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Bhonsle, Latika (2012): Characterization of potentially autoaggressive brain infiltrating CD8+ T cells in multiple sclerosis patients. Dissertation, LMU München: Faculty of Biology
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Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. The disease is thought to be mediated by autoaggressive lymphocytes that attack the nervous myelin sheath, leading to the formation of characteristic lesions in the brain tissue. CD8+ T cells are thought to play a role in the immunopathogenesis of the disease because of the directed infiltration of an immune privileged structure followed by in situ clonal expansion. They are also the dominant brain infiltrating T cell population. However, the events that trigger this autoimmune attack, as well as the molecular target(s) of the autoaggressive T cells remain unknown. The current study is part of a long term strategy to identify the molecular target(s) of these autoaggressive CD8+ T cells. To achieve this, potentially autoaggressive T cells were isolated by laser microdissection from the brain tissue samples of MS patients. Their antigen specific T cell receptors (TCRs) were characterized, reconstructed in vitro in T hybridoma cells and applied in investigating antigen specificities. The α- and β- chains of the MS brain derived TCRs were characterized using a multiplex PCR approach. The TCR chain sequences provide insights into their immune function in context of multiple sclerosis. Firstly, identical TCR β-chains were found to be coexpressed with more than one α-chain in three different instances. This suggests that antigen driven receptor development or the existence of dual TCR molecules may contribute to autoimmunity. Secondly, one TCR clone was detected in cells from three tissue blocks of one patient, indicating that the T cell infiltration is not anatomically restricted during the autoimmune attack. Thirdly, four out of nine T cell receptor molecules, that were characterized together with colleagues, were found to belong to an innate T cell population called the mucosal-associated invariant T (MAIT) cells. These cells have been previously detectected in MS patients and are thought to regulate anti-microbial immunity, possibly providing a link between microbial infection and autoimmunity. The MAIT T cell receptors were expressed in T hybridoma cell lines and used to screen candidate MS antigens and plasmid encoded peptide libraries. In addition, the MHC class I related molecule MR1 that restricts MAIT antigen recognition, was investigated for its anchor residues to shed light on the nature of the bound MAIT antigen. In the long run, these studies promise to contribute to the understanding of multiple sclerosis in particular and autoimmunity in general.