Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. T cells play a central role in MS pathogenesis, but cytotoxic CD8 T cells may be particularly important. Within MS lesions, they are more abundant than CD4 T cells and form clonally expanded populations, indicating active proliferation in response to specific antigens.
To identify these cells at early stages of disease, researchers at the University of California (USA) analyzed cerebrospinal fluid and blood samples from patients with recently diagnosed, treatment-naïve multiple sclerosis. Instead of examining difficult-to-access brain tissue, they used cerebrospinal fluid, which reflects immune processes occurring within the central nervous system.
Using single-cell RNA sequencing and T-cell receptor sequencing, the researchers identified populations of CD8 T cells that selectively expand in the central nervous system of patients with MS and determined the antigens they recognize.
Clonally Expanded CD8 T Cells Were Identified in the Cerebrospinal Fluid of Patients With MS
The researchers identified a CD8 T-cell population that was significantly enriched and clonally expanded in patients with MS. More than 70% of the most expanded T-cell clones belonged to CD8 T cells, despite the analysis including more than twice as many CD4 T cells.
These cells displayed characteristic features of repeated antigen exposure. They actively expressed genes associated with cytotoxic activity, migration into the central nervous system, and the development of a tissue-resident memory T-cell (TRM) phenotype. The pattern of activated genes in cerebrospinal fluid CD8 T cells closely resembled that previously observed in CD8 T cells isolated directly from multiple sclerosis lesions. This finding indicates that the identified clones indeed infiltrate the central nervous system.
Most CD8 T-Cell Clones in MS Are Unique to Individual Patients
Most expanded clones were unique to individual patients. The researchers identified only small groups of related clones with similar receptors, and such groups were almost always restricted to a single individual. These findings demonstrate the highly personalized nature of the immune response in multiple sclerosis and help explain why identifying common antigenic targets remains challenging.
CD8 T Cells in MS Recognize Epstein–Barr Virus Antigens
Three clonally expanded CD8 T-cell populations were identified in three patients with MS. These cells recognized antigens of the Epstein–Barr virus (EBV). Previous studies have shown that EBV infection is a prerequisite for the subsequent development of multiple sclerosis. In the current study, researchers also detected EBV DNA in the cerebrospinal fluid of most patients with MS.
These findings suggest that viral reactivation may sustain the expansion of CD8 T cells within the central nervous system. However, the researchers were unable to demonstrate that the identified CD8 T cells simultaneously recognize self-antigens of nervous tissue. Therefore, the precise mechanism by which these cells contribute to MS pathology remains unresolved.
These findings provide new opportunities for developing biomarkers and novel therapeutic strategies for multiple sclerosis.
Reference
Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis
