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

Abstract

Despite the well-known association of Epstein–Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV-infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV-infected B cells induce T-cell functions relevant for EAE progression. In the current study, we examined the ex vivo cross-talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi-) autologous EBV-infected B-lymphoblastoid cell lines (B-LCLs). Results presented here demonstrate that infection with EBV B95-8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co-stimulation to T cells. At the cellular level, we observed that MNC co-culture with B-LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B-LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL-23R and CCR6, which coincided with enhanced IL-17A production. These results highlight the profound impact that EBV-infected B-LCL cells can have on second and third co-stimulatory signals involved in (autoreactive) T-cell activation.

EBV Infection Empowers Human B Cells for Autoimmunity: Role of Autophagy and Relevance to Multiple Sclerosis

“…This increased expression, combined with the previously documented induction of immunoproteasome elements, indicates the activation of the cross-presentation machinery (12,32). Our studies in the marmoset EAE model indicate that CD80 and CD70 mediate the cross-talk of LCV-infected B cells and autoagressive MOG 34-56 specific CTLs (33). We speculate that our findings in human B cells (Fig.…”

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…Reports of EBV-infected autoreactive plasma cells in the synovium of rheumatoid arthritis patients and in salivary 106]. EBV also upregulated the antigen-presenting machinery of infected B cells and facilitated cross-presentation of immunogenic MOG peptides to CD8 + T cells [107]. In a variety of animal models, EBV-like viruses and EBV itself lead to the development of autoimmune, neurodegenerative, and MS-like disease pathologies.…”

Experimental autoimmune encephalomyelitis in the common marmoset: a translationally relevant model for the cause and course of multiple sclerosis

“…Concerning study 1, we observed the formation of T and B cells containing meningeal infiltrates (in both species), together with small-sized perivascular inflammatory lesions (Jagessar et al, 2013a;Haanstra et al, 2013c). Concerning study 2, we observed peptide-dependent production of IL-17A, while IFNγ and TNFα were produced at a negligible level (Dunham et al, 2017c), which essen-tially reproduces earlier findings in the EAE model induced with MOG34-56/IFA (Jagessar et al, 2012d). The combination of these observations indicates that MOG34-56 loaded LCV-infected B cells are indeed capable of eliciting neuroinflammation, but that cytokines implicated in cGM demyelination in the rat model seem not to be produced in sufficient quantity for eliciting oligodendrocyte death in primate EAE.…”