23 research outputs found
Stepwise Development of MAIT Cells in Mouse and Human
Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)α (iTCRα) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanVα7.2 antibody and MAIT cell-specific iTCRα and TCRÎČ transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRα and TCRÎČ transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naĂŻve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%â4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naĂŻve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and γΎ T cells
Hepatitis B virus preS2Î38-55 variants: A newly identified risk factor for hepatocellular carcinoma.
BACKGROUND & AIMS: Although HBV is a major cause of death in Africa, its genetic variability has been poorly documented. This study aimed to address whether HBV genotype and surface gene variants are associated with HBV-related liver disease in The Gambia. METHODS: We conducted a case-control study nested in the Prevention of Liver Fibrosis and Cancer in Africa programme. Consecutive treatment-naive patients with chronic HBV infection and detectable viral load were recruited: 211 controls with no significant liver disease and 91 cases (56 cirrhosis and 35 HCC cases). HBV genotypes and surface gene variants were determined by Sanger sequencing or next-generation sequencing (NGS) in serum DNA. Aflatoxin B1 (AFB1)-specific codon 249 TP53 mutation was determined by NGS in circulating cell-free plasma DNA. RESULTS: In phylogenetic analysis, 85% of individuals carried HBV genotype E, 14% genotype A, and 1% A/E recombinant viruses. Surface gene variants were more frequently observed in cases (43% and 57% in cirrhosis and HCC cases, respectively) than controls (25%; p 2,000 IU/ml (OR 22.7 [8.0-64.9]), HBsAg levels <10,000 IU/ml (OR 19.0 [5.5-65.3]), and AFB1 exposure (OR 29.3 [3.7-230.4]) on HCC risk. CONCLUSIONS: This study identified a hotspot for HBV preS2 deletions as a strong independent factor for HCC in The Gambia, with HBV genotypes and AFB1 exposure contributing to the high liver cancer risk. LAY SUMMARY: Although HBV-related liver disease is highly prevalent in sub-Saharan Africa, the associated virological characteristics are poorly studied. Using clinical data from African patients chronically infected with HBV, an assessment of the virological variability (genotypes and mutations) and exposure to AFB1, a toxin often contaminating food, was carried out. Our results show that HBV genotypes, the presence of a highly prevalent mutant form of HBV, and AFB1 exposure contribute to the high liver cancer risk in this population
Rhodium-Catalyzed Aqueous Biphasic Olefin Hydroformylation Promoted by Amphiphilic Cyclodextrins
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Anionic Amphiphilic Cyclodextrins Bearing Oleic Grafts for the Stabilization of Ruthenium Nanoparticles Efficient in Aqueous Catalytic Hydrogenation
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Oleic Acid Based Cyclodextrins for the Development of New Hydrosoluble Amphiphilic Compounds
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Physiological pathway for low density lipoproteins across the blood-brain barrier: transcytosis through brain capillary endothelial cells in vitro
International audienceAlthough an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Using an in vitro blood-brain barrier model, we have demonstrated that low density lipoprotein underwent transcytosis through the endothelial cells (ECs) by a receptor-mediated process bypassing the lysosomal compartment. Moreover, caveolae might be involved in these blood-borne molecule transports from the blood to the brain. Although several ligands are known to be internalized through cell surface caveolae, the subsequent intracellular pathways have remained elusive. By cell fractionation experiment and Western blot, we have demonstrated that the LDL receptor is located in the caveolae membrane fraction. Then, low density lipoproteins internalized were detected by electron microscopy in multivesicular bodies. We identified in brain capillary ECs a novel endosomal compartment, mildly acidic, positive for marker Lamp-1 but devoid of any degradative capability. In terms of pH point of view, cellular location and caveolae derived formation, the multivesicular organelles described here can be related to the caveosome structure. Our results could allow us to provide clues to physiological functions of caveolae-caveosome transcellular pathway in brain capillary ECs and may help in the rational design of more effective therapeutic drugs to the brain