EBV-specific T-cell immunity: relevance for multiple sclerosis

Abstract

Genetic and environmental factors jointly determine the susceptibility to develop multiple sclerosis (MS). Improvements in the design of epidemiological studies have helped to identify consistent environmental risk associations such as the increased susceptibility for MS following Epstein-Barr virus (EBV) infection, while biological mechanisms that drive the association between EBV and MS remain incompletely understood. An increased and broadened repertoire of antibody and T-cell immune responses to EBV-encoded antigens, especially to the dominant CD4⁺ T-cell EBV nuclear antigen 1 (EBNA1), is consistently observed in patients with MS, indicating that protective EBV-specific immune responses are deregulated in MS and potentially contribute to disease development. Exploitation of B-cell trajectories by EBV infection might promote survival of autoreactive B-cell species and proinflammatory B:T-cell interactions. In this review article, we illustrate evidence for a causal role of EBV infection in MS, discuss how EBV-targeting adaptive immune responses potentially modulate disease susceptibility and progression, and provide future perspectives on how novel model systems could be utilized to better define the role of EBV and viral pathogens in MS. Insights gained from these studies might facilitate the development of prevention strategies and more effective treatments for MS.

Keywords: Epstein-Barr virus (EBV); T cell immunity; autoimmune disease; multiple sclerosis; neuroinflammation.

Figure 1

EBV life cycle. The life cycle of EBV can be divided into the lytic and latent phases. EBV infects epithelial and B cells in the oropharynx, leading to a high viral load. During the latent phase, EBV spreads by promoting B-cell proliferation while expressing all latency antigens (latency III). In the germinal center reaction, the expression of latency antigens is downregulated to EBNA1, LMP1, and LMP2 (latency II). B cells develop into centroblasts and then centrocytes. Centrocytes leave the germinal center, differentiate into memory B cells, and circulate in the peripheral blood (latency I). Some transition to a stage known as latency 0, where no EBV antigen expression occurs. The EBV-infected memory B cells serve as a reservoir for the virus and can differentiate into plasma cells. EBV occasionally reactivates and re-enters the lytic cycle. Created with BioRender.com.

Figure 2

Autophagy-associated EBNA1 presentation pathway. EBNA1 is a nuclear antigen presented on MHC class II molecules. Its presentation on MHC class I is inhibited by blocking proteasome-dependent protein degradation. Intracellular antigens like EBNA1 can be processed via autophagy, allowing them to enter the pathway for endogenous MHC class II presentation. Lysosomal proteases degrade EBNA1, and in the MHC class II-loading compartments (MIICs), antigen peptides are loaded onto MHC class II molecules. This process is facilitated by the peptide-loading chaperone HLA-DM, which promotes the exchange of peptides on MHC class II molecules and enhances their stability before they are transported to the cell surface for recognition by CD4⁺ T cells. MHC class II molecules are synthesized in the endoplasmic reticulum (ER) and associate with a glycoprotein called invariant chain (blue). This invariant chain contains a targeting signal that directs the MHC class II molecules to the endosomal pathway. Created with BioRender.com.

Figure 3

Potential mechanism through which Epstein–Barr virus infection may trigger the initiation of multiple sclerosis. The initial infection with EBV can trigger a robust immune response, often resulting in infectious mononucleosis (IM). It is a lytic infection that is mainly brought under control by EBV-specific CD8⁺ T cells but also by CD4⁺ T cells. The virus infects B cells and spreads by inducing a latent, growth-transforming infection in the B cells (tB cells: transformed B cells). The strong immune activation during the lytic infection could promote the activation and expansion of autoreactive and cross-reactive T and B cells. These self-reactive cells might be maintained due to constant antigen exposure and deficient immunoregulatory networks. Additionally, one potential role of EBV is to stimulate the proliferation and maturation of B cells while also preventing the apoptosis of autoreactive B cells and plasma cells that generate autoantibodies. Hence, it is conceivable that the activation of self-reactive T cells and the production of cross-reactive antibodies contribute to demyelination in MS. HERV-W ENV may drive the disease progression even further by inhibiting remyelination and promoting inflammation. Created with BioRender.com.