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1. A quick and robust MHC typing method for free-ranging and captive primate species

Author

K. Stanbury, N. Poirier, N. G. de Groot, Ronald E. Bontrop, N.G. de Groot, G. Blancho, G.G.M. Doxiadis, A. J. M. de Vos-Rouweler, C. de Luna, Department of Comparative Genetics and Refinement [Rijswijk, The Netherlands], Biomedical Primate Research Centre [Rijswijk] (BPRC), Writtle College [Essex, UK], University of Essex, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Theoretical Biology and Bioinformatics [Utrecht, The Netherlands], Utrecht University [Utrecht], NIH/NIAID project HHSN272201100013C., and Le Bihan, Sylvie

Subjects
0301 basic medicine, Primates, Male, DNA Copy Number Variations, Genotype, Population, Immunology, Pre-clinical research, Major histocompatibility complex, Major Histocompatibility Complex, 03 medical and health sciences, Hylobates, Genetics, Animals, Humans, Typing, Copy-number variation, education, Microsatellites, Gene, Genotyping, Phylogeny, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Polymorphism, Genetic, biology, Conservation biology, biology.organism_classification, 030104 developmental biology, biology.protein, Microsatellite, Original Article, Female, MHC, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Microsatellite Repeats
Abstract

Gene products of the major histocompatibility complex (MHC) of human and non-human primates play a crucial role in adaptive immunity, and most of the relevant genes not only show a high degree of variability (polymorphism) but also copy number variation (CNV) is observed. Due to this diversity, MHC proteins influence the capability of individuals to cope with various pathogens. MHC and/or MHC-linked gene products such as odorant receptor genes are thought to influence mate choice and reproductive success. Therefore, MHC typing of wild and captive primate populations is considered to be useful in conservation biology, which is, however, often hampered by the need of invasive and time-consuming methods. All intact Mhc-DRB genes in primates appear to possess a complex and highly divergent microsatellite, DRB-STR. A panel of 154 pedigreed olive baboons (Papio anubis) was examined for their DRB content by DRB-STR analysis of genomic DNA. Using the same methodology on DNA of feces samples, DRB variability of a silvery gibbon population (Hylobates moloch) (N = 24), an endangered species, could successfully be studied. In both species, length determination of the DRB-STR resulted in the definition of unique genotyping patterns that appeared to be specific for a certain chromosome. Moreover, the different STR lengths were shown to segregate with the allelic variation of the respective gene. The results obtained expand data gained previously on DRB-STR typing in macaques, great apes, and humans and strengthen the conclusion that this protocol is applicable in molecular ecology, conservation biology, and colony management, especially of endangered primate species. Electronic supplementary material The online version of this article (doi:10.1007/s00251-016-0968-0) contains supplementary material, which is available to authorized users.

Published
2017

2. The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis

Author

Geanncarlo Lugo-Villarino, Anthony Troegeler, Luciana Balboa, Claire Lastrucci, Carine Duval, Ingrid Mercier, Alan Bénard, Florence Capilla, Talal Al Saati, Renaud Poincloux, Ivanela Kondova, Frank A. W. Verreck, Céline Cougoule, Isabelle Maridonneau-Parini, Maria del Carmen Sasiain, Olivier Neyrolles, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Biomedical Primate Research Centre [Rijswijk] (BPRC), and Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection (IM-TB/HIV)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Chemokine, CD14, medicine.medical_treatment, Immunology, DC-SIGN, Microbiology, 03 medical and health sciences, C-type lectin, medicine, Immunology and Allergy, Macrophage, Interleukin 4, ComputingMilieux_MISCELLANEOUS, anti-inflammatory, biology, CLEC7A, Mycobacterium tuberculosis, 3. Good health, macrophages, 030104 developmental biology, Cytokine, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, C-type lectin receptors, lcsh:RC581-607
Abstract

DC-SIGN (CD209/CLEC4L) is a C-type lectin receptor (CLR) that serves as a reliable cell-surface marker of interleukin 4 (IL-4)-activated human macrophages [M(IL-4)], which historically represent the most studied subset within the M2 spectrum of macrophage activation. Although DC-SIGN plays important roles in Mycobacterium tuberculosis (Mtb) interactions with dendritic cells, its contribution to the Mtb-macrophage interaction remains poorly understood. Since high levels of IL-4 are correlated with tuberculosis (TB) susceptibility and progression, we investigated the role of DC-SIGN in M(IL-4) macrophages in the TB context. First, we demonstrate that DC-SIGN expression is present both in CD68+ macrophages found in tuberculous pulmonary lesions of non-human primates, and in the CD14+ cell population isolated from pleural effusions obtained from TB patients (TB-PE). Likewise, we show that DC-SIGN expression is accentuated in M(IL-4) macrophages derived from peripheral blood CD14+ monocytes isolated from TB patients, or in macrophages stimulated with acellular TB-PE, arguing for the pertinence of DC-SIGN-expressing macrophages in TB. Second, using a siRNA-mediated gene silencing approach, we performed a transcriptomic analysis of DC-SIGN-depleted M(IL-4) macrophages and revealed the upregulation of pro-inflammatory signals in response to challenge with Mtb, as compared to control cells. This pro-inflammatory gene signature was confirmed by RT-qPCR, cytokine/chemokine-based protein array, and ELISA analyses. We also found that inactivation of DC-SIGN renders M(IL-4) macrophages less permissive to Mtb intracellular growth compared to control cells, despite the equal level of bacteria uptake. Last, at the molecular level, we show that DC-SIGN interferes negatively with the pro-inflammatory response and control of Mtb intracellular growth mediated by another CLR, Dectin-1 (CLEC7A). Collectively, this study highlights a dual role for DC-SIGN as, on the one hand, being a host factor granting advantage for Mtb to parasitize macrophages and, on the other hand, representing a molecular switch to turn off the pro-inflammatory response in these cells to prevent potential immunopathology associated to TB.

Published
2018
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3. Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

Author

Krista G, Haanstra, Karin, Dijkman, Noun, Bashir, Jan, Bauer, Caroline, Mary, Nicolas, Poirier, Paul, Baker, Claire L, Crossan, Linda, Scobie, Bert A, 't Hart, Bernard, Vanhove, Biomedical Primate Research Centre [Rijswijk] (BPRC), Center for Brain Research [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Effimune SAS [Nantes], Glasgow Caledonian University (GCU), Department of Neuroscience [Groningen, the Netherlands], University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), This work was supported by the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 281493: Tolerance Restoration in Autoimmune Diseases by Selective Manipulation of the CD28 Costimulatory Pathway., European Project: 281493,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,TRIAD(2012), Molecular Neuroscience and Ageing Research (MOLAR), Le Bihan, Sylvie, and Tolerance Restoration In Autoimmune Diseases by selective manipulation of the CD28 costimulatory pathway - TRIAD - - EC:FP7:HEALTH2012-01-01 - 2014-12-31 - 281493 - VALID

Subjects
Encephalomyelitis, Autoimmune, Experimental, Encephalomyelitis, T-Lymphocytes, Immunology, Biology, Lymphocyte Activation, Real-Time Polymerase Chain Reaction, Myelin oligodendrocyte glycoprotein, Immune system, CD28 Antigens, MYELIN OLIGODENDROCYTE GLYCOPROTEIN, medicine, Immunology and Allergy, Animals, Humans, ADULT PATIENTS, B cell, POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Experimental autoimmune encephalomyelitis, CENTRAL-NERVOUS-SYSTEM, CD28, COMMON MARMOSETS, MULTIPLE-SCLEROSIS, medicine.disease, biology.organism_classification, Macaca mulatta, Recombinant Proteins, 3. Good health, Virus Latency, RHEUMATOID-ARTHRITIS, medicine.anatomical_structure, ANTIBODY, Virus Diseases, B-CELLS, NONHUMAN PRIMATE MODELS, biology.protein, Lymphocryptovirus, Antibody, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Costimulatory and coinhibitory receptor–ligand pairs on T cells and APC control the immune response. We have investigated whether selective blockade of CD28–CD80/86 costimulatory interactions, which preserves the coinhibitory CTLA4–CD80/86 interactions and the function of regulatory T (Treg) cells, abrogates the induction of experimental autoimmune encephalomyelitis (EAE) in rhesus monkeys. EAE was induced by intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) in CFA on day 0. FR104 is a monovalent, PEGylated-humanized Fab′ Ab fragment against human CD28, cross-reactive with rhesus monkey CD28. FR104 or placebo was administered on days 0, 7, 14, and 21. FR104 levels remained high until the end of the study (day 42). Placebo-treated animals all developed clinical EAE between days 12 and 27. FR104-treated animals did not develop clinical EAE and were sacrificed at the end of the study resulting in a significantly prolonged survival. FR104 treatment diminished T and B cell responses against rhMOG, significantly reduced CNS inflammation and prevented demyelination. The inflammatory profile in the cerebrospinal fluid and brain material was also strongly reduced. Recrudescence of latent virus was investigated in blood, spleen, and brain. No differences between groups were observed for the β-herpesvirus CMV and the polyomaviruses SV40 and SA12. Cross-sectional measurement of lymphocryptovirus, the rhesus monkey EBV, demonstrated elevated levels in the blood of FR104-treated animals. Blocking rhesus monkey CD28 with FR104 mitigated autoreactive T and B cell activation and prevented CNS pathology in the rhMOG/CFA EAE model in rhesus monkeys.

Published
2015
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4. Biochemical characterization of Plasmodium falciparum CTP:phosphoethanolamine cytidylyltransferase shows that only one of the two cytidylyltransferase domains is active

Author

Alicia Contet, Emilie Pihan, Rachel Cerdan, Marina Lavigne, Kai Wengelnik, Blandine Alberge, Dominique Douguet, Clemens H. M. Kocken, Henri Vial, Sweta Maheshwari, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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), Biomedical Primate Research Centre [Rijswijk] (BPRC), 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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Protein Conformation, Membrane lipids, Cytidylyltransferase, Plasmodium falciparum, Protozoan Proteins, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Mice, Biosynthesis, Animals, Humans, Molecular Biology, Cellular localization, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, Phosphatidylethanolamine, 0303 health sciences, Mice, Inbred BALB C, Binding Sites, Phosphatidylethanolamines, 030302 biochemistry & molecular biology, RNA Nucleotidyltransferases, Cell Biology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, biology.organism_classification, 3. Good health, Amino acid, Protein Structure, Tertiary, Kinetics, Enzyme, chemistry, Female, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

The intra-erythrocytic proliferation of the human malaria parasite Plasmodium falciparum requires massive synthesis of PE (phosphatidylethanolamine) that together with phosphatidylcholine constitute the bulk of the malaria membrane lipids. PE is mainly synthesized de novo by the CDP:ethanolamine-dependent Kennedy pathway. We previously showed that inhibition of PE biosynthesis led to parasite death. In the present study we characterized PfECT [P. falciparum CTP:phosphoethanolamine CT (cytidylyltransferase)], which we identified as the rate-limiting step of the PE metabolic pathway in the parasite. The cellular localization and expression of PfECT along the parasite life cycle were studied using polyclonal antibodies. Biochemical analyses showed that the enzyme activity follows Michaelis–Menten kinetics. PfECT is composed of two CT domains separated by a linker region. Activity assays on recombinant enzymes upon site-directed mutagenesis revealed that the N-terminal CT domain was the only catalytically active domain of PfECT. Concordantly, three-dimensional homology modelling of PfECT showed critical amino acid differences between the substrate-binding sites of the two CT domains. PfECT was predicted to fold as an intramolecular dimer suggesting that the inactive C-terminal domain is important for dimer stabilization. Given the absence of PE synthesis in red blood cells, PfECT represents a potential antimalarial target opening the way for a rational conception of bioactive compounds.

Published
2013
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5. Differential patterns of vocal similarity in tolerant and intolerant macaques

Author

Marco, Arianna De, Rebout, Nancy, Massiot, Elodie, Sanna, Andrea, Sterck, Elisabeth H.M., Langermans, Jan A.M., Cozzolino, Roberto, Thierry, Bernard, Lemasson, Alban, Sub Animal Ecology, LAS/3’R Centre ULS, Animal Ecology, Fondazione Ethoikos, Parco Faunistico di Piano dell'Abatino, Ethologie Cognitive et Sociale, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Department of Biology, Animal Ecology, Utrecht University [Utrecht], Biomedical Primate Research Centre [Rijswijk] (BPRC), Ethologie animale et humaine (EthoS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Ethoikos, Radicondoli, Parco Faunistico di Piano dell'Abattino, Parco Faunistico, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Animal Ecology, Animal Science Department, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Sub Animal Ecology, and LAS/3’R Centre ULS

Subjects
0106 biological sciences, Social style, Vocal communication, [SDV]Life Sciences [q-bio], Behavioral neuroscience, 010603 evolutionary biology, 01 natural sciences, Behavioral Neuroscience, biology.animal, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Kinship, Learning, 0501 psychology and cognitive sciences, Primate, 050102 behavioral science & comparative psychology, ComputingMilieux_MISCELLANEOUS, Dominance, Group membership, biology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Evolutionary biology, Animal Science and Zoology
Abstract

The investigation of vocal similarity between individuals has provided evidence of the flexibility of communication signals. This study evaluates the impact of group membership, affiliative bonds, kinship and dominance on acoustic similarity in two primate species with different social styles, intolerant rhesus macaques and tolerant Tonkean macaques. We focused on the fundamental frequencies of the contact calls emitted by adult females. Close kinship promoted vocal similarity between individuals in both species, and also group membership in Tonkean macaques, indicating the involvement of experiential and/or genetic factors. In rhesus macaques more similarities were observed between partners with strong or weak dominance asymmetry than between those with medium asymmetry, which again points to the role of experience. No evidence was found that dominance influences vocal similarity in Tonkean macaques. Our results provide additional evidence to the flexibility of vocal signals produced by macaques, and reveal that it is influenced by social style.

Published
2019
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6. C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells

Author

Troegeler, Anthony, Mercier, Ingrid, Cougoule, Céline, Pietretti, Danilo, Colom, André, Duval, Carine, Vu Manh, Thien-Phong, Capilla, Florence, Poincloux, Renaud, Pingris, Karine, Nigou, Jérôme, Rademann, Jörg, Dalod, Marc, Verreck, Frank, Al Saati, Talal, Lugo-Villarino, Geanncarlo, Lepenies, Bernd, Hudrisier, Denis, Neyrolles, Olivier, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona (UB), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Freie Universität Berlin, Biomedical Primate Research Centre [Rijswijk] (BPRC), Service d'anatomie et cytologie pathologiques [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Biomolecular Systems [Potsdam], Max Planck Institute of Colloids and Interfaces, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Toulouse III - Paul Sabatier (UPS), Immunometabolism and Macrophages in Tuberculosis/Human Immunodeficiency Virus-1 Co-infection (IM-TB/HIV), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), UPS CREFRE US006, Service d'Histopathologie, and Centre Hospitalier Universitaire de Purpan (CHU Purpan)

Subjects
Mice, Knockout, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, Dendritic Cells, Macaca mulatta, Mice, Inbred C57BL, STAT1 Transcription Factor, PNAS Plus, Interferon Type I, Animals, Tuberculosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lectins, C-Type, Phosphorylation, Signal Transduction
Abstract

International audience; Immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. Tuberculosis (TB) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. Here, we report that C-type lectin dendritic cell (DC) immunoreceptor (DCIR), a key component in DC homeostasis, is required to modulate lung inflammation and bacterial burden in TB. DCIR is abundantly expressed in pulmonary lesions in Mycobacterium tuberculosis-infected nonhuman primates during both latent and active disease. In mice, we found that DCIR deficiency impairs STAT1-mediated type I IFN signaling in DCs, leading to increased production of IL-12 and increased differentiation of T lymphocytes toward Th1 during infection. As a consequence, DCIR-deficient mice control M. tuberculosis better than WT animals but also develop more inflammation characterized by an increased production of TNF and inducible NOS (iNOS) in the lungs. Altogether, our results reveal a pathway by which a C-type lectin modulates the equilibrium between infection-driven inflammation and pathogen's control through sustaining type I IFN signaling in DCs.

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