Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte GlycoproteinJagessar, S. A., Holtman, I. R., Hofman, S., Morandi, E., Heijmans, N., Laman, J. D., Gran, B., Faber, B. W., van Kasteren, S. I., Eggen, B. J. L. & 't Hart, B. A., 15-Aug-2016, In : Journal of Immunology. 197, 4, p. 1074-1088 15 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||15|
|Journal||Journal of Immunology|
|Publication status||Published - 15-Aug-2016|
- EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, MULTIPLE-SCLEROSIS, CROSS-PRESENTATION, MARMOSET MONKEYS, DENDRITIC CELLS, CATHEPSIN-G, PROTEASE INHIBITOR, COMMON MARMOSETS, EAE MODEL, IN-VIVO