This is a summary of Vladyslav Kavaka et al. (2024). 'Twin study identifies early immunological and metabolic dysregulation of CD8+ T cells in multiple sclerosis', published in Science Immunology. DOI:10.1126/sciimmunol.adj8094
The challenge
Multiple sclerosis (MS) is an inflammatory disease of the nervous system in which CD8 T cells are present in MS lesions, but until now it was unclear what role they play in the disease. Are they mere by-products or active facilitators of inflammation? And what prompts their entry from the blood into the central nervous system? Our MS TWIN study offers the ideal conditions to answer this question. It is a large cohort of monozygotic twins with MS and their cotwins, who have a ~25% risk of also developing MS. The twins have the same genetic and early environmental risk factors and, therefore, offer a unique opportunity to investigate high-risk patients before the disease manifests.
Our approach
We selected 12 pairs of twins from the MS TWIN STUDY cohort. We combined single-cell RNA sequencing and T-cell receptor analyses to study CD8 T cells from blood and cerebrospinal fluid samples taken from these twin pairs. We then used high-throughput scRNA-seq and single-cell T cell receptor (TCR) sequencing to examine peripheral and central nervous system (CNS-)-migrated CD8+ T cells in each group. Additionally, we conducted brain tissue analysis, which emphasized the preservation of these immunological and metabolic signatures at the site of neuroinflammation.
Our findings
Our results show that CD8 T cells occur with the same specific changes in MS patients and people with early signs of the disease. In addition, they exhibit increased migration ability, promote inflammation, and show activation markers. These properties show that these CD8 T cells are migratory in the blood and are already embarking on their journey to the central nervous system, where we encounter the same cells. We also found this cell type in the brain tissue of MS patients, which indicates lasting changes in the central nervous system. Moreover, the same CD8 T cells did not only occur in people with MS. They were also present in those who did not yet exhibit any symptoms but in whom there were other signs of inflammation without symptoms being evident. Thus, these cells could be earlier facilitators of MS before symptoms arise.
Implications
These findings could open new therapeutic avenues that involve influencing CD8 T cells to slow or prevent the progress of MS. In addition, CD8 T cells could be used to develop new diagnostic methods that allow MS to be detected early enough to halt irreversible nerve damage.
Creating SyNergies
The study was led by SyNergy clinician scientist Lisa Ann Gerdes and included SyNergy members Thomas Korn, Martin Kerschensteiner, and Eduardo Beltran. This study was only possible due to access to the Macroscale (MRI) and Transcriptome Hub (Single cell analysis) provided by SyNergy. Based on these findings in the MS TWIN STUDY we will scale up our investigations to larger MS cohorts within the SyNergy consortium.
