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité muqueuse et vaccination, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - IFR50 - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR50 - Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM) - Aix Marseille Université (AMU) - Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
MESH: HIV Envelope Protein gp41, HIV Infections, HIV Antibodies, Mice, 0302 clinical medicine, Cytotoxic T cell, MESH : Female, MESH: Animals, MESH : Mucous Membrane, MESH : Administration, Sublingual, AIDS Vaccines, MESH: Immunoglobulin G, Mice, Inbred BALB C, 0303 health sciences, biology, MESH: Dendritic Cells, virus diseases, Genitalia, Female, MESH: HIV Infections, MESH : Mice, Transgenic, HIV Envelope Protein gp41, 3. Good health, Vaccination, MESH : Genitalia, Female, Infectious Diseases, medicine.anatomical_structure, MESH: Administration, Sublingual, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, MESH : Immunoglobulin G, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Cross-Priming, MESH : AIDS Vaccines, MESH: Mice, Transgenic, T cell, Administration, Sublingual, MESH: Mice, Inbred BALB C, MESH : Immunoglobulin A, Mice, Transgenic, MESH : Mice, Inbred C57BL, Gp41, Virus, MESH : T-Lymphocytes, Cytotoxic, MESH : HIV Antibodies, 03 medical and health sciences, Cross-Priming, Immune system, MESH: AIDS Vaccines, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cross-Priming, MESH : HIV Infections, medicine, Animals, Humans, MESH: Immunoglobulin A, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Mucous Membrane, MESH: Humans, General Veterinary, General Immunology and Microbiology, MESH: HIV Antibodies, MESH : Humans, Public Health, Environmental and Occupational Health, MESH: Mucous Membrane, Dendritic Cells, Virology, Immunoglobulin A, Mice, Inbred C57BL, MESH : HIV Envelope Protein gp41, Immunization, MESH : Dendritic Cells, Immunoglobulin G, Immunology, biology.protein, MESH : Animals, MESH: Genitalia, Female, MESH: T-Lymphocytes, Cytotoxic, MESH: Female, T-Lymphocytes, Cytotoxic, 030215 immunology
Abstract

International audience; A vaccine against heterosexual transmission by human immunodeficiency virus (HIV) should generate cytotoxic and antibody responses in the female genital tract and in extra-genital organs. We report that sublingual immunization with HIV-1 gp41 and a reverse transcriptase polypeptide coupled to the cholera toxin B subunit (CTB) induced gp41-specific IgA antibodies and antibody-secreting cells, as well as reverse transcriptase-specific CD8 T cells in the genital mucosa, contrary to intradermal immunization. Conjugation of the reverse transcriptase peptide to CTB favored its cross-presentation by human dendritic cells to a T cell line from an HIV(+) patient. Sublingual vaccination could represent a promising vaccine strategy against heterosexual transmission of HIV-1.

Published
2010
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9. Langerhans cells prime IL-17-producing T cells and dampen genital cytotoxic responses following mucosal immunization

Author

Déborah Rousseau, Bernard Malissen, Cecil Czerkinsky, Fabienne Anjuère, Nicolas Rol, Catherine Hervouet, Adrien Kissenpfennig, Carmelo Luci, Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité muqueuse et vaccination, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mucosal Immunology Section, International Vaccine Institute (IVI), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Mouth Mucosa, MESH: Vaccines, Conjugate, MESH: Interleukin-17, MESH: Amino Acid Sequence, CD8-Positive T-Lymphocytes, Mice, 0302 clinical medicine, MESH: Administration, Intravaginal, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, MESH: Peptide Fragments, Cells, Cultured, MESH: Langerhans Cells, 0303 health sciences, education.field_of_study, biology, integumentary system, MESH: Dendritic Cells, Interleukin-17, hemic and immune systems, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Vagina, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Interleukin 17, MESH: Cells, Cultured, Cholera Toxin, Langerin, Ovalbumin, MESH: Mice, Transgenic, Immunology, Population, Molecular Sequence Data, Mice, Transgenic, chemical and pharmacologic phenomena, MESH: Cytotoxicity Tests, Immunologic, MESH: Coculture Techniques, 03 medical and health sciences, Immunity, MESH: Mice, Inbred C57BL, Animals, Amino Acid Sequence, education, MESH: Mice, MESH: Cholera Toxin, 030304 developmental biology, Vaccines, Conjugate, MESH: Molecular Sequence Data, MESH: Ovalbumin, Epidermis (botany), Mouth Mucosa, Dendritic Cells, Cytotoxicity Tests, Immunologic, Coculture Techniques, Peptide Fragments, Mice, Inbred C57BL, CTL, Administration, Intravaginal, Immunization, MESH: Vagina, Langerhans Cells, biology.protein, MESH: Female, 030215 immunology
Abstract

Langerhans cells (LCs) are dendritic cells (DCs) localized in stratified epithelia, such as those overlaying skin, buccal mucosa, and vagina. The contribution of LCs to the promotion or control of immunity initiated at epithelial sites remains debated. We report in this paper that an immunogen comprising OVA linked to the B subunit of cholera toxin, used as delivery vector, was efficient to generate CTLs after vaginal immunization. Using Lang-EGFP mice, we evaluated the contribution of distinct DC subsets to the generation of CD4 and CD8 T cell responses. We demonstrate that the vaginal epithelium, unlike the skin epidermis, includes a minor population of LCs and a major subset of langerin− DCs. Intravaginally administered Ag is taken up by LCs and langerin− DCs and carried up to draining lymph nodes, where both subsets prime CD8 T cells, unlike blood-derived DCs, although with distinct capabilities. LCs prime CD8 T cells with a cytokine profile dominated by IL-17, whereas Lang− DCs induce IFN-γ–producing T cells. Using Lang-DTR-EGFP mice to ensure a transient ablation of LCs, we found that these cells not only are dispensable for the generation of genital CTL responses but also downregulate these responses, by a mechanism that may involve IL-10 and IL-17 cytokines. This finding has implications for the development of mucosal vaccines and immunotherapeutic strategies designed for the targeting of DCs.

Published
2010
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10. Immunoadjuvant Properties of the Rho Activating Factor CNF1 in Prophylactic and Curative Vaccination against Leishmania infantum

Author

Laurent Boyer, Emmanuel Lemichez, Nassim Mathal, Bernard Ferrua, Daniel Gillet, Patrick Munro, Pierre Marty, Grégory Michel, Toxines bactériennes dans la relation hôtes-pathogènes, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by the Groupe d’Action Contre la Leishmaniose (GACL), by institutional funding from INSERM, grants from the Fondation Infectiopôle Sud, the Agence Nationale de la Recherche (ANR 11BSV3 004 01), the 'Investments for the Future' LABEX SIGNALIFE ANR-11-LABX-0028-01 and the C3M animal facility. NM was supported by DGA and the joint ministerial program of R&D against CBRNE threats. SIMOPRO is a member of the laboratory of Excellence LERMIT supported by the grant from the Agence Nationale de la Recherche (ANR-10-LABEX-33)., We are grateful to Dr Mery Tulic and Carmelo Luci for critical reading of the manuscript. We thank Veronique Corcelle and the C3M animal facility team (Yannick Michelle, Sandrine Verger and Alexandre Ipekdjian) for their help and valuable assistance with animal care., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Life Cycles, MESH: Bacterial Toxins/genetics, Physiology, T-Lymphocytes, [SDV]Life Sciences [q-bio], MESH: Escherichia coli Proteins/metabolism, lcsh:Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Protozoology, Mice, 0302 clinical medicine, MESH: Antigens, Protozoan/immunology, Immune Physiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Medicine and Health Sciences, Public and Occupational Health, MESH: Animals, MESH: Administration, Intranasal, Leishmania infantum, Enzyme-linked immunoassays, lcsh:Science, MESH: Immunity, Humoral/immunology, Protozoans, Leishmania, Mice, Inbred BALB C, MESH: Leishmania infantum/pathogenicity, Multidisciplinary, biology, Escherichia coli Proteins, Vaccination, MESH: Interleukin-2/metabolism, Parasitic diseases, MESH: Bacterial Toxins/metabolism, 3. Good health, MESH: Immunity, Humoral/physiology, medicine.anatomical_structure, MESH: Vaccination/methods, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030220 oncology & carcinogenesis, Vaccination and immunization, Female, Protozoan Life Cycles, Research Article, Bacterial Toxins, Immunology, MESH: Interleukin-4/metabolism, MESH: Mice, Inbred BALB C, Antigens, Protozoan, Spleen, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Research and Analysis Methods, MESH: Leishmania infantum/immunology, Microbiology, Immunoadjuvant, 03 medical and health sciences, Immune system, Antigen, MESH: Escherichia coli Proteins/genetics, MESH: T-Lymphocytes/immunology, medicine, Animals, Immune response, Immunoassays, MESH: Mice, Administration, Intranasal, business.industry, Intracellular parasite, Promastigotes, lcsh:R, Organisms, Biology and Life Sciences, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitic Protozoans, Immunity, Humoral, 030104 developmental biology, Humoral immunity, Immunologic Techniques, Interleukin-2, lcsh:Q, Interleukin-4, Preventive Medicine, business, MESH: Female, Developmental Biology
Abstract

International audience; There is a need to develop new effective immunoadjuvants for prophylactic or therapeutic vaccines against intracellular pathogens. The activation of Rho GTPases by bacterial cytotoxic necrotizing factor 1 (CNF1) elicits humoral protective responses against protein antigens. Here, we set out to investigate whether CNF1 activity initiates humoral immunity against co-administered parasite antigens and anti-microbial immune signaling. We report that co-administration of wild-type (WT) CNF1 with Leishmania (L.) promastigote antigens at the nasal mucosa triggered prophylactic and curative vaccine responses against this parasite. Vaccination of the mucosa with promastigote lysate antigens combined with WT CNF1 conferred protection against high inoculum L. infantum infection, which reached 82% in the spleen. Immune parameter analysis by antigen recall indicated robust T-helper (Th)1 polarization of immune memory cells, with high IL-2 and IFN-γ production combined with decreased IL-4 production. Additionally, we explored the curative effect of WT CNF1 on previously infected animals. We observed that PL combined with WT CNF1, but not the inactive C866S mutant CNF1 (mCNF1), induced a 58% decrease in the parasite burden in the spleen.

Published
2016
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