Analysis of Myelin-Reactive T Lymphocyte Function in Models of Multiple Sclerosis
Patel, Sarju Dilipkumar
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Immune tolerance to self antigens prevents the onset of autoimmune diseases such as Multiple Sclerosis (MS). There are three branches of tolerance which allow the auto-aggressive potential of T lymphocytes to be limited; these are death, anergy-adaptation and regulation. The main body of this work attempts to clarify a role for adaptation in maintaining the sensitivity of the autoreactive T cell repertoire below a ‘threshold for harm’ in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). The well defined myelin basic protein (MBP) Ac1-9 epitope altered peptide ligand (APL) system has been used to develop a model allowing the examination of mechanisms underlying the adaptation of cells. Previous data showed immunisation with the 4Lys (wild-type) epitope mediated disease whereas a superagonist APL with a tyrosine substitution at position 4 (4Tyr) did not, despite showing potency in vitro. This was shown to be a result of both activation induced cell death and adaptation. Here an in vitro model was developed using MBP-reactive TCR transgenic cells to make predictions about the mechanisms underlying adaptation. These data lead to the conclusion that T cells can adapt (become less sensitive) either before or after encounter with the wild-type peptide, leading to a reversal of their pathogenic potential. The MBP APL system and MBP reactive transgenic cells were also used to assess the contribution of epitope spreading in a relapsing-remitting (RR) model of EAE induced with proteolipid protein. The cells were tracked and changes in phenotype and behaviour were monitored. The data show that disease induced with one antigen can be manipulated with cells relevant to a different antigen and that bystander suppression may be an effective weapon in controlling the progression to RR-EAE.