title: Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein.
abstract: EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E-restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20(+) spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40-48 core epitope. Finally, LCV infection also induced expression of LC3-II(+) cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40-48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40-48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs.
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, 2288GJ Rijswijk, the Netherlands; Department of Immunology, Erasmus University Medical Center, 3015CE Rotterdam, the Netherlands; MS Centre ErasMS, 3015CE Rotterdam, the Netherlands;
authors.forename: S Anwar
authors.identifier: 0000-0002-4183-9588
authors.initials: SA
authors.lastname: Jagessar
authors.affiliation: Department of Neuroscience, University Medical Center, University Groningen, 9713AV Groningen, the Netherlands;
authors.forename: Inge R
authors.identifier: 0000-0001-9752-4756
authors.initials: IR
authors.lastname: Holtman
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, 2288GJ Rijswijk, the Netherlands;
authors.forename: Sam
authors.identifier: 0000-0002-0174-1375
authors.initials: S
authors.lastname: Hofman
authors.affiliation: Division of Clinical Neuroscience, University of Nottingham School of Medicine, NG7 2UH Nottingham, United Kingdom;
authors.forename: Elena
authors.identifier: 0000-0002-8222-1514
authors.initials: E
authors.lastname: Morandi
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, 2288GJ Rijswijk, the Netherlands;
authors.forename: Nicole
authors.initials: N
authors.lastname: Heijmans
authors.affiliation: Department of Neuroscience, University Medical Center, University Groningen, 9713AV Groningen, the Netherlands;
authors.forename: Jon D
authors.identifier: 0000-0001-5085-9807
authors.initials: JD
authors.lastname: Laman
authors.affiliation: Division of Clinical Neuroscience, University of Nottingham School of Medicine, NG7 2UH Nottingham, United Kingdom;
authors.forename: Bruno
authors.identifier: 0000-0001-6384-2342
authors.initials: B
authors.lastname: Gran
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre, 2288GJ Rijswijk, the Netherlands; and.
authors.forename: Bart W
authors.identifier: 0000-0001-6808-1204
authors.initials: BW
authors.lastname: Faber
authors.affiliation: Leiden Institute of Chemistry and The Institute for Chemical Immunology, Leiden University, 2333CC Leiden, the Netherlands.
authors.forename: Sander I
authors.identifier: 0000-0003-3733-818X
authors.initials: SI
authors.lastname: van Kasteren
authors.affiliation: Department of Neuroscience, University Medical Center, University Groningen, 9713AV Groningen, the Netherlands;
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, 2288GJ Rijswijk, the Netherlands; Department of Immunology, Erasmus University Medical Center, 3015CE Rotterdam, the Netherlands; Department of Neuroscience, University Medical Center, University Groningen, 9713AV Groningen, the Netherlands; hart@bprc.nl.
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002144:Callithrix; D002469:Cell Separation; D045142:Cross-Priming / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000821:virology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006566:Herpesviridae Infections / Q000276:immunology*; D018143:Lymphocryptovirus; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D016133:Polymerase Chain Reaction; D014412:Tumor Virus Infections / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D063308:Myelin-Oligodendrocyte Glycoprotein