A clinical and immunological study of CD8+ T cells in multiple sclerosis

Prior focus has largely been on the role of CD4+ T cells in Multiple sclerosis (MS) disease pathogenesis, but there is mounting evidence for the role of CD8+ T cells. This thesis aimed to explore the role of CD8+ T cells by; (i) analysing clinical outcomes in MS patients treated with alemtuzumab, (ii) performing an in-depth phenotypic analysis of cerebrospinal fluid (CSF)-resident T cells in MS patients, (iii) examining the CSFresident T cell receptor (TCR) repertoire in MS patients, and; (iv) identifying the pathogenic triggers/antigenic targets of dominant CSF-resident TCRs. Alemtuzumab was shown to be an effective treatment for relapsing MS. Immunophenotyping demonstrated an increased number of CSF-resident CD4+ and CD8+ T cells in MS patients compared with controls although the majority of CSF-resident T cells were of an effector memory phenotype across all groups. This suggests that effector memory T cells enter the CSF as part of normal central nervous system (CNS)immunosurveillance, and is consistent with the fact that I was able to detect Epstein- Barr virus-specific TCRs in all groups at similar frequencies. Clonal expansions were observed in the CD4+ and CD8+ T cell repertoire of all patient groups and so are not aunique feature of MS. However, I did observe a significant increase in TCR diversity in the CD4+ and CD8+ TCR repertoire in MS patients compared to controls. Overall, the results from the Alemtuzumab study strongly support a central role for T cells in MS pathogenesis. Immunophenotyping and clonotyping analysis suggest that CD4+ and CD8+ T cells with an effector memory phenotype preferentially accumulate in the CSF as part of normal immune surveillance. In MS, increased TCR diversity warrants further investigation as it suggests that a more diverse response to CNS antigens may play a role in disease pathogenesis