Identifying the pathogenic triggers of CD8 T-cells in multiple sclerosis . (360G-Wellcome-105753_Z_14_Z)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), affecting 2.5 million individuals worldwide. Treatments are available, but are complicated by side effects and variable response profiles. There is an urgent need to define the pathogenesis of MS and design novel therapeutics. There is evidence that CD8 T-cells play a major role in the pathogenesis of MS. Studies also suggest a role for herpes viruses in MS, however, it remains unclear what triggers di sease. My preliminary data demonstrates that CSF resident T-cells have an antigen-driven phenotype. T-cell receptor (TCR) usage in the CSF resident CD8 T-cell repertoire is highly skewed with a restricted number of dominant TCRs. I hypothesize that a viral infection, such as EBV, triggers CD8 T-cells, which subsequently target and damage host cells. Here, I intend to identify the pathogenic triggers of dominant CSF-resident T-cells, thereby elucidating the aetiology of this debilitating disease. Specific aims: 1. To perform an in-depth phenotypic analysis of T-cell populations in the CSF of MS patients. 2. To identify dominant CSF resident TCRs in MS patients. 3. To define the pathogenic triggers of dominant CSF-resident TCRs.