Twin study identifies early immunological and metabolic dysregulation of CD8+ T cells in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the co-twin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, pro-inflammatory, and activated CD8+ T cell phenotype, which was also evident in co-twins with SCNI and in an independent validation cohort of people with MS (pwMS). Together, our in-depth single-cell analysis indicates a disease-driving pro-inflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease. CD8+ T cells from PBMCs of the MS twin cohort (n = 12; 6 healthy twins, 6 twins with SCNI, and 12 twins with MS; 193,771 cells) and the validation cohort (n = 17; 5 individuals with IIH and 12 individuals with MS; 89,859 cells) were isolated via FACS and processed using the 10X manufacturer's protocol to generate single-cell transcriptome and TCR libraries. The corresponding TCR sequences are included within the metadata of the uploaded objects. --------------------- Author state: Fastq raw data files from humans are not updated due to data protection concerns. --------------------- Author states that fastq raw data files from humans are not provided due to data protection concerns.