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.

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

“…This unique transcript profile, with enhanced expression of key co-stimulatory molecules and altered proteasome and endolysosome function, indicates that the LCV-infected B cell is an atypical APC. Of note, LCV infection also endows B cells with the ability to rescue proteolysis-sensitive self-antigens from destructive processing via citrullination as previously demonstrated, 14 which may be involved in the association between autoimmune disease and progression of primate EAE.…”

Viral infections and multiple sclerosis

“…Animal models for EBV infections use mice infected with murine gammaherpesvirus 68, a mouse pathogen, which upon induction show an accelerated course of EAE [74], or marmosets naturally infected with the gamma1-herpesvirus callitrichine herpesvirus 3 (CalHV3) which, similarly to EBV, infects and immortalizes B cells [75]. It has been demonstrated that CalHV3-infected B cells can act as antigen presenting cells (APCs) not only via MHC class II molecules to CD4 T cells, but also via MHC class I molecules to CD8 T cells [76]. Using this model, a conversion from a tolerogenic destructive processing of MOG peptide to productive processing and autoaggressive T cell activation was demonstrated [77].…”

Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis

“…Yes (Disanto et al, 2012) Yes ('T Hart et al, 2013;Jagessar et al, 2016) Yes (Pierson et al, 2014;Delarasse et al, 2013) Yes (Tsunoda et al, 2002) No (Gudi et al, 2014) Involvement of CD8 1 cells Yes (Lassmann & Bradl, 2017) Yes (Jagessar et al, 2016) Questionable Biozzi ABH mice (Lassmann & Bradl, 2017) DA rats (Constantinescu et al, 2011) Yes (Johnson et al, 2014;Tsunoda et al, 2002) No (Kipp et al, 2017) White matter demyelination Yes (Lassmann & Bradl, 2017) Yes (marmoset) ('t Hart et al, 2013) Yes (rhesus monkey) (Stewart et al, 1991) Strain dependent DA rats (Milicevic et al, 2003;Papadopoulos et al, 2006) Biozzi ABH mice (Jackson et al, 2009) Chronic form of disease (Sato et al, 2011) Yes…”