Mechanisms of central and peripheral T cell tolerance to an antigen of the central nervous system [thesis]

Lei Wang
Myelin reactive T cells are central in the development of the autoimmune response leading to central nervous system (CNS) destruction in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). The underlying cellular and molecular mechanisms, however, are not fully understood. In previous mouse studies, we showed that tolerance to the major component of the myelin sheath, myelin proteolipid protein (PLP), is crucially dependent on its expression in the
more » ... pression in the thymus where central tolerance induction takes place. To analyze the phenotypic and functional changes taking place during the induction of tolerance in the thymus, we investigated the fate of PLP autoreactive CD4+ T cells in TCR-PLP11 transgenic mice, which express a transgenic TCR specific for the dominant PLP174-181 epitope in B6 mice, a EAE-resistant mouse strain of the H-2b haplotype. In previous work we found that a fraction of CD4+ T cells specific for this region appear to escape from tolerance induction. Our data showed that in TCR-PLP11 PLPWT mice, where PLP is transcribed in the thymus similar numbers of CD4+ thymocytes developed, compared to TCR-PLP11 PLPKO mice where PLP expression in the thymus is absent. This indicated that PLP174-181-specific thymocytes were not negatively selected. In the periphery, the PLP174-181-specific T cells displayed a naïve phenotype and therefore were not tolerized by clonal deletion or anergy induction. Potentially autoreactive CD4+ T cells were found in the spleen and lymph nodes of TCR-PLP11 mice but only became activated when stimulated in vitro. These cells were not spontaneously activated in vivo, indicating that PLP is not expressed/presented in the periphery. TCR-PLP11 mice do not develop any clinical or histological signs of EAE. Therefore, ignorance but not deletional tolerance is considered as main tolerance mechanism to avoid CD4+ T cell-mediated autoimmunity in our system. That means that naïve autoreactive CD4+ T cells ignore PLP antigens and recirculate in the periphery [...]
doi:10.5282/edoc.20507 fatcat:iz5f74e33bfn7jnyozh7ftnccy