Expanded T lymphocytes in the cerebrospinal fluid of multiple sclerosis patients are specific for Epstein-Barr-virus-infected B cells, 2024, Gottlieb+

Expanded T lymphocytes in the cerebrospinal fluid of multiple sclerosis patients are specific for Epstein-Barr-virus-infected B cells

Significance
On average, 13% of the T lymphocytes in the cerebrospinal fluid of people with the first symptoms of multiple sclerosis are specific for autologous B lymphocytes infected with Epstein–Barr virus. In the most expanded CSF clones, which are highly likely to play a role in MS pathogenesis, the abundance of lymphoblastoid cell lines-specific T lymphocytes is even higher at 47%. T cells specific for three other common infections do not show a similar abundance in the CSF. These findings demonstrate that LCL-specific T cells are present in the CSF at the earliest stages of MS, suggesting that they are likely to play an important role in pathogenesis. The epitopes on EBV and in the brain are of great interest.

Abstract
Epstein–Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but the role of EBV in the pathogenesis of MS is not clear. Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells.

We obtained blood and CSF samples from eight relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida and sorted the responding cells with flow cytometry after 6 d. We sequenced the RNA for T cell receptors (TCR) from CSF, unselected blood cells, and the antigen-specific cells. We used the TCR Vβ CDR3 sequences from the antigen-specific cells to assign antigen specificity to the sequences from the CSF and blood. LCL-specific cells comprised 13.0 ± 4.3% (mean ± SD) of the total reads present in CSF and 13.3 ± 7.5% of the reads present in blood. The next most abundant antigen specificity was flu, which was 4.7 ± 1.7% of the reads in the CSF and 9.3 ± 6.6% in the blood. The prominence of LCL-specific reads was even more marked in the top 1% most abundant CSF clones with statistically significant 47% mean overlap with LCL.

We conclude that LCL-specific sequences form a major portion of the TCR repertoire in both CSF and blood and that expanded clones specific for LCL are present in MS CSF. This has important implications for the pathogenesis of MS.

https://www.pnas.org/doi/abs/10.1073/pnas.2315857121