The Epstein-Barr Virus Provokes T Cells To Drive Multiple Sclerosis
Suppression of virus-driven immune responses could be key to treating individuals with multiple sclerosis.
The origins of multiple sclerosis (MS) have long been clouded in mystery; however, recent studies have pointed to a link to the Epstein-Barr virus (EBV), which is present in almost all MS patients. While studies have provided evidence establishing EBV as an environmental risk factor in MS development, the underlying immune mechanism linking the two remains unclear.
A study, published in Science Translational Medicine, has now uncovered how EBV triggers responses from a type of T cell (CD4+ T cells) that may drive autoimmunity in MS patients. In addition, the study showed how B-cell depleting therapy calmed this immune response in participants with treatment-naïve MS and participants with MS receiving therapy.
“By identifying a readily measurable, peripherally accessible immune response linked to disease, this work provides a foundation for the rational design and monitoring of EBV-targeted vaccines and antivirals for MS,” the researchers said.
EBV and MS: What's the link?
MS is a chronic autoimmune disease of the central nervous system and is the leading cause of neurological disability in young adults. Approximately 90–95% of healthy adults are estimated to carry EBV, often with little to no symptoms. This figure rises for MS patients—more than 99% of this group test positive for the virus.
A 2022 study, published in Science, examined data from over 10 million US military recruits and found that all but one MS patient documented in the study became EBV-positive prior to their symptoms developing.
What is EBV?
The Epstein-Barr virus (EBV) is a common herpes virus that spreads through bodily fluids, primarily saliva. Most people will get infected with EBV in their lifetime, especially in childhood, and will not have symptoms. EBV can cause infectious mononucleosis, which is much more likely in individuals who contract EBV as adults.
CD4+ T cells have been identified as central drivers of MS and are present in elevated numbers in the cerebrospinal fluid of MS patients. Genetic evidence points to EBV-infected B cells presenting peptide antigens that are recognized by CD4+ T cells.
“A lot of things we know about MS have come from clues we've seen in the clinic based on which drugs people respond to. And there's a newer MS drug that was trialed recently called frexalimab that acts on this part of the immune system that has to do with CD4+ T cells, and it lowers MS activity,” Dr. Natalia Drosu, National MS Society postdoctoral fellow at Massachusetts General Hospital and one of the study authors, said in a press briefing.
This led the researchers to investigate the EBV antigens recognized by CD4+ T cells in hopes of shedding light on MS pathogenesis.
“One of the major challenges with research on Epstein-Barr virus, unlike other viruses, is that it's very, very hard to measure directly, because the active virus is present at very low levels in blood,” explained Drosu. “So the immune response, we thought, could be something that could be easier to measure, and that makes this something that could be tracked, for example, when testing future treatments targeting EBV.”
Using enzyme-linked immunospot assays across healthy controls and treated and untreated MS patients, the researchers observed that CD4+ T cells from individuals with MS predominantly target components of EBV viral particles, specifically the late lytic capsid and glycoprotein antigens. These EBV-specific T-cell responses were two times higher in untreated MS patients compared with healthy controls, where responses to other herpes viruses remained similar.
Having established that CD4+ T cells primarily recognize EBV viral particles and that this response is elevated in untreated MS patients, the researchers next investigated whether this response is affected by B cell depletion therapy.
Anti-CD20 therapy
Anti-CD20 therapies are a form of B cell depletion therapy. They are monoclonal antibodies that selectively deplete CD20-expressing B cells and T cells, which includes a small subset of proinflammatory CD4+ T cells that express the CD20 marker.
Analysis of 60 MS patients before and six months after initiating anti-CD20 therapy revealed that CD4+ T-cell responses to the virus shrank by 2.5-fold. These results were validated in a second smaller cohort of nine participants sampled approximately one year after the last anti-CD20 dose. The second cohort also showed a significant reduction in EBV-specific responses.
These reductions were relatively selective for EBV, with less pronounced effects on responses to other viruses, suggesting a particular impact on EBV-specific immunity rather than generalized immunosuppression.
“The pronounced effect of B-cell targeting therapies on both EBV-specific T-cell responses and viral shedding suggests that depleting infected B cells simultaneously removes both the antigen source and key antigen-presenting cells,” explained the researchers.
Implications for EBV-targeting vaccines and antivirals
These findings have important implications for the design of EBV-targeting therapeutic strategies. The researchers suggest that vaccine approaches targeting viral particle antigens should be examined with caution as they could expand the pathogenic CD4+ T-cell compartment.
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They suggest an alternative strategy could be to boost CD8+ T-cell responses against immediate early or lytic antigens, which are expressed within hours before viral particle assembly. “Enhanced surveillance against cells expressing these antigens could halt the lytic cycle before pathogenic CD4+ T-cell antigens are produced,” the researchers said.
The study also helps establish benchmarks for clinical trial design, with the researchers proposing that dosing should aim to achieve suppression of EBV-specific responses comparable to that observed with disease-modifying therapies.
“I think the most exciting opportunities come from targeting EBV directly,” Dr. Michael Levy, associate professor at Massachusetts General Hospital and Harvard Medical School and one of the study authors, said during a press briefing. “There are therapeutic opportunities like T-cell engagers that people are working on and other ways of trying to reduce or deplete EBV from the body. CAR T might be a viable strategy, a one-and-done type of treatment.”
“I think it's also possible that targeting EBV might help other diseases, from lupus to certain cancers. It's certainly possible that a specific medication against EBV could have benefits beyond MS,” he continued.
It's important to note that the study has limitations. It analyzed only peripheral immune responses rather than those in the central nervous system where damage from MS typically occurs. However, the researchers argue that based on their findings “anti-EBV strategies may be effective even without CNS penetrance if they can substantially reduce or eliminate the source of viral particles driving peripheral T-cell activation.”
Future studies with larger sample sizes will need to confirm the findings of the study and address whether EBV-specific CD4+ T-cell responses predict clinical outcomes.
Reference: Bjornevik K, Mahler JV, Bilodeau PA, et al. CD4+ T cells reactive to Epstein-Barr virus late lytic antigens are enriched in individuals with multiple sclerosis. Sci Transl Med. 2026;18:eadz6566. doi: 10.1126/scitranslmed.adz6566
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